REVIEW

Pathophysiology and Therapeutic Perspectivesof Oxidative Stress and Neurodegenerative Diseases:A Narrative Review

Martina Rekatsina . Antonella Paladini . Alba Piroli . Panagiotis Zis .

Joseph V. Pergolizzi . Giustino Varrassi

Received: August 13, 2019 / Published online: November 28, 2019� The Author(s) 2019

ABSTRACT

Introduction: Neurodegeneration is the termdescribing the death of neurons both in thecentral nervous system and periphery. Whenaffecting the central nervous system, it isresponsible for diseases like Alzheimer’s disease,Parkinson’s disease, Huntington’s disorders,amyotrophic lateral sclerosis, and other lessfrequent pathologies. There are several commonpathophysiological elements that are shared inthe neurodegenerative diseases. The common

denominators are oxidative stress (OS) andinflammatory responses. Unluckily, these con-ditions are difficult to treat. Because of theburden caused by the progression of these dis-eases and the simultaneous lack of efficacioustreatment, therapeutic approaches that couldtarget the interception of development of theneurodegeneration are being widely investi-gated. This review aims to highlight the mostrecent proposed novelties, as most of the pre-vious approaches have failed. Therefore, olderapproaches may currently be used by healthcareprofessionals and are not being presented.Methods: This review was based on an elec-tronic search of existing literature, usingPubMed as primary source for important reviewarticles, and important randomized clinical tri-als, published in the last 5 years. Reference listsfrom the most recent reviews, as well as addi-tional sources of primary literature and refer-ences cited by relevant articles, were used.Results: Eighteen natural pharmaceutical sub-stances and 24 extracted or recombinant prod-ucts, and artificial agents that can be usedagainst OS, inflammation, and neurodegenera-tion were identified. After presenting the mostcommon neurodegenerative diseases and men-tioning some of the basic mechanisms that leadto neuronal loss, this paper presents up to dateinformation that could encourage the develop-ment of better therapeutic strategies.Conclusions: This review shares the new poten-tial pharmaceutical and not pharmaceutical

Enhanced Digital Features To view enhanced digitalfeatures for this article go to https://doi.org/10.6084/m9.figshare.10247852.

M. RekatsinaDepartment of Anesthesia, Moorfields Eye Hospital,NHS Foundation Trust, 162 City Road, LondonEC1V 2PD, UK

A. Paladini � A. PiroliDepartment of MESVA, University of L’Aquila,L’Aquila, Italy

P. ZisMedical School, University of Cyprus, Nicosia,Cyprus

J. V. PergolizziNEMA Research, Naples, FL, USA

G. Varrassi (&)Paolo Procacci Foundation, Via Tacito 7, 00193Rome, Italye-mail: giuvarr@gmail.com

Adv Ther (2020) 37:113–139

https://doi.org/10.1007/s12325-019-01148-5

options that have been recently introducedregarding OS and inflammatory responses inneurodegenerative diseases.

Keywords: Anti-inflammatory drugs; Cognitivedecline; Inflammatory responses; Neurodegen-erative diseases; New therapeutic approaches;Oxidative stress; PEA; Treatment of oxidativestress

Key Summary Points

This study has made clear most of thereasons why oxidative stress definitelymay represent an important reason forneuroinflammation andneurodegeneration

The recent literature is rich of proposals ofnatural and synthetic products that haveshown some success in blocking theoxidative stress processes

Most of the substances indicated in thispaper would deserve a deeper clinicalinvestigation. This could represent anadvancement in therapy, for pathologiesthat till now do not have specific andsuccessful treatments

INTRODUCTION

The industrialized world is aging rapidly. TheEuropean Union (EU) Joint Programme–Neu-rodegenerative Disease Research (JPND) statesthat by the year 2030, a quarter (25%) of theEuropean population will be over age 65, a sig-nificant increase over the current 16% [1]. Theimplications for a ‘‘graying’’ Europe are not yetfully understood, but surely include an increasein debilitating and challenging-to-treat neu-rodegenerative diseases. Included among theseis the devastating condition of Alzheimer’s dis-ease, the most prominent subpopulation ofdementia patients [1]. Other forms of neurode-generative diseases include amyotrophic lateral

sclerosis (ALS), Parkinson’s disease, spinal mus-cular atrophy, Huntington’s disease, prion dis-eases, motor neuron diseases, andspinocerebellar ataxia [1]. By and large, neu-rodegenerative disease treatment—whereoptions exist at all—address symptoms ratherthan underlying pathophysiology.

The collective term neurodegenerative dis-ease refers to a myriad of conditions that affectthe neurons in the brain. Typically, neurode-generative diseases are irreversible, progressive,and associated with loss of function [2]. Typicalphysiological signs of neurodegenerative condi-tions are demyelination, loss of dendrites, andneuronal death [3, 4]. As the neuronal structuresdeteriorate, a gradual and progressive loss ofcognitive skills (dementia) and/or motor skills(ataxia) ensues, which can result in mentalimpairment, functional loss, and debilitation [1].Although neurodegenerative diseases are mostprevalent in the elderly, they can occur inpatients at all ages [5–8]. The underlying patho-physiology common to all forms of neurode-generative disease seems to involveneuroinflammation and oxidative stress (OS)[4, 9]. This major challenge for modern medicineis to find ways to effectively manage neurode-generative diseases in patients who are livinglonger and may be multimorbid [3]. The objec-tive of this review was to examine new approa-ches to these neurodegenerative diseases,specifically in relation to new therapeuticstrategies involving neuroinflammation and OS,with the aim of providing an overview that maygive insight to clinicians caring for patients inthese challenging clinical situations. This articleis based on previously conducted studies anddoes not contain any studies with human par-ticipants or animals performed by the authors.

METHODS

The electronic database PubMed was searchedon 21 February 2019. Our search terms included‘‘Oxidative Stress,’’ ‘‘Inflammatory Responses,’’‘‘Neurodegenerative Diseases,’’ ‘‘Parkinson,’’‘‘ALS,’’ ‘‘Huntington,’’ ‘‘Alzheimer,’’ ‘‘Spinalmuscular atrophy,’’ ‘‘Prion disease,’’ and‘‘Spinocerebellar ataxia’’. Inclusion criteria were

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papers published in the last 5 years, Englishlanguage, full text available, and most recent.This review also examined the bibliographiesfrom the most recent reviews and additionalsources of primary literature, as well as refer-ences cited by relevant articles. For the man-agement of neurodegenerative diseases and OS,inclusion criteria were (1) the article had topresent a specific treatment of the aforemen-tioned diseases, either natural, extracted,recombinant products, or artificial agents; (2)the treatment had to target OS and inflamma-tion; and (3) the substance must have beeninvestigated in the last 5 years. These inclusioncriteria were selected because to date, no ther-apies have been able to cure or reverse neu-rodegenerative diseases. This is a narrative andnot a systematic review.

RESULTS

The initial search identified 147 articles fromwhich 95 were included as relevant. Moreover,54 additional articles were included from thesecondary search of the primary literature ref-erence lists reviews.

Neurodegenerative Diseases and TheirPathogenesis

For a better understanding of the therapeuticapproaches that will be presented, a shortsummary of the neurodegenerative diseases andtheir pathogenesis is helpful.

Alzheimer’s DiseaseThe most frequently occurring neurodegenerativedisease is Alzheimer’s disease. The prominentsymptoms of Alzheimer’s disease include progres-sive and irreversible cognitive deficits which can beaccompanied by changes in mood and behavior[9]. Memory loss is common as the disease advan-ces. Alzheimer’s disease has been associated withtangled strands of intracellular tau known as neu-rofibrillary tangles and extracellular deposits ofamyloid-b (Ab) plaques in the brain [10]. The pla-que deposits have been linked to OS, which mayplay a substantial role in AD pathogenesis [11–13].

Parkinson’s DiseaseParkinson’s disease is likewise an irreversible,progressive neurodegenerative disease [14] thataffects about 1% of people over age 50 [15]. AsParkinson’s disease progresses, the patient loses50% to 70% of all dopaminergic neurons in thesubstantia nigra. With the loss of the brain’sdopaminergic fibers, the patient develops pro-gressively worsening motor symptoms, whichare a hallmark of Parkinson’s disease [9].Growing evidence has implicated OS as well asimmunological shifts in the pathogenesis ofParkinson’s disease. As excessive amounts ofreactive oxygen species along with other freeradicals accumulate, they overwhelm thedopaminergic neurons and cause them todeteriorate, setting the stage for the pathologyof Parkinson’s disease [16]. A number ofpotential contributors to OS have been impli-cated in the disease process of Parkinson’s dis-ease, namely mitochondria, endoplasmicreticulum, a-synuclein, and dopamine. Itappears likely that it is their interplay ratherthan their individual actions that contribute toprogressive neurodegeneration [17]. The role ofneuroinflammation may be crucial to thepathogenesis of Parkinson’s disease, in that ithas destructive effects on the nigrostriataldopaminergic pathways. This, in turn, activatesthe glial cells of the brain (mainly the microgliaand the astrocytes) to release various solublefactors which may be pro-inflammatory and/orneurotoxic [18].

