MSC and pathophys Cerebral ischemia and stroke.pdf

 Stroke is the third leading cause of death, ranking behind cardiac disease and all forms of cancer.  Stroke is a leading cause of serious, long-term disability  Every 45 seconds someone (USA statement) has a stroke, and every 3 minutes someone dies of one.  Stroke can accou...

 Stroke is the third leading cause of death, ranking behind cardiac disease and all forms of cancer.  Stroke is a leading cause of serious, long-term disability  Every 45 seconds someone (USA statement) has a stroke, and every 3 minutes someone dies of one.  Stroke can account for about half of all hospital admissions for acute neurological disease (depending on country).  Economic burden of this disease is tremendous…..!!  2017 figure: 60 billion Euros (EU country study) per year.  “TIME IS BRAIN”.  High Blood Pressure - Hypertension. [Risk doubles with every 7.5mm  diastolic BP].  Heart Disease  Vascular Disease  Diabetes Mellitus  Diet/High Cholesterol  Alcoholism  Poor Health  Smoking  Contraceptive Pill (3 times ).  COVID IS A RISK FACTOR FOR STROKE! Literature Statements and Figures available for Covid-19: 21% of SARS-CoV-2/Covid-19 patients have both neurological symptoms and thromboembolic events. 7.6 fold increased chance of stroke over and above influenza (avoid both!). 1.3% of ALL Covid-19 patients WORLDWIDE have been stroke victims. January 2022 World data: Covid-19 infection: 328M cases, 5.54M deaths Approx. 4.3M stroke victims worldwide due to Covid-19 alone! Intensive care unit (ICU) patients with Covid-19: 31% thrombotic complications. Covid-19 is an independent risk factor for stroke in hospitalised patents. Covid-19 induced abnormal blood coagulation/hyper coagulability can lead to stroke (often observed in Covid IV cannulated patients). Covid 19/SARS-CoV-2: pathological mechanisms – MANY!!. 1. Cytokine Storm –proinflammatory cytokines (role of IL6). 2. Coagulation dysfunction: triggers coagulation/blood clot pathway. 3. CNS invasion: infects endothelial cells/Blood Brain Barrier. 4. Angiotensin converting enzyme 2 (ACE2) expressed in heart/blood vessels/ gut/ lung/ kidneys. 5. ACE2 in Brain: on neurons, glial cells, cerebral blood vessel endothelium. 6. Covid-19 binds to ACE2 and “hijacks” to gain CNS entry via ACE2. 7. ACE2 expression 3X higher in adult males to females. Covid-19 and ischemic stroke-recent reviews. Covid-19 and Ischemic stroke: Mechanisms of hypercoagulability (Review) Zhang S, et al. International Journal of Molecular Medicine (2021), 46: 21 A review of ischemic stroke in Covid-19: currently known pathophysiological mechanisms. Tang X, and Zheng F. Neurological Sciences (2021), published online 21 October https://doi.org/10.1007/s10072-021-05679-0  Physiotherapy.  Re-Open the vascular occlusion with thrombolytic agents (clot-busters). - Tissue Plasminogen Activator (t-PA), - Streptokinase/Urokinase.  Prevent reocclusion – antithrombolytic therapy. - Aspirin.  Many failed Clinical Trials!  Future therapies? STROKE VICTIM: PET Scan 86yr Male Atrial fib. Diabetes 8 Hours 4 Days  49yr Female Hypertension BP240/130!! Diabetes mellitus Simplified Cerebral Ischemic Cascade  Interleukins:IL-1; IL-6.  Tumor Necrosis Factor - TNF-α.  Adhesion molecules (ICAM; ELAM)  Tissue metalloproteases.  Nitric oxide (NO) – NOS (nNOS, iNOS) reacts with O2 to produce reactive oxygen species (ROS) – toxic radicals (peroxynitrite). n-NOS contributes to infarct – knockouts have smaller infarcts.  Anti-inflammatory cytokines: IL-10 (may block IL-1 and TNF)  Growth factors: NGF; BDNF; G (glial) DNF; TGF-β  Heat Shock Proteins: HSP90 – enters nucleus/binds to DNA  HSP70/72/27 – prevent protein destruction.  