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
β
1

2

carteolol X

ISA; 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 X

MSA; prototypical beta-
blocker
sotalol

X

several other significant
mechanisms
timolol X X X X

primarily used for glaucoma
β
1
-selective

acebutolol X X X

ISA
atenolol X X X X

betaxolol X X X

MSA
bisoprolol X X X

esmolol X

X

ultra 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