Experimental Neurology 238 (2012) 265–272

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Experimental Neurology

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Review

Neuropeptide Y and its role in CNS disease and repair

M. Decressac a,⁎, R.A. Barker b

a Wallenberg Neuroscience Center, Department of Experimental Medical Sciences, Lund University, Lund, Swedenb Department of Clinical Neurosciences, Cambridge Centre for Brain Repair, University of Cambridge, Forvie Site, Robinson Way, Cambridge, UK

⁎ Corresponding author. Fax: +46 46 222 0559.E-mail address: Mickael.Decressac@med.lu.se (M. De

0014-4886/$ – see front matter © 2012 Elsevier Inc. Allhttp://dx.doi.org/10.1016/j.expneurol.2012.09.004

a b s t r a c t

a r t i c l e i n f o

Article history:Received 6 July 2012Revised 9 September 2012Accepted 20 September 2012Available online 27 September 2012

Keywords:Neuropeptide YNeurogenesisNeuroprotectionNeurodegenerative diseases

Neuropeptide Y (NPY) is widely expressed throughout the CNS and exerts a number of important physiolog-ical functions as well as playing a role in pathological conditions such as obesity, anxiety, epilepsy, chronicpain and neurodegenerative disorders. In this review, we highlight some of the recent advances in our under-standing of NPY biology and how this may help explain not only its role in health and disease, but also its pos-sible use therapeutically.

© 2012 Elsevier Inc. All rights reserved.

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 265NPY and neurogenesis in the adult brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

NPY and hippocampal neurogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266NPY and neurogenesis in the subventricular zone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 266

NPY in neurodegenerative and neurological diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269NPY in Alzheimer's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269NPY and Huntington's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269NPY and Parkinson's disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 269

Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 270

Introduction

It has been 30 years since neuropeptide Y (NPY) was isolated fromthe porcine brain and subsequently sequenced by Tatemoto et al. toreveal a 36 amino acid long peptide with tyrosine residues (Y)flanking its amino and carboxy terminals (Tatemoto, 1982; Tatemotoet al., 1982). Embryologically it starts to be expressed during earlybrain development and in the fully mature central nervous system(CNS) is found in many sites but especially the hypothalamus, hippo-campus, amygdala and nucleus accumbens (Adrian et al., 1983; Allenet al., 1983, 1986; Woodhams et al., 1985).

cressac).

rights reserved.

As with all neuropeptides, NPY is synthesized in neuronal cellbodies, especially GABAergic neurons, and transported by fast antero-grade transport to the synaptic nerve terminal where it can act as amodulator of neurotransmission both pre- and post-synaptically.Four G-protein coupled receptors, Y1, Y2, Y4, Y5 and Y6 receptors, me-diate thewide range of physiological effects of this peptide and each ofthem has a distinct expression pattern in the brain (Dumont et al.,1998;Michel et al., 1998; Naveilhan et al., 1998). At the ultrastructurallevel, while a post-synaptic localization has been reported for all re-ceptors, only Y2 is described as being pre-synaptic thereby mediatingauto-receptor regulation (Colmers et al., 1991; Stanic et al., 2011).

New tools, such as the development of specific NPY receptor ago-nists and antagonists and the generation of targeted receptor knock-outs has led to a resurgence of interest in the action of NPY inphysiological and pathological processes. While great progress has

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been made into defining the role of this peptide in the regulation offood intake, blood pressure, seizure activity, anxiety, bone formation,pain, depression and drug addiction, new functions for it in the path-ogenesis of neurodegenerative disorders have only recently started tobe investigated (Chee and Colmers, 2008; Hokfelt et al., 2008; Lin etal., 2004; Pedrazzini et al., 2003). In particular there is now a growingbody of literature on its role in neurogenesis and neuroprotection(Xapelli et al., 2006). The present review summarizes these novelfindings on the role of NPY.

NPY and neurogenesis in the adult brain

Neurogenesis constitutively occurs in two restricted regions ofthe adult brain: the dentate gyrus (DG) of the hippocampus and thesubventricular zone (SVZ) and during the last decade, several studieshave identified NPY as an important regulator of this.