Multiple SclerosisMultiple sclerosis, a chronic progressive neu-rodegenerative disease, is characterized byinflammation and demyelination [9]. Thedestruction of the myelin sheaths of the nervesas well as axonal damage and glial scarringproduce its classic symptoms of muscle spasms,neuropathic pain, paralysis, and optic neuritis.During this process, an inflammatory state ispromoted, mainly via myelin antigen-specificTH cells [19]. As lesions form, monocytes arerecruited, which in turn produce reactive oxy-gen species. Observations of white matter andcerebral cortex lesions suggest that demyelina-tion and neurodegeneration might lead to thepresence of oxidized lipids in the myelin

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membranes, in apoptotic oligodendrocytes, andin neuronal axons [20, 21].

Amyotrophic Lateral SclerosisAmyotrophic lateral sclerosis (ALS) involves theprogressive and irreversible degeneration of themotor neurons located in the brain cortex,brain stem, and spinal cord [22]. Most patientsdiagnosed with this condition will die within3–4 years after the onset of symptoms [23]. Theworld-famous physicist Stephen Hawking is theexception, surviving over 50 years after his ALSdiagnosis. As the name suggests, ALS involvesmuscular atrophy (amyotrophic) and scarring ofthe spinal cord (lateral sclerosis) [24]. Patientswith ALS suffer progressive paralysis, dysphagia,and respiratory insufficiency. ALS is thought tobe caused by any or several of 150 mutations inthe superoxide dismutase 1 (SOD1) antioxidantsystem [25] which cause injury and death ofmotor neurons [26] and mitochondrial dys-function [23]. The SOD1 mutation involvesmisfolding of the protein.

Motoneuron injury is a characteristic of ALSbut its etiology has not been thoroughly eluci-dated. Extracellular mutant SOD1 is associatedwith motoneuron injury, but it is not known ifthis injury is the result of mutant SOD1 actingdirectly on the motoneurons or if there is somesort of indirect mediation via microglia acti-vated by mutant SOD1. Activated microglia arepresents at sites of neuronal injury [25].

Duchenne Muscular DystrophyDuchenne muscular dystrophy is a progressive,fatal, X-linked genetic disorder of chronicinflammation involving dystrophin genemutations. OS is a contributor to the patho-genesis of Duchenne muscular dystrophy [27].The muscle wasting associated with Duchennemuscular dystrophy involves the nuclear factorerythroid 2 (NF-E2)-related factor 2 along withincreased levels of oxidized glutathione, com-bined with the accumulated oxidative damageacquired with aging [27]. The enzyme hemeoxygenase 1 (HO-1) and the cytokine inter-leukin (IL)-6 suggest that this OS is associatedwith chronic inflammatory response [27].

Pathogenesis of NeurodegenerativeDiseases: Main Common Mechanisms

The molecular mechanisms behind neurode-generative diseases suggest intriguing aspects oftheir pathology [28–32]. The primary reasonsfor neurodegeneration appear to involveabnormal processing of proteins [28], geneticdisorders [5], misfolding and aggregation ofvarious proteins [32], activating cellular apop-tosis [33], triggering mitochondrial dysfunc-tion, creation of free radicals, and OS [32].

Link Between OS and NeurodegenerativeDiseasesAs more is learned about neurodegenerativediseases, OS appears to be a main contributor todisease pathogenesis [32]. OS occurs when theoxidant molecules produced by the body arenot adequately counterbalanced by the body’snatural antioxidant defenses. During times ofOS, free radicals overwhelm the body’sendogenous antioxidant defense system, lead-ing to potentially ill effects. Free radicals arenatural, physiological by-products of the nor-mal aerobic metabolism, but under pathologicalconditions, free radicals can be produced inabnormally large—and harmful—amounts [34].A growing body of evidence supports the ideathat OS leads to the development of neurode-generative diseases [32, 35–37]. OS might bedefined as an elevated concentration of freeradicals above the threshold recognized as beingtoxic [38]. In other words, OS might occurbecause of excessive radical oxygen speciesproduction or attenuated antioxidant defensesor a combination of both [16, 38]. The way inwhich this might occur is the subject of a fewhypotheses. For example, a mutation in SOD1might cause oxides to be overproduced [39].Another hypothesis states that disrupted glu-tathione production and homeostasis mightpromote OS [38]. A systematic review of neu-rodegenerative disease mechanisms found thatthe generation of free radicals triggered theactivation of multiple noxious pathways asso-ciated with the development of neurodegener-ative diseases via multiple different mechanisms[40]. These multiple mechanisms, possibly

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seven or more, interact with each other incomplex and not thoroughly elucidated ways. Itis the interplay of these mechanisms ratherthan any one mechanism in isolation that maypromote neurodegeneration [40]. On the basisof these ideas, a potential target for drugdevelopment to treat neurodegenerative diseasewould be agents that are able to modulate freeradical production [40].

InflammationInflammation is the normal, natural, expected,and adaptive reaction of the body to injury withthe purpose of encouraging both the removal ofthe harmful stimulus and self-protection.Although the inflammatory response is integralto the immune system, imbalances can damagehost tissue and even lead to organ dysfunction[41]. As a general rule, inflammation is onlyproblematic when it fails to subside within theappropriate time [42]. Neuroinflammationoccurs when the peripheral nervous system(PNS) and/or central nervous system (CNS)becomes inflamed, and this potentially insidi-ous condition can set the stage for the devel-opment of chronic neurodegenerative diseases[43].

CNS Environment AlterationsAs part of the healthy immune system, the CNSresponds rapidly to injury and infection[42, 44]. In conjunction with pathological situ-ations, cells from the body’s peripheral immunesystem, such as macrophages, are able to crossthe blood–brain barrier (BBB) [42]. In fact, oneof the most crucial recent advances in medicinehas been the discovery and elucidation of anelaborate cross-talking communications net-work between the immune system and the CNS.In this network, an array of pro-inflammatorycytokines acts to cause the host to respondswiftly to stress, trauma, infection, and pathol-ogy via the inflammatory response. This com-plex cascade of responses involves activitiesfrom glial cells and mast cells, which act asinflammatory mediators. These inflammatorymediators may well play a role in the develop-ment and perpetuation of chronic pain, neu-rodegenerative disease, and neuropsychiatric

disorders [41, 45]. A disturbance in the CNSenvironment, for example an infection or aneuronal injury, will activate the microglia andastrocytes. On the basis of the extent and degreeof this disturbance, the cells may first respondby producing and releasing cytokines. Cytoki-nes are important neurotropic factors that haveonly recently been elucidated, albeit incom-pletely. Prolonged neuronal damage may causethe microglia and astrocytes to release pro-in-flammatory cytokines which, in turn, recruitsthe immune system to action and produces alocalized inflammatory response. Furthermore,these activated microglia and astrocytes pro-duce reactive oxygen species. On the one hand,reactive oxygen species can defend againstmicrobial infection but, on the other hand, itcan contribute to neurodegenerative processes[46–48]. When mitochondrial impairment cau-ses an excessive buildup of reactive oxygenspecies, this may damage neurons and releasecytosolic factors that serve to activate neigh-boring microglia and astrocytes. These nearbymicroglia and astrocytes will, in turn, releasemore pro-inflammatory cytokines along withreactive oxygen species and reactive nitrogenspecies. The release of these cytokines promotesthe inflammatory response and exacerbatesneuronal damage. Thus, the ongoing activationof glial cells creates a vicious circle, which bothperpetuates and amplifies chronic neurodegen-erative processes [49].

Microglia as Part of Immune SystemMicroglia serve an immunoprotective role byscavenging for damaged neurons, infectiousagents, and other potentially injurious sub-stances [50]. It is thought that microglia helpwith the neuroplasticity of brain remodelingduring learning and memory, possibly throughneurotrophic factors. Microglia also promoteoverall healthy brain physiology [51]. Thus,microglia are associated with numerous essen-tial neuronal functions, such as, but not limitedto, maintaining appropriate brain function,scavenging for neuronal debris, promotingneuroplasticity, and releasing specific neu-rotrophic factors [52, 53]. Under normal con-ditions, the microglia in the CNS exist in aphysiological branched form, but when

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stimulated, they become pro-inflammatory[54]. When these microglia become pro-in-flammatory, their cell bodies increase in sizeand they abandon their usual functions in orderto promote inflammation. Among other things,this means they cease monitoring and main-taining the brain, which may lead to neuronaldisruption or damage. In the event thatinflammation is uncontrolled and/or becomeschronic, functional deficits can result [17].When CNS homeostasis is disturbed, microgliamay release various cytokines and growth fac-tors to facilitate the repair of affected neurons.While microglial activation is an essentialcomponent of the healthy immune system,abnormal or prolonged microglial activationbecomes maladaptive. During abnormal micro-glial activation, a host of pro-inflammatorycytokines and cytotoxic mediators may beinduced, including but not limited to IL-12, IL-1b, IL-6, tumor necrosis factor (TNF) alpha, andreactive oxygen species. The onslaught of thesesubstances can injure the brain by damagingneurons, and, in that way, promote neurode-generative diseases [55–57]. Neurodegenerativediseases are associated with advancing age [1],because in younger individuals microglia acti-vation is typically modest and resolved quickly,so that brain homeostasis is rapidly restored,but older individuals have a primed phenotypeof microglia [54] which has a more powerfuland prolonged response, resulting in the pro-duction of larger quantities of pro-inflamma-tory cytokines over a longer period of time(Fig. 1). These primed microglia are associatedwith persistent neuroinflammation, which maydamage brain tissue and impair neuronal func-tion [58] (Fig. 2).

