ISCHEMIC STROKE

Stroke occurs due to reduced perfusion to a brain region, resulting in death or

permanent neurological deficits including hemiplegia, numbness, loss of sensory

and vibratory sensation, balance problems, ptosis, decreased reflexes, visual field

defects, apraxia, and aphasia due to neuronal damage of pathways of the central

nervous system (CNS), including the brain stem or cerebellum.

Ischemic stroke accounts for 85% of all strokes [1]. Cerebral ischemia in patients

may be produced by thrombosis or embolism due to atherosclerosis from large or

small vessels, embolism of cardiac origin, systemic hypoperfusion, occlusion of

small blood vessels, venous thrombosis, or undetermined causes leading to

reduced perfusion (No. 5 in Trial of Org 10172 in Acute Stroke Treatment, or

TOAST, classification). Based on the location of the symptoms, ischemic stroke is

classified as total anterior circulation infarct, partial anterior circulation infarct,

lacunar infarct, or posterior circulation infarct. Computed Tomography scan and

magnetic resonance imaging , has been used to detect cerebral ischemia.

PATHOGENESIS AND NEUROPROTECTION

Reduced perfusion of the brain initiates the ischemic cascade, leading to

development of a reversible ischemic penumbra surrounding an irreversible area

of infarction (Fig. 1). At a microscopic level, the reduced blood flow results in

failure of the mitochondrial electron transport chain and oxidative

phosphorylation, producing ATP depletion and failure of the Na-K-ATPase pump

and leading to increased neuronal sodium and calcium influx. The resulting

anoxic depolarization leads to release of excitatory neurotransmitters such as

glutamate, causing neuronal toxicity [2]. Damage is also caused by reactive

oxygen species (ROS), free radicals, arachidonic acid, nitric oxide, and cytokines

generated in this process, leading to inflammation and further microcirculatory

compromise. Activation of the immune system and apoptosis are also responsible

for the pathogenesis. These pathological events do not necessarily occur

sequentially and may instead follow a variable spatial and temporal course [2]. In

addition, they are interlinked, triggering each other in a positive feedback loop

that culminates in neuronal destruction [3].

Necrotic cell death is responsible for core infarction where hypoxia is most

severe, leading to severe energy depletion and cellular collapse. In the penumbra,

which is not yet irreversibly damaged and is potentially salvageable, the hypoxia

is less severe due to collateral blood flow, and cells undergo apoptotic cascade [4].

Hence, neuronal protection in the ischemic penumbra and prevention of

neurological deficits is the main goal of therapy with neuroprotective agents

targeting the downstream events or mediators of the cascade that causes ischemic

stroke [5]. Inhibition of the molecular mechanisms underlying the ischemic

cascade has been recognized as an important target for the treatment of ischemic

stroke.

Beta blocker

Carvedilol, a widely used antihypertensive agent, has also been shown to inhibit

lipid peroxidation and to scavenge free radicals in experimental animals. Free

radicals lead to excitotoxicity and are neurotoxic to the ischemic brain areas either

following or enhancing glutamate release [32]. Carvedilol has been shown to

inhibit the release of human neutrophil-generated superoxide and superoxide

radicals [33]. In vitro, primary cultures of rat cerebellar neurons with free radical

generating system were used. Carvedilol inhibits the DHF-Fe+3/ADP free radical-

generating system and Fe+2/vitamin C-catalyzed lipid peroxidation. In vivo, CA1

hippocampal neurons were protected against oxygen free radicals, suggesting

carvedilol's potential as a therapeutic agent in ischemic stroke [9].

The main objective of this trial is to assess the efficacy and safety of propranolol

in middle cerebral artery stroke patients. The primary hypothesis is as follows:

Early administration of propranolol reduces the frequency of cardiovascular

and/or neurological complications including vascular death in the first 30 days

after acute ischemic stroke. Secondary hypotheses are as follows: Early

administration of propranolol improves neurological and functional outcome of

patients with acute ischemic stroke. Early administration of propranolol reduces

post-stroke immunodepression and therefore lowers the rate of pneumonia after

acute ischemic stroke, without increasing the frequency of auto-aggressive, CNS

antigen-specific T cells. Early administration of propranolol influences alterations

in cardiologic, electrophysiologic phenomenons as a reaction to autonomic

dysregulation after acute ischemic stroke. Early administration of Propranolol

reduces growth of infarct as determined by MRI examinations in the first 6 days.

The antioxidant activity of carvedilol clearly emanates from the carbazole moiety

which is unique to carvedilol. The antioxidant activity resides equally in both of

the enantiomers of carvedilol, as well as in some of its metabolites which are

devoid of either the alpha 1-adrenoceptor blocking activity or beta-adrenoceptor

blocking activity. This novel antioxidant property of carvedilol may account, at

least in part, for its cerebroprotection. The data discussed in this article suggest

that carvedilol may not only provide effective and safe antihypertensive therapy

and therefore reduce a major risk factor for stroke, but will also be better able to

provide additional benefits to patients by protecting against oxygen free radicals

generated during cerebral ischemia and stroke.