NPY and hippocampal neurogenesisThe existence of neural stem cells in the hippocampus has now

been shown in most mammalian species and is seen throughout life,although decreases with age. Notably, the continuous renewal and in-corporation of neurons in the circuitry of the adult hippocampus isthought to contribute fundamentally to certain learning and memoryprocesses (for review Deng et al., 2010). Neural stem cells locatedwithin the subgranular zone give rise to transient amplifying cellsthat in turn differentiate into neuronal progenitors and from thereto immature neurons which migrate through the granule cell layerbecoming polarized as they mature. They send axonal projectionsalong the mossy fibre pathways to the CA3 subfield and also extenddendrites in the opposite direction toward the molecular layer. Ap-proximately three weeks after birth, these new mature neurons be-come fully integrated into the hippocampal circuitry with establishedafferent and efferent connections within the local neuronal network(for review Suh et al., 2009).

The first piece of evidence for a role for NPY in this process camefrom the observation that NPY and its receptors, especially Y1, Y2and Y5, are heavily expressed both in the developing and adult hippo-campal regions (Allen et al., 1983; Naveilhan et al., 1998; Woodhamset al., 1985). In particular within the DG, NPY is stored in GABAergicinterneurons located in the hilus, which send long processes through-out the granule cell layer in close proximity to the DG neural precursorcells (Sperk et al., 2007). Since a tonic GABAergic input is known toplay an important role in the kinetics of the proliferation and matura-tion of DG progenitors, it seemed logical to assume that the co-releaseof NPY could have a similar function.

Howell et al. (2003) were the first to provide functional evidencefor such an effect of NPY on DG neural precursor cell proliferation.Using primary hippocampal cultures from early post-natal and adultwild type and Y1 receptor knockout mice, they demonstrated thatNPY exerts a proliferative action on both nestin- and β-tubulin-positive precursors. This effect is specifically mediated via the Y1 re-ceptor that is expressed by these cells, and involves an ERK1/2 signal-ling pathway. Notably, Y1 receptor knockout mice exhibit reducedproliferation of both precursor cells and the generation of immaturedoublecortin-positive neuroblasts in the DG compared to wild-typemice. Furthermore, NPY treatment not only promoted the differ-entiation of newly generated cells toward a neuronal fate (Howellet al., 2003, 2005, 2007), but directly stimulated the proliferation ofhippocampal progenitors. Furthermore it has now also been shownthat NPY potentiates the pro-neurogenic effect of fibroblast growthfactor-2 on these progenitors, by increasing the expression of its re-ceptor FGFR1 (Rodrigo et al., 2010).

Using transgenic mice and pharmacological approaches, our groupfurther confirmed this property in vivo. ICV delivery of NPY in wild-type animals stimulated, through the Y1 receptor, the proliferationof DG precursors and promoted their differentiation into mature

granular neurons (Decressac et al., 2011b) (Figs. 1A–B). In this studywe did not look at hippocampal dependent behaviors so it is not pos-sible to say how these NPY-induced changes in neurogenesis affect thecognitive functions of the hippocampus, if at all.

Animal models of brain pathologies where adult neurogenesis is al-tered have also provided interesting information about a role for NPY inthis process. In the transgenic R6/2 mouse model of Huntington's dis-ease there is an impairment of hippocampal neurogenesis (Phillips etal., 2005) andwe found in parallel a significant reduction in the numberof NPY-immunoreactive neurons in the DG, although infusion of NPY inthis model did not rescue this deficit (Decressac et al., 2010a). This sug-gests that the loss of this population of NPY cells in this model of HD isnot critical in regulating neurogenesis. In line with this is the findingthat in Alzheimer's disease the NPY neurons are also severely affectedby the neurodegenerative disease process (Chan-Palay et al., 1986),but in this case neurogenesis is increased in the DG (Jin et al., 2004).

While the exact role of NPY in neurogenesis and neurodegenerationremains somewhat obscure, its role in epilepsy seems clearer. Firstly itsanti-epileptic action through the inhibition of glutamate release is wellknown (Colmers et al., 1988, 1991; Sorensen et al., 2008) and in addi-tion there is an up-regulation of NPY and NPY receptor expression inthe DG after seizures and this may be important in seizure-inducedneurogenesis (Furtinger et al., 2001, 2002; Kokaia, 2011). In supportof this role for NPY in epilepsy, studies have shown that mice lackingNPY or the Y1 receptor have a reduced basal and seizure-induced prolif-eration in the DG (Howell et al., 2007; Laskowski et al., 2007). OverallthereforeNPY seems to be intimately associatedwith diseases that affectthe hippocampus and this includes it having a possible role inmodulat-ing neurogenesis in some pathological conditions.

