Neuroprotection for stroke

NEUROPROTECTIVE DRUGS IN STROKE: CURRENT STATUS

DR. SUMIT KAMBLESENIOR RESIDENTDEPT. OF NEUROLOGYGMC, KOTA

• Neuroprotection is specifically defined as the “protection of neurons” and is a strategy used to potentially protect the brain in a number of different cerebral conditions including Parkinson’s disease, traumatic brain injury and ischemic stroke.

• There are currently no approved treatments for the myriad of damaging pathological processes that persist in the brain long after the acute stage.

• Include processes of inflammation, excitotoxicity, oxidative stress, apoptosis, and edema resulting from disruption of the blood brain barrier.

• In hemorrhagic stroke, additional processes include physical damage from mass of accumulated blood itself, cytotoxicity of blood components, and vasospasm in subarachnoid hemorrhage

Pathogenesis and pathophysiology of ischemic stroke

• Deprivation of oxygen supply to the brain tissue leads to activation of the ischemic cascade with a series of molecular mechanisms.

• There is depletion of adenosine triphosphate and consequent high levels of lactate and unbuffered hydrogen ions.

• These hydrogen ions facilitate the generation of ferrous iron-mediated free radicals that result in astroglial injury.

• Failure of energy dependent mechanisms including ion pumps leads to deterioration of membrane ion gradients, opening of selective and unselective ion channels, and equilibration of most intracellular and extracellular ions .

• Thus potassium ions leave the cell, sodium, chlorine and calcium enter and many excitatory neurotransmitters (glutamate, aspartate) are released in potentially toxic concentrations.

• Raised intracellular calcium accelerates many potentially injurious processes.

• Calcium activates phospholipases which hydrolyse membrane-bound glycerophospholipids to free fatty acids and these in turn facilitate free radical peroxidation of other membrane bound lipids.

• Calcium similarly activates both proteases that lyse structural proteins as well as nitric oxide synthase that initiates free radical mechanism.

• Intracellular entry of calcium is made largely possible by the activation of two types of receptors: Voltage gated (L-type) and/or several N-methyl-D-aspartate (NMDA) and quisqualate (Q) post synaptic receptor/channel complexes by glutamate.

MECHANISMS OF ACTION

1. Prevention of Early Ischemic Injury 2. Prevention of Reperfusion Injury

1. Prevention of Early Ischemic Injury • Neuroprotective agents limits acute injury to neurons in

ischemic penumbra. • Neurons in the penumbra are less likely to suffer irreversible

injury at early time points than are neurons in the infarct core. • Many of these agents modulate neuronal receptors to reduce

release of excitatory neurotransmitters, which contribute to early neuronal injury.

2. Prevention of Reperfusion Injury

• Neuroprotective agents prevent potentially detrimental events associated with return of blood flow.

• Although return of blood flow to the brain is generally associated with improved outcome, reperfusion may contribute to additional brain injury.

•  Returning blood contains leukocytes that may occlude small vessels and release toxic products.

• Neuroprotective agents that work primarily during reperfusion may have a longer window of therapeutic effect than drugs that work earlier in the ischemic cascade.

Targets for Neuroprotection in Stroke

a. Inflammation.b. Oxidative Stress.c. Blood-Brain Barrier Disruption.d. Excitotoxicity.e. Apoptosis.f. Autophagy

• Many different neuroprotection approaches targeting different aspects of the ischemic cascade were tested previously in animal stroke models and clinical development programs.

• Despite many successful treatment experiments in animals regarding both infarct size reduction and improved functional outcome, no neuroprotective drug demonstrated unequivocal efficacy in clinical trials.

NEUROPROTECTIVE AGENTS FOR TREATMENT OF STROKE Prevention of Early Ischemic Injury

1. Free Radical Scavengers a. Edaravone

Exerts antioxidant effects by inhibiting hydroxyl radical-dependent and -independent lipid peroxidation

Also suppresses the increase in the levels of hydroxyl and superoxide anion radicals

Unlike other free radical scavengers, edaravone readily crosses the blood–brain barrier (BBB)

Japanese Guidelines for the management of stroke 2009 suggest edaravone for the treatment of acute ischemic stroke as a grade B recommendation. Currently only approved in Japan.