Antioxidants: Mn-superoxide dismutase (Mn-SOD); Cu/Zn-SOD;  Endothelial nitric oxide synthase (e-NOS) (vasodilator/neuroprotective) Multiple sclerosis Cerebral trauma/stroke/ Head injury 1. Drugs to improve blood flow: - Anti-thrombotic- Low molecular weight heparins - Anti-platelet – Aspirin; Clopidogrel - [Fibrinogen deleting –Ancrod]. - Improve capillary flow – pentoxifylline - Thromobolytics (clot busters) : Pro- urokinase/ streptokinase/tissue plasminogen activator (TPA).  2. Neuroprotective Agents:  - Calcium channel blockers: - flunarizine; nimodipine  - Calcium chelators  - Free radical scavengers/antixoxidants – Ebselen; Tirilizad; NXY-059  - GABA (gamma amino butyric acid) agonists – clomethiazole  - Glutamate receptor antagonists – AMPA antagonists/NMDA antagonists (magnesium infusion)  - Growth factors  - Leucocyte adhesion inhibitor  - Nitric oxide inhibition  - Sodium channel blockers.  StrokePrevention (and 2nd stroke prevention). - Anticoagulants - Antihypertensive agents - Anti-platelet agents - Vitamins - Stop smoking;healthy diet! Cochrane Database Review.  Rationale: majority of strokes due to arterial blockage (blood clot) in the brain.  Restore blood flow before brain damage occurs – Thrombolytic agent (“clot busters”)  Data analysed: 18 trials (5727 patients) – 50% trials are TPA.  Overall significant reduction in dead /dependent patients.  Increased mortality in first 7-10 days – intracranial haemorrhage. Possible administration to haemorrhagic stroke victims!!!   Mechanical Intra-Arterial Thrombectomy (Clot Retrieval) Only applicable to “large vessel” strokes. Small subgroup (less than 2%) Stroke patients who fail to improve following intravenous Tissue Plasminogen Activator (t-PA) where the blocked vessel fails to open.  Proposal - polytherapy to reduce ischaemic heart disease and stroke.  Predicted that 1/3rd of over 55yrs may benefit – gaining 11 years of life.  Proposed formulation: (i) Statin (cholesterol-lowering) : eg Atorvastatin or simvastatin. (ii) 3 BP lowering agents – thiazide diuretic/beta blocker/ACEI (or AngII antagonist) (iii) Folic acid (to lower homocysteine) (iv) Aspirin (antiplatelet)  Choice of thiazides/ beta-blockers/ ACEI / ANGII antagonist/ Ca++channel blocker.  Three drug combination expected to: reduce: Stroke incidence by 65%; Ischaemic heart disease by 45%.  POLYPILL estimated to reduce stroke incidence by 80%. STROKE TRIALS REGISTRY EXTENSIVE HISTORICAL TARGET LIST.  Clinical trials in stroke and cardiovascular disease.  In 2015,over 3500 different interventions including drug, surgery, aftercare and nothing!  In 2020, 1908 stroke trials registered with the clinical trial center listing: “centerwatch”/search “stroke”: www.centerwatch.com  www.strokecenter.org/trials  UK site: www.nhs.uk/conditions/stroke  Sekerdag et al. Cell death mechanisms in stroke and novel molecular and cellular treatment options. Current Neuropharmacology. 2018: 16, 1396-1415. (Bentham Science Publishers).  Wu and Tymianski. Targeting NMDA receptors in stroke: new hope in neuroprotection. Molecular Brain. 2018: 11,15. (Open Access).  Jayaraj et al. Neuroinflammation:friend and foe for ischemic stroke. Journal of Neuroinflammation. 2019:16,142. (Open Access).  Das et al. Treatment approaches to Lacunar Stroke. Journal of Stroke and Cerebrovascular Disorders. 2019: 28(8), 2055-2078 (Public Access).  Chrostek et al. Efficacy of stem cell-based therapies for stroke. Brain Research. 2019: November 01, 1722 (Public Access).