NPY and neurogenesis in the subventricular zoneIn addition to the DG, the generation of new neurons in adulthood

is also seen in the subventricular zone (SVZ). The SVZ lies immediatelybeneath the lateral wall of the lateral ventricles, where proliferation ofresident neural precursors is influenced by several factors present inthe cerebrospinal fluid (CSF), adjacent ependymal cells, and innerva-tion from striatal cells or more distally from nigral dopaminergicneurons (O'Keeffe et al., 2009; Suh et al., 2009). SVZ stem cells giverise to transient amplifying cells that subsequently differentiate intoimmature neurons that migrate in chains, along the rostral migratorystream (RMS), to the olfactory bulb (OB) where they differentiate intogranular neurons or periglomerular neurons, establish synaptic con-nections and become electrophysiologically active (for review seeSuh et al., 2009). Since olfaction is essential in rodents, replacementof OB neurons from the SVZ precursors is a critical and continuous pro-cess and is thought to be important in certain forms of olfactory mem-ory. Its role in humans is less clear-cut (Sanai et al., 2011).

NPY, like several growth factors and neurotransmitters, is nowknown to play a role in SVZ neurogenesis both during developmentand adult life. At embryonic days 13 and 14, a period correspondingto the peak of cellular proliferation in the rodent SVZ, high levels ofthis peptide are found in this region (Woodhams et al., 1985) althoughno direct association has been demonstrated so far between these twoevents.

In the adult brain while NPY-containing GABAergic neurons arescattered throughout the adjacent striatum, the density of theNPY-positive fibres increases markedly around the SVZ (Figs. 1C–D).Moreover, NPY-expressing cells, which also display markers of neuralprogenitors such as Sox2- and Nestin, lie in close proximity to theproliferating doublecortin-positive neuroblasts (Thiriet et al., 2011)(Fig. 1D). All of which suggests a possible role for NPY in regulatingSVZ neurogenesis, a process that may also be dependent on the levelsof NPY present in the CSF (Maeda et al., 1994).

Although the expression of NPY in the striatal/SVZ region has beenknown for years, its direct involvement in the regulation of SVZ pro-genitor cell proliferation has only emerged over the last few years.

Fig. 1. Pro-neurogenic effect of NPY in the adult rodent brain. A–B: BrdU immunostaining illustrating the proliferative effects of NPY on hippocampal progenitors. MoreBrdU-positive cells are observed in the DG 48 h after ICV injection of NPY compared to saline injection. C: NPY-expressing cells and a dense NPY innervation are observed in theadult SVZ. D: NPY-positive fibres (green) are in close contact to SVZ doublecortin (DCX)-positive neuroblasts and stimulate their proliferation. E–F: BrdU immunohistochemistryshowing the proliferative effect of NPY on SVZ neurogenesis. The number of BrdU-positive proliferating cells is increased 48 h after ICV injection of NPY (F) compared to salineinjection (E). E–F: 3 weeks after a single ICV injection of NPY (H), a marked proliferation of DCX-positive cells (red) is observed in the SVZ compared to saline treatment(G) (blue: ToPro-3; green: GFAP).

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Hansel et al. (2001) first reported the neuroproliferative effect of NPYin the olfactory epithelium and demonstrated that it promoted theproliferation of postnatal neuronal precursor cells without affectingcell death, while having no effect on gliogenesis. This effect was me-diated through the Y1 receptor and the downstream activation ofthe protein kinase C-dependant ERK1/2 pathway. In addition, micewith targeted deletion of NPY display a significant reduction in thenumber of olfactory neurons, and recently it has been shown thatATP initiates neuronal proliferation in the olfactory epithelium viaNPY up-regulation, release, and Y1 receptor activation (Jia and Hegg,2010). This data supports the hypothesis that NPY is important in

the maintenance of olfactory epithelium under physiological condi-tions as well as after injury (Jia and Hegg, 2011).