Administration of edaravone within 72 h of ischemic stroke onset significantly reduces infarct volume and provides sustained benefits over a 3-month follow-up period Recent study showed that administration of edaravone during tPA infusion could enhance recanalization in 40 patients with acute ischemic stroke

 Tirilazad Did not show benefit in an acute stroke trial.Drug also was investigated in subarachnoid hemorrhage and in traumatic brain injury

 NXY-059 Phase 3 trials Stroke-Acute Ischemic NXY Treatment (SAINT I), SAINT II

SUN N4057 or Piclozotan,

Serotonin agonist

 TS-011 Blocks the synthesis of 20-hydroxyeicosatetraenoic acid (20-HETE)

Lovastatin, Normobaric oxygen.Ebselen

2. Modulating the N-methyl-D-aspartate receptors

Dextromethorphan Noncompetitive NMDA antagonist and metabolite of cough suppressant, Caused hallucinations and agitation; it also produced hypotension.

GV150526 Safe and well tolerated, No improvement was observed in any of the 3-month outcome measures.

Magnesium Reduce ischemic injury by increasing regional blood flow, antagonizing voltage-sensitive calcium channels, and blocking NMDA receptor,

Intravenous Magnesium Efficacy Study (within 12 hours)Administration of Stroke Therapy—Magnesium Phase III (FAST-MAG) Trial.

 NA-1 Reduces NMDA mediated injury by disrupting down-stream pathways, associated with a reduction in MRI-based infarcts

Selfotel,  Aptiganel HCl (Cerestat)

Competitive NMDA antagonistTrials were stopped prematurely

• 3. Modulating non NMDA receptors

 Nalmefene (Cervene)

Narcotic receptor antagonist that reduces levels of excitatory neurotransmittersNo clinical benefit was found in a phase III trial

 Lubeluzole Block sodium channels, reduce the release of nitric oxide, a neurotransmitter generated by activation of the NMDA receptor. Not effective

Clomethiazole g-aminobutyric acid agonist, decreases excitatory neurotransmissionClomethiazole Acute Stroke Study.- result was negative

Calcium channel blockers

Nimodipine is of value in preventing secondary ischemic infarction as a result of vasospasm following subarachnoid haemorrhage.

a-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid antagonist, ONO 2506, Serotonin agonist repinotan,

Piracetam Positive allosteric modulator of the AMPA receptor, Act on ion channels or ion carriers, thus leading to increased neuron excitability,Increase cell membrane permeability.

Exert its global effect on brain neurotransmission via modulation of ion channes.

Cochrane review of 1002 pts

No difference between the treatment and control groups for functional outcome, dependence or proportion of patients dead or dependent. Adverse effects were not reported.

• Others

High-dose human albuminApart from functioning as a haemodiluent, albumin induces systemic mobilization of n-3 polyunsaturated fatty acids and help to replenish polyunsaturated fatty acids lost from neural membranes.

Trial, however, was stopped early for futility.

Hypothermia• Reduces brain damage from ischemia by preventing disruption

of the brain-blood barrier. • It also lowers the basal metabolic rate and counteracts the

ischemic cascade in the penumbra. • One study is evaluating hypothermia (treatment within 300

min) in conjunction with a combination of caffeine and ethanol.• Cooling in Acute Stroke (COAST-II) trial, • Controlled Hypothermia in Large Infarction (CHILI) trial• European Stroke Research Network for Hypothermia

(EuroHYP)-1 trial

Prevention of Reperfusion Injury4. Anti-adhesion antibodies

anti-ICAM-1 (Enlimomab)

Block an intercellular adhesion molecule (ICAM) on the endothelium to prevent adhesion of white blood cells to the vessel wall.Treated subjects were found to have higher mortality rates and worse outcomes than subjects in the placebo group.

Human antileukocytic antibody, Hu23F2G

Phase III trial showed no benefits.

Tetracycline antibiotics Shown to reduce leukocyte infiltration. Phase I dose-finding trial using minocycline to treat ischemic stroke (6-h window) was completed.In addition to providing potential neuroprotection, minocycline also appears to decrease levels of matrix metalloproteinase-9, which has been associated with recombinant tissue plasminogen activator (rtPA)–associated cerebral hemorrhage.

• 5. Membrane stabilization

Citicoline 

• Precursor of phosphatidylcholine, vital component of neuronal membrane.

• Reduces the dysfunction of BBB, decreases cerebral edema, activates cerebral energy metabolism.

• Provides the cytidine & choline. Choline is essential for the synthesis of Acetylcholine (the cholinergic neurotransmitter)

• Inhibits Phospholipase A2 thereby :• preserves neuronal membrane integrity• promotes neuronal membrane repair• inhibits the release of free fatty acids & ARA • inhibits free radical damage

• A phase II trial showed improved outcome in stroke patients treated with either a 500- or 2000-mg/d dose of citicoline.