Role of TNF in OS, Inflammatory Response,and NeurodegenerationTNFa (once known as cachectin) is part of theTNF superfamily and is a cytokine of theimmune system with many functions, includ-ing initiating and promoting inflammation.While TNFa plays an important role in thehealing process, uncontrolled it can bring aboutneurodegeneration. The activation of the path-way for nuclear factor kappa-light-chain-en-hancer of activated B cells (NF-jB) in glial cells

leads to the elevated production of pro-inflam-matory cytokines, which, in turn, results in theproduction of the inducible form of nitric oxide(iNOS), cyclooxygenase (COX)-2, and nicoti-namide adenine dinucleotide phosphate(NADPH) oxidase subunits, thereby activatingNADPH oxidases, ultimately leading to theproduction of reactive oxygen species. Addi-tionally, reactive oxygen species can activatethe NF-jB pathway, thereby amplifying theTNF/reactive oxygen species/NF-jB responses.This, in turn, exacerbates neuronal damage,which further promotes neuroinflammation,resulting ultimately in a feed-forward loop that

Fig. 1 Oxidative stress and mitochondrial damage havebeen implicated in the pathogenesis of several neurode-generative diseases, including Alzheimer’s disease, Parkin-son’s disease, and amyotrophic lateral sclerosis. Oxidativestress is connected with immune and glial cells crosstalk-induced inflammation. Oxidative stress and inflammationfeed on each other and together contribute to thedevelopment of neurodegeneration. Oxidative stressinduces activation of microglia and astrocytes with aconsequent increase of pro-inflammatory mediator pro-duction and, in turn, glial activation leads to toxic radicalrelease, exacerbating neuronal damage. Consequently, theresultant cellular damage amplifies the inflammatoryresponse, with glial activation and leukocyte recruitment,leading to further inflammation. RNS reactive nitrogenspecies, ROS reactive oxygen species

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causes and perpetuates chronic neurodegenera-tion [49].

Key Role of MitochondriaReactive oxygen species are produced by themitochondria they damage. Normally, reactiveoxygen species are produced by physiologicalmitochondrial activity. If mitochondria aredamaged, the ETC Complex I (nicotinamideadenine dinucleotide [NADH] dehydrogenase)and Complex III (cytochrome bc1) may producean overabundance of reactive oxygen species,which can damage cells [17]. Newly discoveredgenes related to Parkinson’s disease, such asPINK1, PARK2 (Parkin), DJ-1, and LRRK2,encode proteins that help to regulate the bal-ance between mitochondria and reactive oxy-gen species. For that reason, mitochondrialdamage can dysregulate this balance andpotentially lead to any number of neurodegen-erative diseases, including Parkinson’s disease[59–63]. Mitochondria are vulnerable to damagerelated to OS, as they are some of the body’smain sites for the production of reactive oxygen

species. Mitochondrial DNA (mtDNA) is notprotected by histone proteins like nuclear DNA,meaning that mtDNA is more susceptible tooxidative damage [64]. The aging processexposes mtDNA to damage which can be 10–20-fold greater than the damage to nuclear DNA atthe same age; the production of reactive oxygenspecies also increases with advancing age[65, 66]. The majority of the proteins encodedby mtDNA are involved in ETC, so any muta-tions or deletion of the mtDNA would challengethe equilibrium of the ETC and result inincreased production of reactive oxygen species,thereby perpetuating the cycle of increasingmitochondrial damage [67].

Viral InsultNeurodegeneration is known to occur followingviral insult. This suggests that the microglia andastrocytes play a key role in the process ofneuronal disruption. Viruses have two mainprongs of attack: they can injure neurons bydirect action (causing neuronal damage) or theycan induce apoptosis in neuronal cells (causing

Fig. 2 Differences between resting and primed microglia.The phenotype of microglia in aging is predominantlyprimed. This phenotype responds to stimuli in a moreintense manner, i.e., producing greater amounts of pro-

inflammatory mediators and for extended periods. Primedmicroglia induce persistent neuroinflammation, capable ofdamaging tissue integrity and neuron function. Copyright,with permission from Pain Nursing Magazine

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neuronal death). These viral assaults may leadto neurodegenerative conditions. The neurode-generative diseases of the elderly, such as Alz-heimer’s disease, multiple sclerosis, and ALS,may occur as a result of the viral-induced neu-ronal apoptosis [68].

Currently Proposed Treatments

Natural Pharmaceutical Approaches (Table 1)Pomegranate (Punica granatum) The pome-granate fruit, which originated in India but istoday cultivated around the world, is rich inantioxidants. The primary polyphenol antioxi-dant of the pomegranate is punicalagin (PN) or2,3-hexahydroxydiphenoyl-gallagyl-D-glucose.As a natural antioxidant, PN offers many healthbenefits and has an anti-inflammatory effect.

The potential neuroprotective benefit of PN inthe treatment of Parkinson’s disease has beendescribed in the literature [69].

Medicinal Plants Traditional Persian medi-cine (Falij, Ra’shah, Nisyan, Khadir, Istirka)emphasizes the role of certain plants for pre-venting and treating neurological conditions.These botanicals use cellular and molecularmechanisms to slow or stop apoptosis, includ-ing anti-apoptotic agents (BCL-2) or bydecreasing the expression and activity of pro-apoptotic proteins (BAX, caspase-3, and cas-pase-9). These traditional plants are thought toalleviate inflammation and reduce the produc-tion of pro-inflammatory cytokines (TNFa, var-ious IL cytokines) while at the same timepromoting antioxidation by enhanced

Table 1 Natural pharmaceutical approaches

Substance name Year of investigation Reference

Punica granatum (pomegranate) 2018 [69]

Medicinal plants (Falij, Ra’shah, Nisyan, Khadir, Istirka) 2018 [70]

Vitamin D 2018 [71]

Vitamin C 2016 [72]

Bakkenolide B 2018 [73]

Mediterranean diet and extra-virgin olive oil 2009–2018 [74–81]

Flavonoid-rich ethanol extract from the leaves of Diospyros kaki 2018 [82]

Curcumin 2017 [83]

Resveratrol 2017 [84]

Aged garlic extract (AGE) 2016 [85]

Phytochemicals and botanical extracts 2016 [86, 87]

Hericium erinaceus 2016 [88]

Walnut (Juglans sigillata Dode) 2016 [89]

L-3-n-Butylphthalide (Chinese celery) 2012, 2016 [90, 91]

Gastrodia elata Blume 2015 [92]

Chrysophanol 2015 [93]

Marine carotenoid astaxanthin, omega-3 fatty acids 2014 [94]

Palmitoylethanolamide (PEA) 2015–2019 [68, 95–98]

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production of superoxide dismutase and cata-lase. These traditional plants can modulate thetranscription, transduction, and signaling ofvarious inflammatory pathways (including ERK,p38, MAPK). By regulating these inflammatorycascades far upstream, they can help limitapoptosis and OS and, in this way, may helpprevent or treat neurodegenerative conditions[70].

Vitamin D Vitamin D reduces OS, offers bothneuroprotective and anti-inflammatory actions,and may exert preventive effects on neurode-generative diseases [71].

Vitamin C When vitamin C (200 and 400 mg/kg body weight) was administered to rats whohad colchicine-induced Alzheimer’s disease(cAD), the rats recovered some memory deficits,hippocampal neuroinflammation was reduced,and further neurodegeneration was prevented.The hippocampal neuroinflammation had hadan adverse effect on the peripheral immuneresponses which was also recovered. However,when the rats with cAD were administeredhigher doses of vitamin C (600 mg/kg), memoryimpairments resulted along with hippocampalneuroinflammation, and neurodegenerationalong with altered peripheral immune respon-ses. These are all pro-oxidant, rather thanantioxidant, effects [72].

Bakkenolide B Bakkenolide B is a naturalsubstance obtained from the Petasites japonicusplant which has been shown to suppress bothinflammatory and allergic responses. Treatmentwith bakkenolide B reduced production ofmicroglia, IL-1b, IL-6, IL-12, and TNFa [73].