More recently, using SVZ cell cultures, Agasse et al. (2008) showedthat NPY stimulates SVZ precursor cell proliferation and that thispro-neurogenic effect was mediated by activation of the Y1 receptor.Moreover, NPY had a dual action since it promoted both neurogenesisthrough an ERK1/2 signalling pathway and axonogenesis through theactivation of a JNK cascade. This effect was further investigated and itwas shown that endogenous NPY produced by SVZ cells may act inan autocrine/paracrine manner to fine tune neurogenesis. In particu-lar it appeared to exert a chemokinetic and mitogenic action on SVZ

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progenitor cells while not affecting the self-renewal of SVZ stem cells(Thiriet et al., 2011).

In vivo, the pro-neurogenic effects of NPY on SVZ progenitors wasinitially shown using mice lacking either the Y1 or Y2 receptor (Stanicet al., 2008). Notably, these transgenic mice had fewer Ki-67-positiveproliferative cells and doublecortin-positive neuroblasts in the SVZand RMS compared to wild-type animals. They also exhibited lesscalbindin- (a marker of interneurons in the glomerular layer of theOB), calretinin- (a widely distributed neuronal marker in the OB),and TH-positive interneurons in the OB compared to wild-type ani-mals. Subsequently, it was shown that ICV injection of exogenousNPY had a robust proliferative effect on SVZ neuroblasts (Decressacet al., 2009) (Figs. 1E–H). Using pharmacological approaches andtransgenic mice knocked out for Y1 or Y2 receptor, we confirmed

Fig. 2. The possible neuroprotective effects of NPY in the diseased striatum. A schematic figbrain and their implications for pathological conditions. In the striatum, NPY is expresseglutamatergic and nigral dopaminergic neurons, and establish connections with a varietyneuroprotective for striatal neurons in this pathological condition. In PD, NPY may also exertof this peptide on the inhibition of glutamate release, it could reduce glutamate excitotoxiccell death may also be counteracted by its action on suppressing inflammatory processespro-neurogenic effect on SVZ neural stem cells and enhances the migration of newbornNPY could promote the self-repair capacity of the adult brain. SVZ: subventricular zone; DA

that this effect was due to the specific activation of the Y1 receptoron doublecortin-positive neuronal precursors in the SVZ. We alsoshowed that, upon NPY stimulation, the new neurons generated outof the SVZ migrate not only the OB, via the RMS, but also towardthe striatum where they preferentially differentiate into DARPP-32-positive GABAergic neurons (Fig. 2). However, it remains unknownwhether these striatal-like neurons can integrate within the host net-work, establish synaptic connections and exert any functional effects.Therefore, in contrast to its role in the DG, NPY is clearly implicated inSVZ neurogenesis by acting in an autocrine/paracrine fashion with apro-neurogenic effect on neural cells both in vitro and in vivo aswell as stimulating the migration of newborn neuroblasts.

This pro-neurogenic function has been further explored in thecontext of pathologies affecting the striatal/SVZ regions such as in

ure illustrating the hypothetical actions of NPY on neuronal and glial cells in the adultd by medium-sized aspiny GABAergic neurons that receive inputs from both corticalof neighbouring cells. Since NPY-expressing neurons are spared in HD, NPY may bea neuroprotective effect on midbrain dopamine neurons. Considering the potent effectity that may be contributing to some of the pathology in PD and HD. Non-autonomousresulting from the activation of glial cells, which occur in both disorders. NPY has aneuroblasts toward the striatum. By recruiting the endogenous pool of progenitors,: dopamine.

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Huntington's disease (see below) as well as other conditions suchas brain trauma, inflammation and stroke; disorders which are allknown to trigger endogenous repair mechanisms through the recruit-ment of SVZ progenitors (Fig. 2).

NPY in neurodegenerative and neurological diseases

While clinical manifestations such as motor or cognitive deficitsassociated with neurodegenerative diseases usually reflect wide-spread neuronal dysfunction and death in the CNS, it is now recog-nized that the pathological processes leading to this cellular lossinvolve both cell-autonomous and non cell-autonomous mechanisms.Although many of these conditions have unknown aetiologies, it isclear that a cascade of pathological processes including inflammation,epigenetic and transcriptional deficits, oxidative stress, protein aggre-gation or genetic mutations may synergistically contribute to thedevelopment of these conditions (for review see Glass et al., 2010;Lee et al., 2011; Sananbenesi and Fischer, 2009).