• A post hoc subgroup analysis of the phase III trial suggested that patients with more severe strokes (National Institutes of Health Stroke Scale >8) had better functional outcome with citicoline.

• A large international trial, ICTUS Study: International Citicoline Trial on acUte Stroke enrolled 2298 patients with moderate-to-severe strokes within 24 hours of stroke onset. Trial did not show efficacy for citicoline compared with placebo.

6. Neuronal healing

Trafermin Basic fibroblast growth factor, help regulate neuronal healing after ischemia.

Epoetin Beta Have anti-apoptotic and anti-inflammatory effects, to mobilize endothelial progenitor cells into the circulation, and to enhance angiogenesis.Yip et al.- significantly reduced the occurrence of major adverse neurological events (defined as recurrent stroke, NIHSS ≥ 8, or death) after treatment for 90 days after acute ischemic stroke

Filgrastim Granulocyte colony stimulating factor (G-CSF) reduced infarct size, prevented BBB damage, and had an anti-inflammatory effectAX200 for the treatment of ischemic stroke (AXIS)-2

Neuroprotection in Hemorrhagic Stroke

• Pathologies of ischemic and hemorrhagic stroke share many of the same damaging processes, such as inflammation, oxidative stress, and excitotoxicity.

• Treatments that are neuroprotective in one may also be beneficial in the other,

• Processes such as cytotoxicity, however, are unique to hemorrhagic stroke and are directly related to the accumulation of blood in the brain.

Heme oxygenase (HO) Inhibitor

Inhibit Heme oxygenase (HO) that converts heme to iron and other products. Free iron reacts with hydrogen peroxide to formhydroxyl radicals, leading to oxidative stress.

Deferoxamine Chelation of ironFree iron reacts with hydrogen peroxide to formhydroxyl radicals, leading to oxidative stress.

Valproic acid Decreases the expression of HO-1

NEUROPROTECTANT FOR PREVENTION OF STROKE• Antihypertensive Drugs

Valsartan Reduces cerebral NADPH oxidase activity and levels of reactive oxygen species, Prevents neuronal apoptosis, suppression of inflammatory cytokines such as monocyte chemoattractant protein1 (MCP1) and tumor necrosis factor (TNF)-αJapanese Investigation of Kinetic Evaluation in Hypertensive Event and Remodeling Treatment (JIKEI HEART) studyKyoto Heart studyNew or recurrent stroke was significantly reduced, by 40%, in the valsartan group

Losartan, Eprosartan and Telmisartan

Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared losartan and the β-blocker atenololMorbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) studyOngoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study , PRoFESS

• Lipid-Lowering Drugs

Atorvastatin Lowered lipid levels; decreased collagen-induced platelet aggregation; improved whole blood viscosity; improved red blood cell deformability; improved von Willebrand factor activity; and improved endothelial dysfunctiondecreased markers of oxidative stress and inflammatory angiogenesis Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) studyCollaborative Atorvastatin Diabetes Study (CARDS)Participants had no documented previous history of cardiovascular disease, an LDL-cholesterol concentration of 4.14 mmol/L or lower, a fasting triglyceride level of 6.78 mmol/L or less, and at least one of the following: retinopathy, albuminuria, current smoking or hypertension. The incidence of stroke was significantly reduced by 48% with atorvastatin.

Simvastatin Scandinavian Simvastatin Survival Study (4S), 4444 patients with angina pectoris or previous MI and serum cholesterol 5.5–8.0 mmol/L on a lipid-lowering diet were randomized to double-blind treatment with simvastatin or placebo . Over the 5.4 years median follow-up period, simvastatin significantly lowered the incidence of stroke, by 30%.

Pravastatin CARE study

Rosuvastatin JUPITER study, 17,802 apparently healthy men and women were randomly assigned to rosuvastatin or placebo. Patients with normal lipid levels but elevated high-sensitivity C-reactive protein showed a 48% reduction in the risk of stroke when taking rosuvastatin, a reduction that was significant.

• Hypoglycemic Drugs

Pioglitazone Inhibits oxidative stress , it increases adiponectin levels in patients with metabolic syndrome and it improves endothelial dysfunction in cerebral vessels in patients with T2DM

Recurrent stroke was significantly reduced by 47% in patients with a prior history of stroke who received pioglitazone compared with those treated with placebo in the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROACTIVE) study

AHA/ASA 2013 RECOMMENDATION

THANK YOU

REFERRENCES

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• Clinical trial registry• Uptodate.com