Mediterranean Diet and Extra-Virgin OliveOil A review of scientific evidence about theMediterranean diet and its emphasis on extra-virgin olive oil found this diet may decrease therisk for neurodegenerative diseases [74]. Thehealth benefits of olive oil were presented in2016 by Parkinson and Cicerale [75]. Their workcame after an announcement that phenoliccompounds such as oleocanthal or oleuropeinfound in olive oil might confer neuroprotectionand possibly prevent Alzheimer’s disease

[76, 77]. In fact, the Prevencion con DietaMediterranea study (PREDIMED) found that theMediterranean diet with extra-virgin olive oiland nuts was associated with improvements incognition [78]. The Mediterranean diet maybenefit patients at all stages of Alzheimer’s dis-ease by slowing the rate of cognitive decline,delaying dementia, and reducing the risk ofdeath [79]. Moreover, other benefits of extra-virgin olive oil include neuroprotective effectsin the setting of depression, Parkinson’s disease,traumatic brain injury, and multiple sclerosis[80, 81].

Flavonoid-Rich Ethanol Extract from Leaves ofDiospyros kaki Flavonoid is a collective termfor a diverse group of phytonutrients found inmost fruits and vegetables. Overall, flavonoidsact as antioxidants and offer neuroprotection byfighting neurotoxins. Flavonoids can reduce Abproduction. Because flavonoids in generalreduce or inhibit neuroinflammation, they tendto promote proper function of the cerebrovas-cular system and, in that way, may improvecognition [82].

Curcumin Recently gaining in popularity,curcumin (found in the turmeric plant) hasknown anti-inflammatory, antioxidative, andantitumor properties. Widely used around theworld as an herbal remedy, curcumin or tur-meric is increasingly recommended by Westernmedicine as a pain reliever. It may also conferneuroprotection [83]. Turmeric is also used as aspice and is particularly popular in Indiancuisine.

Resveratrol Resveratrol (3,40,5-trihydroxy-trans-stilbene) is a phytonutrient found natu-rally in about 70 plants, including the skin andseeds of grapes. In addition to the powerfulantioxidant effect of resveratrol, its antitumoractivity is currently being studied in cancerpatients. Resveratrol has demonstrated neuro-protective properties in several in vivo andin vitro models because it inhibits glutathionedepletion. Glutathione is an antioxidant pro-duced by the CNS involved in numerous cellu-lar processes. When glutathione is depleted, theneuronal system becomes vulnerable [84].

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Aged Garlic Extract (AGE) Aged garlic extract(AGE) is made when the garlic plant Alliumsativum is marinated under ambient conditionsin aqueous ethanol for four or more months.Through this process, much of the sharp tasteand offensive odors of the garlic plant areeliminated and, more importantly, the antiox-idative properties of the product are amplified.Neuroprotective benefits in Alzheimer’s disease,Parkinson’s disease, Huntington’s disease, andcerebral ischemia have been observed with AGE[85]. AGE appears to act on the signaling path-ways involved in OS and neuroinflammation,although this mechanism of action remains tobe more fully elucidated [85]. Two componentsof AGE, S-allyl-L-cysteine and N(a)-(1-deoxy-D-fructos-1-yl)-L-arginine, seem to attenuate neu-roinflammation in the microglia by modulatingthe nuclear factor erythroid 2-like (Nrf2)-medi-ated pathways as well as attenuating otherforms of oxidative stress signaling [85].

Phytochemicals and Botanical Extracts NF-jB is a transcription factor involved in multiplephysiological and pathological conditions.Among other things, NF-jB regulates DNAtranscription, production of cytokines, andplays a role in cell survival. Thus, NF-jB isdirectly or indirectly involved in immunologi-cal responses, apoptosis, inflammatory pro-cesses, and carcinogenesis. The role of NF-jBand Nrf2 was investigated to better elucidatetheir contribution to OS and inflammationassociated with neurodegenerative diseases.Botanical polyphenols have been shown toinhibit lipopolysaccharide (LPS)-induced nitricoxide responses and enhanced antioxidantresponses modulated by Nrf2 [86]. Using animmortalized rat astrocyte (DI TNC1) cell linewhich expressed a luciferase reporter driven bythe NF-jB or their Nrf2/antioxidant responseelement (ARE), investigators showed how thesetwo pathways could be regulated by phyto-chemicals (such as quercetin, rutin, cyanidin,cyandini-3-O-glucoside) and botanical extractsfrom Withania somnifera (ashwagandha),Sutherlandia frutescens (sutherlandia), andEuterpe oleracea (acaı). All three of these botan-ical extracts inhibited LPS-induced NF-jB-re-porter activity. For example, quercetin inhibited

the LPS-induced NF-jB reporter activity on theone hand and induced reporter activity of Nrf2/ARE on the other hand. Cyanidin and glycosidehad similar effects but only when used at muchhigher concentrations. Investigators stated thatashwagandha extract was more effective thansutherlandia and acaı extracts in promotingNrf2 and HO-1 expression in DI TNC1 astro-cytes, which illustrates how botanical polyphe-nols and extracts have different abilities interms of downregulating LPS-induced NF-jBand upregulating NRF2/ARE [87].

Hericium erinaceus Hericium erinaceus is amushroom that was found to confer certainneuroprotective properties in animal studies.Rats administered the mushroom orally werefound to have upregulated lipoxin A4 (LXA4) invarious parts of their brains. LXA4 is thought tohelp reduce inflammation by halting theinflammatory processes and increase redox-sensitive proteins in response to cellular stress,such as heat shock proteins, HO-1, and thiore-doxin [88]. Heat shock proteins have beenimplicated as a potential pathway for the pre-vention of protein misfolding, which has beenassociated with certain types of irreversibleneuronal damage. It has been suggested thatagents that can activate LXA4 signaling wouldbe able to modulate the vitagene proteins thatrespond to stress cues; in that way, agents thatactivate LXA4 might be good targets for reduc-ing the neuroinflammation and neurodegener-ation associated with Alzheimer’s disease [88].

Walnut (Juglans sigillata Dode) Peptidesfrom the walnut have been studied for theirhypothesized ability to protect against neuro-toxicity. Mice were injected bilaterally in thehippocampus with amyloid-b peptide 25–35 tocreate an animal model of Alzheimer’s disease[89]. Mice were then treated orally with walnutpeptides (200, 400, 800 mg/kg) or distilled water(placebo) for 5 weeks. The water maze and step-down avoidance tests were used to test the miceat 5 weeks for spatial learning and memory.Walnut peptides improved the cognitive abili-ties and memories of the animals compared toplacebo. Furthermore, the two higher-dosewalnut peptide groups (400 or 800 mg/kg) had

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restored levels of antioxidant enzymes andinflammatory mediators. This in vivo studysuggests that walnut peptides might exert aneuroprotective effect in Alzheimer’s disease byreducing neuroinflammation and enhancingthe endogenous antioxidant system [89].

L-3-n-Butylphthalide One of the chemicalcomponents from Chinese celery (Apium grave-olens L.), L-3-n-butylphthalide (L-NBP), hasshown neuroprotective benefits in animalmodels of stroke and Alzheimer’s disease [90]. Asynthetic version of this substance is anapproved anti-ischemic agent available inChina. In a preclinical study, C57BL/6 micewere administered systemic LPS that resulted inthe release of pro-inflammatory cytokines andactivated cerebral microglia. When these micewere treated with L-NBP, the production of pro-inflammatory cytokines such as TNFa, IL-1b, IL-6, and IL-10 was suppressed, and the morpho-logical activation of microglia was decreased[91]. The phosphorylation level of the Januskinase (JAK) mitogen-activated protein (MAP)pathways was also inhibited with the adminis-tration of L-NBP in these mice. HO-1, whichhelps to catalyze the degradation of heme andhas anti-inflammatory and antioxidativeeffects, was also evaluated in this murine studyand found that L-NBP was associated with anupregulation of HO-1 expression.

Gastrodia elata Blume Highly regarded intraditional Chinese medicine, the tianma flowerfrom the orchid family (Gastrodia elata Blume)has been used in Chinese folk medicine forcenturies to treat a wide range of complaintsranging from headache to convulsions. Today itis known for its analgesic and sedative effects,and it shows promise in the treatment of neu-rological disorders. An extract from its rhizomehas been observed to provide neuroprotectiveeffects. In an animal model of brain injury, thisextract helped brain cells to recover their func-tion, likely by inhibition of both OS and theinflammatory response [92].