In addition in several neurodegenerative and neurological disor-ders, it is postulated that the loss of neuronsmay, at least in part, relateto excitotoxicity caused by excessive levels of extracellular glutamate(Fig. 2). Therefore molecules capable of buffering this amino acid orinhibiting its release, such as NPY, could have neuroprotective actions.To date, this property of NPY has beenmostly studied in the context ofepilepsy. Extensive work carried out in rodent models of epilepsy hasrevealed a pro-epileptic effect for the Y1 receptor, while both Y2 andY5 receptors, when activated by NPY, have anti-epileptic actions con-sequent upon their inhibition of glutamate release (Noe et al., 2008;Woldbye et al., 2010). In addition, NPY knockout mice more frequent-ly develop spontaneous seizures and are more sensitive to convulsiveagents (Baraban et al., 1997; Erickson et al., 1996). These observationssuggest that NPY, or more specifically Y2/Y5 receptor specific agonistsmay be promising molecules for the treatment of epilepsy (Riban etal., 2009). In contrast to this well-characterized effect of NPY, onlyfew studies have explored the potential of this peptide in other CNSdisorders including Alzheimer's disease (AD), Parkinson's disease(PD), Huntington's disease (HD) and amyotrophic lateral sclerosis(ALS).

PD and HD are neurodegenerative diseases affecting a range ofneuronal populations including selective ones within the basalganglia. After AD, PD is themost prevalent neurodegenerative disorder,while HD is an order of magnitude less common. Both PD and HD sharesome common features such as prominent motor signs, dysfunction ofthe nigro-striato-cortical axis, and aggregation of disease-causing pro-teins (i.e. alpha-synuclein and huntingtin). In AD, neurodegenerationprimarily affects association cortices and perihippocampal areas, withdefects in protein handling (tau and A-beta peptide) resulting in theformation of the pathological hallmarks of this condition. Unfortunate-ly, no cure is currently available for any of these diseases and currenttreatments only provide a temporary symptomatic relief.

NPY in Alzheimer's diseaseAD is an age-related neurodegenerative disease that impairs cogni-

tive functions, primarily episodic memory, and is characterized patho-logically by the formation of amyloid plaques and tau neurofibrillarytangles. Profound morphological changes in the NPY-positive neuronswithin the brain are seen and this includes a reduction in their numberin the cortex and hippocampus at post-mortem (Beal et al., 1986c;Chan-Palay et al., 1985, 1986; Minthon et al., 1990). Martel et al. alsoreported a marked reduction in NPY binding sites in the temporalcortex and hippocampus of post-mortem AD brains as compared toage-matched controls. In transgenic mouse models of AD, it has beenshown that hippocampal and cortical NPY-expressing neurons arethe first neuronal populations to exhibit neuropathological featuressuggesting that they are one of most vulnerable to the disease process(Ramos et al., 2006; Rancillac et al., 2010;Wilcock et al., 2008). Despite

contradictory reports, it appears that plasma and CSF levels of NPY arereduced during the course of the disease compared to control patients.While this does not prove a role for this peptide in AD pathogenesis orphysiopathology, it does suggest that it could be an interesting bio-marker to monitor the progression of the disease and may be linkedto its evolution in some way (Edvinsson et al., 1993). However, howthe variations in CSF NPY correlate to NPY cell loss is unclear as is its re-lationship to the disease stage of the patient.

In an attempt to link NPY to disease pathogenesis, Rose et al.(2009) have recently demonstrated that the infusion of NPY frag-ments derived from neprilysin processing can have a neuroprotectiveeffect in the APP transgenic mouse model of AD and on primary cul-tures of human neurons. This finding was confirmed in another invitro study showing that NPY prevents cell loss due to the toxic effectof Aβ(25–35) in SH-SY5Y neuroblastoma cells and cortical neuronsthrough the stimulation of neurotrophin expression, i.e. nerve growthfactor and brain-derived neurotrophic factor (Croce et al., 2011, 2012).