Inflammation

Following ischemia – both sublethal and severe – evidence of inflammation has

been observed. In particular, increased expression levels and release of the soluble

form of tumor necrosis factor (TNF-α) was detected following ischemic

preconditioning (Romera et al., 2004). Arguing for a role beyond an

epiphenomenon, ischemic tolerance has been found to be induced by the

application of TNF-α) itself (Nawashiro et al., 1997), and application of a TNF-α)

antibody or antisense during ischemic preconditioning blocked neuroprotection

against subsequent severe ischemia (Romera et al., 2004). Additionally, increased

activity of the upstream convertase of TNF, TACE, was demonstrated following

ischemic preconditioning, leading to increased formation of active TNF-α) The

consequences of TNF-α) induction are poorly understood; under severe ischemic

conditions, both detrimental and protective roles have been argued (Barone and

Feuerstein, 1999). Application of TNF-α) antisense or a TNF-α) inactivating

antibody during in vitro ischemic preconditioning prevented both the decreased

glutamate release and the increased expression of the neuronal excitatory amino

acid transporter 3 (EAAT3) normally observed following preconditioning

(Romera et al., 2004), although the physiological relevance of glutamate levels

during tolerance paradigms has been widely debated. Although TNF-α) may be

involved in ischemic tolerance, the mechanism remains unclear.

ANTI-INFLAMMATORY AGENTS

Inflammation is important contributor to neurological deterioration in cerebral

ischemic stroke [70]. Because inflammation occurs over a long period of time

after the onset of stroke, anti-inflammatory agents have a relatively wide

therapeutic window.

Beta blocker

Beta-blockers antagonise the effects of sympathetic nerve stimulation or

circulating catecholamines at beta-adrenoceptors which are widely distributed

throughout body systems. Beta1-receptors are predominant in the heart (and

kidney) while beta2-receptors are predominant in other organs such as the lung,

peripheral blood vessels and skeletal muscle. Beta-blockers antagonise the effects

of sympathetic nerve stimulation or circulating catecholamines at beta-

adrenoceptors which are widely distributed throughout body systems. Beta1-

receptors are predominant in the heart (and kidney) while beta2-receptors are

predominant in other organs such as the lung, peripheral blood vessels and

skeletal muscle.

Kidney: Blockade of beta1-receptors inhibit the release of renin from juxta-

glomerular cells and thereby reduce the activity of the renin-angiotensin-

aldosterone system.

Heart: Blockade of beta1-receptors in the sino-atrial node reduces heart rate

(negative chronotropic effect) and blockade of beta1-receptors in the myocardium

decrease cardiac contractility (negative inotropic effect).

Central and peripheral nervous system: Blockade of beta-receptors in the

brainstem and of prejunctional beta-receptors in the periphery inhibits the release

of neurotransmitters and decreases sympathetic nervous system activity.

The mode of action in lowering blood pressure remains controversial.

Conventionally, the antihypertensive action of beta-blockers is attributed to

cardiac effects (decreased heart rate and Pharmacokinetics Beta-blockers vary in

the degree of elimination by the kidney or the liver, usually with extensive first-

pass metabolism. Lipid-soluble beta-blockers, e.g. labetalol, metoprolol, pindolol

and propranolol, typically depend upon hepatic metabolism for clearance,

whereas water soluble beta-blockers e.g. atenolol are cleared by the kidney.

Drugs eliminated by the liver tend to exhibit wide inter-individual variability in

bioavailability. The half-life of most beta-blockers is relatively short; those

eliminated by the kidney tend to have longer half-life.

Clinical Uses

Class/Drug HTN Angina Arrhy MI CHF Comments

Non-selective

β1/β2

carteolol XISA; long acting; also used

for glaucoma

carvedilol X X α-blocking activity

labetalol X X ISA; α-blocking activity

nadolol X X X X long acting

penbutolol X X ISA

pindolol X X ISA; MSA

propranolol X X X XMSA; prototypical beta-

blocker

sotalol Xseveral other significant

mechanisms

timolol X X X X primarily used for glaucoma

β1-selective

acebutolol X X X ISA

atenolol X X X X

betaxolol X X X MSA

bisoprolol X X X

esmolol X Xultra short acting; intra or

postoperative HTN

metoprolol X X X X X MSA

nebivolol X

relatively selective in most

patients; vasodilating (NO

release)

Abbreviations: HTN, hypertension; Arrhy, arrhythmias; MI, myocardial

infarction; CHF, congestive heart failure; ISA, intrinsic sympathomimetic

activity.

Beta-Blockers in Acute Ischemic Stroke

Karen L. Furie, MD reviewing Laowattana S and Oppenheimer

SM. Neurology 2007 Feb 13.

In this exploratory study, researchers examined potential benefits of beta-blockers

in acute ischemic stroke.

Acute stroke can increase sympathetic activity, a complication associated with

poor outcome. Beta-blockers inhibit the sympathetic response and have been

reported to reduce infarct volume in animal models. Researchers conducted this

case-control study to examine the effect of beta-blocker use on stroke severity.

They analyzed data collected on 111 subjects (average age, 62) within 14 days

(median, 3 days) after ischemic stroke onset; 22 subjects had been taking beta-

blockers and 89 had not. At study entry, the researchers used power spectral

analysis of heart rate variability (HRV) to estimate cardiac sympathovagal tone

and the Canadian Neurologic Scale to score stroke severity.

Of 22 variables assessed, only beta-blocker use was significantly associated with

stroke severity in univariate analyses. Beta-blockers remained an independent

predictor of stroke severity after controlling for age, sex, heart disease, aspirin and

statin use, and stroke subtype. Blood pressure was not included in the model.

Among 14 biomarker variables assessed to explore mechanisms of the beta-

blocker effect, erythrocyte sedimentation rate, thrombin level, and power spectral

analysis of HRV were significantly different in beta-blocker users and nonusers.

- See more at: http://www.jwatch.org/jn200706260000002/2007/06/26/beta-

blockers-acute-ischemic-stroke#sthash.RW6r8I8v.dpuf