Chrysophanol Chrysophanol is an anthraqui-none well known in traditional Chinese andKorean medicine. It is widely distributed around

the world in two main natural domains: Bacte-ria and Eukarya. It has a reputation for benefitsin anticancer, hepatoprotection, neuroprotec-tion, anti-ulcer, and antimicrobial applications.Its neuroprotective effects and its ability toreduce OS were evaluated in vitro with LPS-in-duced inflammatory responses in bovine BV2cells. In this study, chrysophanol reduced theexpression of iNOS and COX-2, and, in thatway, nitric oxide and prostaglandin E2 produc-tion were reduced [93]. Chrysophanol inhibitedDNA oxidation and was also able to reduce celldamage in these BV2 cells caused by intracel-lular reactive oxygen species. To measure theoverall antioxidant effect, the expression levelsof various antioxidative enzymes, such assuperoxide dismutase, and glutathione werecalculated. Chrysophanol was shown to exhibitpotential anti-inflammatory and antioxidativeeffects in the microglia, making it a potentiallyvaluable therapeutic product in the treatmentof neurodegenerative diseases [93].

Marine Carotenoid Astaxanthin and Omega-3Fatty Acids Seafood is frequently recom-mended by dieticians for its health benefits,most of which come from omega-3 and omega-6 polyunsaturated fatty acids (PUFAs), n-3/n-6PUFAs, and antioxidants. The ratio of omega-3to omega-6 PUFAs is more important to healththan their individual quantity. The intake of theproper ratio of omega-3 to omega-6 PUFAs canallow for effective anti-inflammatory responsesthat may be able to prevent or delay neurolog-ical disorders. Early in vivo and clinical studiesusing the marine carotenoid astaxanthin foundin salmon, shrimp, and lobster show that it canprotect against neuronal damage caused by freeradicals that can lead to neurodegenerativeprocesses and cognitive deficits [94]. Nutraceu-tical products have been created with a bal-anced ratio of omega-3 and omega-6 PUFAscombined with astaxanthin as protectionagainst neurodegeneration caused by OS in theCNS. Other antioxidants such as krill oil can becombined in such products.

Palmitoylethanolamide (PEA) Palmi-toylethanolamide (PEA) is an endogenous lipidthat was first brought to the attention of

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physicians when the anti-inflammatory effectsof egg yolks were studied. (PEA occurs naturallyin egg yolks.) PEA is available today as a ‘‘specialfood for medical purposes,’’ as registered bysome pharmaceutical agencies. It down-modu-lates mast cell activation, allowing it to exertcontrol over certain glial cell behaviors. PEA, anacylethanolamide found in diverse bodily tis-sues, including the nerve cells, can be synthe-sized by the body as needed. In fact,endogenous PEA levels vary regularly in thebody, for example with stress, injury, or pain[95]. PEA is associated with reducing mast cells,down-modulating the pro-inflammatory medi-ators released by these mast cells, and sup-pressing microglial cell activation. Theseactivities are thought to be the reason PEA isassociated with anti-allodynic and anti-hyper-algesic effects. At the molecular level, PEA is aperoxisome proliferator-activated receptoralpha (PPARa) ligand with anti-inflammatory,analgesic, and neuroprotective properties [96].Clinical trials using PEA in humans have shownpromise. For example, PEA was effective in apreliminary trial of patients with failed backsurgery syndrome [96] and in another study ofpatients with fibromyalgia [97] because of itsanti-inflammatory properties. These neuropro-tective and anti-neuroinflammatory propertiesmake PEA an interesting substance to consideras a novel therapy for Alzheimer’s disease. Beg-giato and colleagues found that astrocytes con-tribute to the neurotoxicity induced byamyloid-b42 (Ab42); PEA could blunt the acti-vation of Ab42 and, in that way, induce astro-cyte activation and improve neuronal cellsurvival in murine astrocyte–neuron co-cultures[98]. On the basis of the neuroprotective attri-butes exhibited in experimental models ofneurodegenerative diseases, an ultra-mi-cronized (um) form of PEA has been developedand investigated for the treatment of cognitiveimpairment [68]. In these studies, it was foundthat PEA may be a component of the home-ostasis involved in the resolution of neuroin-flammation. In an animal model of Parkinson’sdisease, chronic PEA treatment was able tocounteract behavioral impairments, motor dys-function, loss of nigrostriatal neurons, astrocyteactivation, altered iNOS expression, and

proteins associated with the microtubules. Inthis Alzheimer’s disease model, when Ab25–35peptides were injected into the intracerebralventricles of the murine brain, PEA treatmentcould ameliorate behavior impairments andreduce lipid peroxidation, iNOS, and caspase-3activation [68]. In human patients with ALS,PEA improved their clinical conditions anddelayed tracheotomy and death [68].

Extracted or Recombinant Productsand Artificial Agents (Table 2)Melatonin As a natural substance that acts likea neurotransmitter, melatonin plays a role in avariety of bodily functions. Produced endoge-nously and mainly but not exclusively by thepineal gland, melatonin has known benefits fortreating sleep disorders, boosting naturalimmunity, and offering anti-aging benefits aswell. An indolamide, melatonin is perhaps beststudied for its regulation of circadian rhythms,but it may be involved in a host of other func-tions such as oxidation, apoptosis, and mito-chondrial homeostasis. When inflammatorypathologies disrupt the last three processes,melatonin appears to offer some therapeuticbenefits, particularly in patients with neurode-generative diseases or bowel disease. Among theneurodegenerative conditions in which mela-tonin has been studied are Alzheimer’s disease,ALS, multiple sclerosis, and Huntington’s dis-ease; melatonin may also be effective in treatingpatients with ulcerative colitis [99].

Curcumin/Melatonin Hybrid 5-(4-Hydroxy-phenyl)-3-oxo-pentanoic Acid [2-(5-Methoxy-1H-indol-3-yl)-ethyl]-amide (Z-CM-I-1) Thecombination of curcumin plus melatonin as anoral hybrid compound might be effective as adisease-modifying agent in the treatment ofAlzheimer’s disease. In an in vivo study using atransgenic model of Alzheimer’s disease, Z-CM-I-1 administered at 50 mg/kg orally over12 weeks decreased the accumulation of amy-loid-b in the hippocampal and cortex regions ofthe brain and it further reduced inflammatoryresponse and OS. In addition, with Z-CM-I-1there was significant improvement of synapticdysfunction (as shown by increased expressionof synaptic marker proteins, PSD95, and

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Table 2 Extracted or recombinant products and artificial agents

Substance Year of investigation References

Melatonin 2018 [99]

Curcumin/melatonin hybrid 2015 [100]

Thioredoxin-interacting protein (TXNIP) 2018 [101]

Mitochondria-targeted molecules 2017 [102]

Hydrogen sulfide (H2S) 2017, 2018 [103, 104]

Heat shock proteins 2017 [105]

Intranasally administered erythropoietin (Neuro-EPO) 2017 [106]

Cyclo(His-Pro) 2016 [107]

RGS1 and RGS10 proteins 2016 [108]

Chitosan oligosaccharides (COS) 2016 [109]

Pharmacological antagonism of interleukin-8 receptor CXCR2 2015 [110]

Microglial alpha-7 nicotinic acetylcholine receptors (nAChRs) 2015 [111]

Stem cells of human dental pulp 2015 [112]

Piracetam 1994–2018 [113–118]

Fasudil 1993, 2015 [119, 120]

Intranasal plasma rich in growth factors: Endoret 2015 [121]

Suppression of glia maturation factor expression 2014 [122]

Preservation of mitochondrial neuroglobin 2018 [123]

Glucagon-like peptide 1 2017 [124]

Radix Astragali calycosin 2017 [125]

Therapies targeting metabolic hormones (insulin, leptin, and amylin) 2002–2016 [126–132]

Rosiglitazone 2017 [133]

Silver nanoparticles 2015 [134]

Immunomodulatory agents 2013–2019 [18, 91, 135–148]

Fingolimod

Tanshinone I

Tanshinone IIA

Dimethyl fumarate

Lenalidomide

Thalidomide

Ginsenoside Rg1

CNI-1493

Pycnogenol

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synaptophysin which shows protective effectsagainst synaptic degeneration). Z-CM-I-1 alsoincreased the expression levels of complexes I,II, and IV of the mitochondrial electron trans-port chain in the brain tissue of mice [100].

Thioredoxin-Interacting Protein (TXNIP)TXNIP is produced endogenously and inhibitsthioredoxin, a thiol-reducing and antioxidativesystem in the body. In the healthy individual,the role of TXNIP is to control the processes ofstress and inflammation induced by redox andglucose. During cerebrovascular accident andbrain disease, TXNIP is upregulated. Recentstudies suggest that pharmacological inhibitionor even genetic deletion of TXNIP can serve toprotect the neurological system, possiblyreducing the adverse effects of neurodegenera-tive disease or stroke [101].

Mitochondria-Targeted Molecules In the earlystages of Alzheimer’s disease, patients areknown to experience synaptic pathologies andmitochondrial oxidative damage. For this rea-son, mitochondria-targeted molecules wereconceived as therapeutic targets that mightdelay or prevent the advancement of Alzhei-mer’s disease. Mitochondria-targeted moleculesare designed to deliver treatment directly to themitochondria, reducing reactive oxygen speciesand mitochondrial dysfunction and, in thatway, preventing or delaying neurodegenera-tion. Mitochondria-targeted molecules are cell-penetrating triphenyl phosphonium lipophiliccation-based derivatives of tetrapeptide mole-cules or choline esters of glutathione and N-acetyl-L-cysteine [102].