NPY and Huntington's diseaseHuntington's disease (HD) is an inherited autosomal dominant

disorder that is defined clinically by abnormal movements, changesin mood and cognitive impairment. The genetic basis of this disorderis a CAG repeat expansion in the first exon of the huntingtin geneleading to an abnormally long polyglutamine repeat in the proteinpromoting its aggregation. Although the exact mechanisms underly-ing disease pathogenesis remains unclear, the pathological processleads over time to neuronal dysfunction and death especially in thestriatum (Imarisio et al., 2008). Interestingly, striatal somatostatin/NPY-co-expressing neurons are selectively spared and in fact in post-mortem human HD brain, the number of NPY-positive cells is increasedin the basal ganglia, including the putamen and caudate nucleus(Dawbarn et al., 1985). In addition, if the number of NPY-positive neu-rons is correlated against the pathological grade of disease in the stria-tum, then there is a threefold increase of NPY-immunoreactivity inmild and severe grade cases (Beal et al., 1986b, 1988; Mazurek et al.,1997). NPY striatal neurons are also shown to be spared in the R6/2transgenic mouse model of HD at a manifest stage (14 weeks old)(Decressac et al., unpublished data).

In line with the effect of NPY on SVZ neurogenesis discussed above,the SVZ of HD patients is enriched for NPY-positive cells consistentwith an increase in neurogenesis (Curtis et al., 2007). Furthermore,the degree of cell proliferation correlates with the pathological sever-ity and the number of CAG repeats in the htt gene (Curtis et al., 2003).In contrast in R6/2 transgenic mice, where striatal degeneration isvery limited, neurogenesis in the SVZ is probably not up-regulated, al-though the data on this is not clear-cut (Batista et al., 2006; Decressacet al., a, 2010b; Phillips et al., 2005). These findings all suggest thatvariations in NPY expression associated with HD pathology may pro-mote the generation of new cells from the SVZwhich could potentiallyreplenish those lost within the striatum to the disease process (Fig. 2).However, while ICV delivery of NPY in the R6/2 mice has been shownto extend lifespan, ameliorate motor performances and cerebral atro-phy, it does not appear to promote cell replacement despite promot-ing SVZ neurogenesis (Decressac et al., 2010a) (Fig. 2). In this caseNPY may be having a neuroprotective mechanism that targets moreprotein aggregation, or the astrocytic and microglial reaction (Fig. 2).Further work is needed to look at this specifically, but again highlightsthe potential role for NPY in HD.

NPY and Parkinson's diseaseParkinson's disease is classically characterized by the progressive

loss of dopamine neurons in the substantia nigra and the presenceof alpha-synuclein-containing inclusions, i.e. Lewy bodies, in the sur-viving neurons (although the disease clearly has pathology thatextends outside this system). Depletion in striatal dopamine causesthe development of some of the clinical features of PD including

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bradykinesia and rigidity and to date, no disease-modifying therapythat halts the disease process is available, and pharmacological andsurgical treatments only provide symptomatic relief.

Anatomical and functional studies have revealed that NPY interactswith the dopaminergic system (Fig. 2). Vuillet et al. (1989) examinedthe ultrastructural relationship between the nigro-striatal projectionsand NPY neurons in the rat striatum and observed direct synaptic con-tacts. This fits with the earlier observation that following dopaminedeafferentation of the striatum using 6-hydroxydopamine (6-OHDA)there was a marked increase in the number of NPY neurons in thestriatum and nucleus accumbens (Kerkerian et al., 1986; Salin et al.,1990). Using another toxin that is commonly employed to model PD,1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Obuchowicz et al. (2003)observed a similar increase in the number of NPY neurons in the stria-tum in mice. When treated with deprenyl (a monoamine oxidase-B in-hibitor) or after transplantation of ventral mesencephalic tissue, NPYimmunoreactivity in the striatumwas normalized in these lesioned an-imals (Moukhles et al., 1992; Obuchowicz et al., 2003).

While these studies show that the nigrostriatal dopaminergicpathway regulates striatal NPY neurons, for a role to be shown in PD,the converse needs to be demonstrated and pharmacological studieshave done just that. ICV injection of NPY induces a dose-dependent in-crease in the striatal dopamine release, monitored in freely movingrats by voltametry, as well as an alteration in the extracellular concen-trations of glutamate and GABA (Kerkerian-Le Goff et al., 1992). Thesefindings have been further confirmed by administrating NPY directlyinto the striatum or onto striatal organotypic slices, and showingthat it promotes the synthesis and release of dopamine through theY2 receptor, while the activation of the Y1 receptor had an oppositeeffect (Adewale et al., 2005, 2007; Beal et al., 1986a) (Fig. 2). All ofwhich fits with the fact that Y1 and Y2 receptor subtypes are highlyexpressed in the developing and adult striatum and have a role in do-paminergic neurotransmission (Kopp et al., 2002; Naveilhan et al.,1998). Using a functional autoradiographic method, Shaw et al. (2003)observed that both Y1 and Y2 receptors are also expressed by dopami-nergic neurons and that Y2 is more abundant in the striatum andsubstantia nigra than Y1 receptors (Fig. 2). However, the precise ultra-structural localization of these receptors on the pre-and post-synapticelements requires clarification.