Hydrogen Sulfide (H2S) Receptors foradvanced glycation end products (RAGE) arereceptors expressed in numerous CNS andperipheral cells, including neurons, astrocytes,microglia, and others. These receptors bind to aselect number of ligands, including non-enzy-matically glycated proteins and certain lipids.The importance of RAGE is its critical role in theinflammatory process and the possible role itmay play in neurodegeneration. H2S inhibitsdimer formation of RAGE and, in that way,impairs the stability of its membrane. Byreducing the RAGE membrane, H2S may protectcells against the adverse effects of inflammation[103, 104]. Its role in the treatment of variousneurodegenerative diseases remains to beclarified.

Heat Shock Proteins Heat shock proteins(HSPs) took their name when a family of pro-teins was discovered which was created duringheat shock. Although heat shock proteins retaintheir old name, it is now known that they areproduced in response to any number of externaland internal stressors including thermal stress,wound healing, tissue remodeling, and others.These ubiquitous HSPs are found in nearly allliving organisms and many of them have achaperon function, whereby they help ensurethe proper folding of new proteins that may beformed as a result of stress. Protein misfoldingcan result in permanent damage, includingirreversible neurological damage. In addition toprotecting cells against damage caused byinflammation, HSPs assure proper folding ofnew proteins and destroy misfolded proteins.

During periods of disease, HSP productionmay be upregulated to prevent pathology-re-lated damage. HSP is also upregulated in

Table 2 continued

Substance Year of investigation References

Cyclosporin

Acetoside

SA00025

C5aR antagonist DF3016A

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response to the accumulated stress of aging.Certain HSPs can produce extracellular mes-sengers called chaperonins to aid in modulatingthe immune responses of the CNS. Since HSPsare able to modulate the body’s natural immunesystem, they may have specific neuroprotectivebenefits. For these reasons, HSPs have been thesubject of scientific attention as they may beable to play an important therapeutic role in thetreatment of neurodegenerative diseases [105].

Intranasally Administered Erythropoietin(Neuro-EPO) Erythropoietin (EPO) is a cyto-kine secreted primarily by the kidneys and liverwhich has certain cytoprotective actions in thebrain, protecting it from inflammatory andneurodegenerative assaults. An intranasal for-mulation of erythropoietin has been developedand is marketed as Neuro-EPO. Neuro-EPO wasevaluated for its neuroprotective properties in atransgenic mouse model of Alzheimer’s disease[106]. Low-dose Neuro-EPO was able to restoredeficits in memory, learning, and the recogni-tion of new objects. In addition, it reducedneuroinflammation, apoptosis induction, OS,and amyloid load along with alleviating alteredmemories.

Cyclo(His-Pro) Thyrotropin-releasing hor-mone (TRH) is synthesized by the hypothala-mus and confers neuroprotective benefits.Spontaneous cyclization of TRH produces His-Pro, a cyclic dipeptide. Cyclo(His-Pro), the cyc-lic dipeptide histidyl-proline, can be synthe-sized de novo endogenously and has beenfound throughout the body, in particular in theCNS, blood, and gastrointestinal tract. Cyclo(-His-Pro) regulates glial cells and can cross theblood–brain barrier. In the brain, cyclo(His-Pro)can affect a variety of inflammatory and stressresponses because of its effect on the Nrf2–NF-jB signaling axis. It has been hypothesized thatcyclo(His-Pro) has the ability to interfere withmany of the biological processes driving neu-rodegeneration and may be an important sub-stance to study for the potential restoration ofneuronal integrity. Cyclo(His-Pro) is also beingstudied for its possible role in the treatment ofALS [107].

Regulator of G-Protein Signaling (RGS): RGS1and RGS10 Proteins Guanine nucleotide-binding proteins (G proteins), part of a largefamily of GPPase enzymes, transmit signals ofextracellular origin to the cell’s interior.A G protein is able to bind to guanosinetriphosphate (GTP), which essentially opens thesignaling switch; when they bind to guanosinediphosphate (GDP), the switch is turned off.Regulators of G-protein signaling (RGS) werefirst thought to use the proteins that acceleratedthe GRPase processes in order to act as negativeregulators of G-protein-coupled receptor sig-naling. All RGS proteins contain some con-served RGS domain, but the size and regulatoryfunctions of the domain vary. Among the manyRGS proteins, RGS1 and RGS10 are relativelysmall and are involved in the inflammatory andautoimmunological responses in the peripheraland central nervous systems. RGS1 and RGS10may be important targets for future drugdevelopment for anti-inflammatory interven-tions that might stem neurodegenerative pro-gression [108]. RGS1 and RGS10 are of particularinterest for treatment of multiple sclerosis andParkinson’s disease.

Chitosan Oligosaccharides (COS) Chitosan isan abundant polysaccharide with antioxidantproperties and little cytotoxicity. In a rat modelof Ab1–42-induced Alzheimer’s disease, chi-tosan oligosaccharides inhibited OS and neu-roinflammatory response and thus conferredimprovements in cognitive deficits as shown bythe water maze and passive-avoidance tests[109]. The antioxidative properties of COS inthe hippocampus were evaluated biochemicallyincluding their effects on apoptosis (TUNELassay) and variations in inflammatory media-tors (immunohistochemistry). When COS wereadministered to these rats at doses of 200, 400,or 800 mg/kg, the COS effectively reduced def-icits in learning and memory. Neuronal apop-tosis was ameliorated at these same doses. Inthis study, the neuroprotection conferred byCOS aligned closely with OS inhibition, asshown by the evidence of diminishing levelsof malondialdehyde, 8-hydroxy-20-deox-yguanosine and increasing levels of glutathioneperoxidase along with superoxide dismutase

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activities. It appears that by reducing the releaseof pro-inflammatory cytokines, such as IL-1band TNFa, chitosan oligosaccharides may sup-press the inflammatory response and decreasequantifiable signs of inflammation [109].

Pharmacological Antagonism of IL-8 ReceptorCXCR2 IL-8 is a cytokine that is produced bymany types of normal cells, including neu-trophils and macrophages; IL-8 is then stored inendothelial cells. IL-8 ligands bind to theCXCR1 and CXCR2 receptors and trigger vari-ous biological functions. The binding of IL-8 toCXCR2 contributes to the chemotactic respon-ses seen in Alzheimer’s disease. A murine modelof Ab1–42-induced Alzheimer’s disease was usedto evaluate the pharmacological antagonism ofCXCR2 with SB332235 as a means to inhibitreceptor-mediated inflammatory reactivity and,in that way, improve neuronal viability [110].This competitive CXCR2 antagonist signifi-cantly reduced the expression of CXCR2 andmicrogliosis but left astrogliosis unaltered. Thisimplies that CXCR2-dependent inflammatoryresponses may play a key role in induced Alz-heimer’s disease in rats. Thus, the pharmaco-logical modulation of this receptor may inhibitinflammatory reactivity, providing neuropro-tection against oxidative damage [110].

Microglial Alpha-7 Nicotinic AcetylcholineReceptors (nAChRs) The CNS is replete withnAChRs that are expressed in both neurons andnon-neuronal cells. These nAChRs are receptorpolypeptides that respond to endogenousacetylcholine and their activity is involved innumerous physiological functions, such asmemory, learning, ambulation, attention, andothers. The a7 subtype of nAChR may beinvolved in neuroprotection, synaptic plastic-ity, and neuronal survival. As such, it is a ther-apeutic target for numerous neurologicaldisorders. When a7-nAChR is activated, it opensan anti-inflammatory pathway that appears tobe related to the recruitment and activation ofJanus kinase 2/signal transducer and activatorof transcription 3 (JAK2/STAT3) pathways.JAK2/STAT3 pathways are involved in NF-jBnuclear translocation but can also help to reg-ulate OS via the Nrf2/HO-1 axis [111].

Stem Cells of Human Dental Pulp Stem cellsfor human exfoliated deciduous teeth (SHEDs)were used to produce a serum-free conditionedmedium applied in a mouse model of Alzhei-mer’s disease. The SHEDs were administeredintranasally to mice which demonstrated sub-stantial improvement in cognitive function.The conditioned medium made from SHED wasfound to contain factors involved in severalneurological processes such as neuroprotection,axonal elongation, neurotransmission, inflam-matory suppression, and the regulation ofmicroglia. SHED conditioned medium attenu-ated pro-inflammatory effects caused by b-amyloid plaques, triggered the induction ofcertain anti-inflammatory microglia, and over-all helped to create an anti-inflammatory envi-ronment suitable for tissue regeneration [112].

Piracetam Nootropics are natural or syntheticdrugs aimed at improving mental capacity.Piracetam, a synthetic derivative of gamma-aminobutyric acid (GABA), is a first-generationprototype nootropic drug. Piracetam remainsenigmatic in that its mechanism of actionremains unknown; it does not have an effectsimilar to GABA. In the cortical myoclonus,piracetam is anti-myoclonic [113]. Piracetamhas been recommended for enhancing mentalcapacity and has been used to aid learning andsharpen memory [114]. Piracetam has been usedfor pediatric patients to treat breath-holdingspells [115], epilepsy [116], and autism spec-trum disorders where improvements were notedin a pediatric subpopulation [117]. Piracetam-induced neuroprotection remains to be eluci-dated; the possible role of a caspase-indepen-dent pathway has been investigated and itappears that piracetam may confer protectionagainst LPS-induced inflammatory responsesand apoptosis [118]. Piracetam appears to haveantioxidative, anti-apoptotic, and neuroprotec-tive actions against mitochondria.

Fasudil Fasudil is a calcium channel blockerand vasodilator that works by inhibiting theRho kinase isoforms (ROCK1 and ROCK2). Fas-udil has been used to treat cerebral vasospasm,such as might occur in a subarachnoid hemor-rhage, and to ameliorate the cognitive decline

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associated with stroke [119]. Since the ROCKpathways are involved in the dopaminergicneuronal degeneration, fasudil may be apotential therapeutic agent to treat Parkinson’sdisease. In a mouse model of Parkinson’s diseaseinduced by 1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine (MPTP), fasudil was tested for itseffectiveness in treating dopaminergic neuroninjury [120]. Fasudil demonstrated neuropro-tective benefits against dopaminergic neuronsand facilitated the recovery of motor functionin the MPTP mice and suppressed inflammatoryresponses (IL-1b, TNFa, NF-jB-p6, and TLR-2),and reduced OS (iNOS and gp91Phox). Thereduction in OS might be associated withenzymatic inhibition of ROCK or glycogensynthase kinase-3b or both. Microglial activa-tion in the CNS can be either neuroprotective,on the one hand, or pro-inflammatory, on theother. To better describe these diverse actions,the phenotypes microglia M1 (pro-inflamma-tory) and M2 (neuroprotective) have beendescribed, but have yet to be fully elucidated. Ithas been observed that M1 and M2 phenotypescan change with time, disease progression, andother factors. Administration of fasudil can shiftmicroglia M1 to microglia M2, that is transitionthe microglial environment from a pro-inflam-matory and potentially cytotoxic state to one ofneuroprotection. Fasudil may also optimize theexpression of antioxidative factors [119].

Intranasally Administered Plasma Rich inGrowth Factors: Endoret Growth factors aresubstances required to stimulate growth in liv-ing cells and may include vitamins and hor-mones. Growth factors may also help mediateneuroprotection. In a rodent model of Parkin-son’s disease, plasma rich in growth factors(PRGF) under the brand name Endoret wasadministered as a moderator the inflammatoryresponse. Endoret offered neuroprotection inthis animal model of Parkinson’s disease bydecreasing the inflammatory response andimproving motor abilities. These benefits wereassociated with a marked decrease in NF-jBactivation as well as reduced expression of nitricoxide, COX-2, and TNFa in the substantia nigra.It has been hypothesized that PRGF (Endoret)may be able to prevent dopaminergic

degeneration by way of an NF-jB-dependentsignaling process [121].

Suppression of Glia Maturation FactorExpression Glia maturation factor (GMF) isone of several neurotrophic factors that areinvolved in the development and proper func-tion of the nervous and immune systems.Altered GMF expression can have a directimpact on the production of reactive oxygenspecies and inflammatory mediators, which areproduced by the 1-methyl-4-phenylpyridinium(MPP?) by way of NF-jB. In GMF knockoutneurons and glia, the lack of GMF led to adecrease in the production of reactive oxygenspecies and the downregulation of NF-jB-me-diated production of TNFa and IL-1b comparedto wild-type neurons and glia. The overexpres-sion of GMF induced dopamine-related neu-rodegeneration, while the downregulation ofGMF (by GMF-specific sharp-hairpin RNA)conferred neuroprotection from the toxiceffects induced by MPP. In summary, it appearsthat a deficiency in GMF improves the antioxi-dant balance, as evidenced by observeddecreased lipid peroxidation levels, less reactiveoxygen species, and increased levels of glu-tathione. Furthermore, GMF deficiency alsoattenuated the dopamine-associated neuronalloss by downregulating the inflammatoryresponses mediated by way of the NF-jB path-ways [122]. GMF appears to play a role inmediating OS and the release of MPP?, both ofwhich can result in the loss of dopamineneurons.

Preservation of Mitochondrial Neu-roglobin Conditioned medium prepared fromhuman adipose-derived mesenchymal stemcells (CM-hMSCA) has been developed with thegoal of offering therapeutic benefit in neu-ropathological conditions. The concept behindCM-hMSCA is to offer protection to astrocytesso that they can maintain their neuroprotectivefunctions. In a model of human astrocytes withscratch injury, CM-hMSCA was shown to regu-late cytokines IL-2, IL-6, IL-8, IL-10, granulo-cyte–macrophage colony-stimulating factor,and TNFa. Moreover, CM-hMSCA downregu-lates calcium (at the cytoplasmic level),

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mitochondrial dynamics, and the mitochon-drial respiratory chain. CM-hMSCA can alsomodulate the expression of any number ofproteins involved in several signaling pathways,such as the AKT/pAKT and ERK1/2/pERK. CM-hMSCA may also be able to mediate the cellular-level localization of neuroglobin, an intracellu-lar hemoprotein expressed mainly in the centraland peripheral nervous systems. These obser-vations strongly suggest that CM-hMSCA holdspromise as a potential protective agent forastrocytes in patients with brain pathology[123].

Glucagon-Like Peptide 1 Glucagon-like pep-tide 1 (GLP-1) is an incretin hormone producedin the gut as a product of pre-proglucagon, apolypeptide that splits to produce numeroushormones that are similar to the parent (hencethe name ‘‘glucagon-like’’). One role of incretinsis to enhance the synthesis and secretion ofinsulin from the pancreas in response to food.Originally, it was thought that GLP-1 wasmainly related to insulin but it is now clear thatin addition to glucose control, it has multipleadditional functions in the brain, heart, andkidney. Both GLP-1 and GLP-1 receptor agonistshave antioxidative properties that make themeffective in the treatment of certain chronicdiseases, such as diabetes. The activation ofGLP-1 receptor signaling may enhance neuro-genesis, reduce apoptosis, and protect neuronalfunction, making it a promising area for furtherstudy in the treatment of neurodegenerativediseases [124].

Radix Astragali Calycosin Calycosin belongsto the class of 7-hydroxyisoflavones and isextracted from the dry root of the Radix Astra-gali plant used in traditional Chinese medicine.Calycosin is the main bioactive chemical of thisplant and acts like a typical phytoestrogen bybinding to estrogen receptors. It has beenshown to improve cognitive impairment causedby diabetes mellitus, which suggests that itmight improve cognitive function in patientswith Alzheimer’s disease. Using APP/PSO trans-genic mice as a model for Alzheimer’s disease,investigators intraperitoneally injected the ani-mals with three different doses of calycosin (10,

20, and 40 mg/kg) [125]. In these mice, caly-cosin mitigated OS and activated the proteinkinase C pathway, reducing the inflammatoryresponse in the hippocampus and improvingcognition.

Therapies Targeting Metabolic Hor-mones Age- and lifestyle-related changes inmetabolism are often a result of increases in OSand inflammation, factors facilitating metabolicdysfunction and cognitive decline [126, 127].Changes in insulin, leptin, and amylin resultingfrom poor diet, aging, or metabolic disease canresult in cognitive decline and contribute to thedevelopment of AD [129–131]. Therefore, ther-apies that aim to return these metabolic systemsto a homeostatic state hold the highest thera-peutic potential for the subsequent treatment ofboth metabolic and cognitive diseases [132].

Rosiglitazone Advanced glycation end prod-ucts (AGEs) are potentially harmful compoundsthat accumulate with advancing age. AGEs canbe produced endogenously or assumed with thediet. AGEs are associated with the pathogenesisof neuronal deficits observed in diabetes.Hyperglycemia accelerates and increases theproduction of AGEs, and high levels of AGEmay be associated with premature aging andany number of diseases, including Alzheimer’sdisease, heart disease, and kidney failure.Rosiglitazone is an antidiabetic drug that can bedescribed as a peroxisome proliferator-activatedreceptor gamma (PPARc). Rosiglitazone belongsto a family of ligand-activate nuclear receptorsand its ligands are associated with a variety ofphysiological, pathological, and inflammatorypathways. AGEs are suspected of playing a rolein the neuronal impairment that is associatedwith diabetes mellitus; rosiglitazone appearseffective against AGE-mediated neurotoxicityon human neural stem cells. Rosiglitazone canactivate PPARc-dependent signaling, which hasbeen shown to confer neuroprotection in AGE-treated human neural stem cells. This impliesthat there may be a role for PPARc ligands in thetreatment of neurodegenerative disorders [133].