In PD patients, changes in NPY expression have been reported. Inline with the observations made in the toxin models, post-mortemPD brains exhibit an increase in the number of NPY-expressing cells,especially in the caudate nucleus and putamen, compared to controls(Cannizzaro et al., 2003). Modifications of NPY expression in other re-gions such as the cortex and the hippocampus are more controversial(Beal et al., 1988). Similarly, measurement of NPY levels in the CSF ofPD patients has produced contradictory results (Martignoni et al.,1992; Yaksh et al., 1990).

These changes in NPY expression observed in patients and animalmodels of PD may:

(1) reflect an endogenous, but ineffective, neuroprotective re-sponse of the brain against the neurodegenerative process;

(2) contribute to the pathogenic process, or(3) be simply downstream and secondary to the loss of dopami-

nergic tone.

We recently tried to address this issue by testing the effect of NPYin cell culture and mouse models of PD. The use of pharmacologicalagonists and antagonists as well as transgenic mice revealed thatNPY protected dopaminergic neurons from 6-OHDA-induced toxicityin vitro and in vivo. This effect was mediated through the Y2 receptorsand involved ERK1/2 and Akt pathways, but did not influence theexpression of BDNF and glial cell line-derived neurotrophic factor(Decressac et al., 2011a) (Fig. 2).

A role for NPY in PD may not only relate to its neuroprotective ac-tion on the dopamine neurons, but also through an inhibitory effect

on glutamate release (Fig. 2). NPY striatal cells are targets for corticalglutamatergic neurons (Kerkerian et al., 1990b; Vuillet et al., 1989)and deafferentation of the striatum from its glutamatergic input resultsin a significant increase in the number of striatal NPY-expressing cells.Combined nigral and cortical lesions counteract the effects of eachother, and this may be mediated via the NPY system (Kerkerian et al.,1990a).

Interestingly if NPY can inhibit glutamate release in the striatum, itwould be interesting to see what effect this agent has on L-dopa-induced dyskinesias (LID), a troublesome side-effect observed in PDpatients given chronic L-DOPA therapy. This clinical complication isknown to be caused, at least in part, by excessive striatal glutamate re-lease and studies have demonstrated that administration of inhibitorsof the glutamate system (e.g. amantadine) or specific metabotropicreceptors, especially the mGluR5, have an effect in reducing LID(Rylander et al., 2010). Therefore, inhibiting the release of glutamatefrom the cortico-striatal projections using NPY could potentially im-pact on L-DOPA-induced dyskinesia.

Conclusions

While being highly expressed in the hypothalamus and intensive-ly studied for its role in feeding regulation, NPY is also present inmany other brain regions where it undoubtedly plays other impor-tant roles. In this respect there is emerging evidence that it plays arole in the regulation of neural stem cell proliferation in the two con-stitutive neurogenic niches of the adult brain. In addition, it acts as aneuromodulator and affects the release of several neurotransmitterssuch as dopamine and glutamate and by so doing may underliesome of the features and pathophysiological pathways of somechronic disorders of the CNS. Finally, NPY appears to have someneuroprotective actions in cell culture and in animal models of dis-ease although it remains to be determined which pathological mech-anisms NPY acts on in a significant way. In this respect, the effects onneurogenesis and glutamate release may be important, as might itsreported actions on suppressing inflammation and encouraging theproduction of neurotrophic factors (Ferreira et al., 2010; Ferreira etal., 2011; Ferreira et al., 2012) (Fig. 2).

While the field of NPY research benefits from the availability ofpowerful tools (e.g. transgenic mice, viral vectors, specific NPY recep-tors agonists and antagonists), little is known about the physiologicalactions of this peptide in many human brain regions in health anddisease.

In summary, NPY biology is emerging as an exciting and dynamicarea of research where key regulatory processes in the normal anddiseased brain are being revealed, and through which novel therapiesfor treating CNS diseases may emerge.

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