Silver Nanoparticles Silver nanoparticles(AgNPs) are actually predominantly silver oxide

130 Adv Ther (2020) 37:113–139

in the form of particles ranging in size fromabout 1 to 100 nm. These silver nanoparticleshave antibacterial properties and are used in avariety of consumer and medical products.Neural cells can uptake nanoparticles in the sizerange of 3–5 nm. The potential effects of silvernanoparticles on gene expression related toinflammation and neurodegeneration wasstudied in murine brain ALT astrocytes, micro-glial BV2 cells, and neuron N2a cells [134]. Afterbeing exposed to silver nanoparticles at doses of5, 10, and 12.5 lg/ml, the neural cells showed amarked increase in secretion of IL-1b andinduced gene expression of C-X-C motifchemokine 13 (CXCL13), macrophage receptorwith collagenous structure, and glutathionesynthetase [134]. This study also found thatafter treatment with silver nanoparticles, amy-loid-b plaques (a pathological feature of Alz-heimer’s disease) were deposited in neural cells.Following exposure to silver nanoparticles, geneexpression of the amyloid precursor protein wasinduced. By the same token, protein levels,neprilysin, and low-density lipoprotein receptorwere decreased in neural cells. The results fromthis study suggest that silver nanoparticles maybe able to alter gene and protein expressionrelated to amyloid-b deposition and couldpotentially induce the neurodegeneration ofAlzheimer’s disease [134]. Further study iswarranted.

Immunomodulatory Agents The role ofimmunomodulation is changing medicine andit has been suggested that immunomodulatorypharmacological agents might be an earlyintervention for patients with clinical signs ofParkinson’s disease or even as a prophylactictreatment in patients at elevated risk for devel-oping Parkinson’s disease [18]. Murine studieshave shown that various immunomodulatorscould reduce motor deficits and alleviatedopaminergic neurotoxic effects. Some, but notall, immunomodulators have an anti-inflam-matory action, decrease OS, and reduce theproducts of lipid peroxidation. They may alsodecrease the activities of microglia and astro-cytes and decrease the infiltration of T cells intothe substantia nigra. When animals with brainlesions were pretreated with fingolimod,

tanshinone I, dimethyl fumarate, thalidomide,or cocaine- and amphetamine-regulated tran-script peptide, this prophylaxis amelioratedmotor deficits and nigral dopaminergic neuro-toxicity [18].

More specifically:Fingolimod or FTY720 reduced functional

motor deficits and reduced the loss of TH?

neurons in the substantia nigra. It also attenu-ated the decrease of striatal dopamine and itsmetabolite levels [91].

Tanshinone I ameliorated the dopaminergicneurotoxicity in the substantia nigra and stria-tum and protected the striatum from OS byincreasing glutathione levels [135].

Tanshinone IIA reduced apomorphine-in-duced contralateral rotations and alleviated theloss of TH? neurons in the substantia nigra andstriatum. It also attenuated the reduction ofdopamine and its metabolites [136, 137].

Dimethyl fumarate reduced motor deficitswhile protecting dopaminergic neurons in thesubstantia nigra against a-syn toxicity. It like-wise decreased microgliosis and astrogliosis[138, 139].

Lenalidomide was shown to improve motordeficits and improve dopamine fiber loss in thestriatum, together with a decrease inmicrogliosis in the striatum and hippocampus.It also reduced the expression of certain proin-flammatory cytokines, namely TNFa, IL-6, IL-1b, and IFN-c and increased the expression ofthe anti-inflammatory cytokines IL-10 and IL-13 [140].

Thalidomide, like lenalidomide, restoreddopamine fiber loss in the striatum, andreduced the expression of TNFa, IL-6, IL-1b, andIFN-c [140].

Ginsenoside Rg1 decreased dopaminergicneuronal loss in the substantia nigra. The reg-ulatory T cells in the blood were increased andthe serum levels of TNFa, IFN-c, IL-1b, and IL-6were reduced. Microgliosis was inhibited andinfiltration of CD3? T cells into the substantianigra was also reduced [141].

CNI-1493 attenuated dopaminergic cell lossin the substantia nigra, alleviated striatal loss ofdopamine content, and reduced microgliosis inthe substantia nigra [142].

Adv Ther (2020) 37:113–139 131

Pycnogenol improved behavioral motor defi-cits [143].

Cyclosporin enhanced motor and cognitivefunction, decreased the striatal level of humana-syn and partially restored the level of THprotein, exhibited an anti-inflammatory effectby lowering the expression level of NFATc3 andalleviated mitochondrial stress in the midbrain[144].

Acetoside reduced parkinsonism symptoms[145].

SA00025 was partially neuroprotective ofdopaminergic neurons and fibers. It alsobrought about changes in microglial morphol-ogy, indicative of a resting state and a decreasein reactive microglia. The astrocyte GFAPstaining intensity in the substantia nigra and IL-6 levels were also decreased [146].

C5aR antagonist DF3016A. Complement(C) membrane receptors and proteins are con-stitutively expressed by the CNS. Part of it is theC5a, which represents the terminal effector ofthe C cascade. This part is mostly involved inpain and neuroinflammation, with severalclinical consequences [147]. Recently, a novelselective C5aR antagonist (DF3016A) has shownthe capacity to protect the neurons against aneuroinflammation-related process, in an ani-mal model [148]. This could represent a newtherapeutic approach to controlling CNS neu-roinflammatory conditions and neurodegener-ation due to OS.

Other Approaches

Intermittent FastingIntermittent fasting is a popular practice asso-ciated with weight loss that requires the dieterto eat only for a set number of hours of the day,e.g., he or she may eat only for eight consecu-tive hours per day and must refrain from eatingfor 16 h daily. Intermittent fasting may haveother health benefits in addition to weight loss,in that it appears to induce adaptive responsesin the brain that suppress inflammation. Inorder to study whether the benefits of inter-mittent fasting might be lessened with age, astudy found that intermittent fasting canreduce the risk for brain functional deficits and

neurodegenerative disorders associated withinflammatory response, independent of age(Table 3) [149].

CONCLUSIONS

The lack of established treatments for the pre-vention and treatment of neurodegenerativediseases requires greater study into the under-lying causes of neurodegeneration and, morespecifically, the role of OS and neuroinflam-matory responses. In this review, we presentedboth natural pharmaceutical approaches as wellas treatments with extracted or recombinantproducts and artificial agents. Progress is beingmade as many new substances and treatmentsshow considerable promise, but greater andmore thorough clinical study is urgently neededparticularly as populations age. We suggestmore in vivo experiments and we would cau-tiously suggest that combination approachesmay be allow more effective treatment.

ACKNOWLEDGEMENTS

The authors are very grateful to Mariella Fuscofor her scientific feedback and Luca Di Giacomofor his continuous technical assistance with thegraphic design.

Funding. This paper has been possiblethanks to the grant provided by the Paolo Pro-cacci Foundation, Via Tacito 7, 00,193 Roma,Italy. It was also partially funded by the grantreceived by ‘‘Fondazione Internazionale Salva-tore Maugeri’’, Research Project ‘‘Modello diUnita di Terapia del Dolore e di Cure Palliative,Integrate con Associazioni di Volontariato’’. NoRapid Service Fee was received by the journal forthe publication of this article.

Table 3 Other approaches

Year of investigation Reference

Intermittent fasting 2015 [149]

132 Adv Ther (2020) 37:113–139

Medical Writing Assistance. The authorsacknowledge medical editing services by Jo AnnLeQuang of LeQ Medical whose activity hasbeen supported by Paolo Procacci Foundationand ‘‘Fondazione Internazionale SalvatoreMaugeri’’ funds.

Authorship. All named authors meet theInternational Committee of Medical JournalEditors (ICMJE) criteria for authorship for thisarticle, take responsibility for the integrity ofthe work as a whole, and have given theirapproval for this version to be published.

Author Contributions. M Rekatsina carriedout most of the research and drafted the initialmanuscript. All the other authors have con-tributed to review and ameliorate the quality ofthe paper. All the authors have reviewed andapproved the final draft of the manuscript.

Disclosures. Martina Rekatsina, Alba Piroli,Panagiotis Zis have nothing to disclose. Anto-nella Paladini is a member of the journal’s Edi-torial Board. Joseph V. Pergolizzi is a member ofthe journal’s Editorial Board. Giustino Varrassiis a member of the journal’s Editorial Board.

Compliance with Ethics Guidelines. Thisarticle is based on previously conducted studiesand does not contain any studies with humanparticipants or animals performed by theauthors.

Open Access. This article is distributedunder the terms of the Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense (http://creativecommons.org/licenses/by-nc/4.0/), which permits any non-commercial use, distribution, and reproductionin any medium, provided you give appropriatecredit to the original author(s) and the source,provide a link to the Creative Commons license,and indicate if changes were made.

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