NOTE: Quiz Wednesday, review in class Monday, covering: BOOK: Chpts 7, 8 & 11 NOTES: Weeks 9 through 12 TOPICS: ADHD, Parkinson's, Epilepsy, Anesthetics, Analgesics, Anxiety, Anxiolytics, Alzheimers, Stroke EPIDEMIOLOGY OF STROKE: TYPES OF STROKE There are four main types of stroke: Two caused by blood clots or other particles + Cerebral thrombosis + Cerebral embolism Two by hemorrhage + Cerebral hemorrhage + Subarachnoid hemorrhage Cerebral thrombosis and embolism: Account for 70-80% of all strokes Caused by clots or particles that plug arteries Thrombosis: a blood clot + Accounts for over 50% of all strokes + Usually caused by arteriosclerosis + Often occur at night or early morning, when blood pressure is low + And often preceded by a transient ischemic attack (TIA), a "ministroke" Cerebral embolism - + This type of stroke occurs when a wandering clot (an embolus) forms in a blood vessel away from the brain, usually in the heart + Cerebral embolism accounts for from five to 14 percent of all strokes + The most common cause of these emboli is blood clots that form during atrial fibrillation, a disorder found in close to 2 million Americans + In atrial fibrillation the two small upper chambers of the heart, the atria, quiver instead of beating effectively. Blood isn't pumped completely out of them when the heart beats, allowing the blood to pool and clot + About 15 percent of strokes occur in people with atrial fibrillation Cerebral and subarachnoid hemorrhages are caused by ruptured blood vessels Cerebral hemorrhages occur in brain proper + Account for about 10% of all strokes + Often the result of a burst aneurysm. Aneurysms are blood-filled pouches that balloon out from weak spots in the artery wall + Aneurysms often caused or aggravated by high blood pressure Subarachnoid hemorrhages occur on surface of the brain, but below the meninges + Account for about 7% of all strokes Hemorrhages have a much higher fatality rate than strokes caused by clots + In 50 percent of the cases, people with cerebral hemorrhages die of increased pressure on their brains EPIDEMIOLOGY OF STROKE Stroke killed an estimated 159,942 people in 1996 Is the third largest cause of death in the USA Stroke is a leading cause of serious, long-term disability + About 4,400,000 stroke survivors are alive today Some 600,000 people suffer a new or recurrent stroke each year + About 500,000 of these are first attacks and 100,000 are recurrent attacks In 1996 females accounted for 60.9 % of stroke fatalities 28 percent of annual stroke victims are under age 65 Risk factors for stroke Increasing age - The chance of having a stroke more than doubles for each decade of life after age 55 Male sex - Overall, men have about a 19% greater chance of stroke than women Heredity (family history) Race - Blacks have a much higher risk of death and disability from a stroke than whites High blood pressure - High blood pressure is the most important risk factor for stroke Cigarette smoking Previous stroke + The use of oral contraceptives combined with cigarette smoking greatly increases stroke risk Diseases which predispose: + Diabetes + Cardiovascular disease, including ateriosclerosis and atrial fibrillation Geographic location - Strokes are more common in the southeastern United States than in other areas These are the so-called "stroke belt" states PHARMACOLOGICAL TREATMENT OF STROKE: NEURONS DON'T DIE FROM ISCHEMIA, THEY ARE KILLED! And neuronal cell death is a slow process, taking hours or even days and giving SOME room for intervention Currently thought that one might have as much (or as little) as 3 hrs to intervene after stroke and before permanent cell death Hence the recent clumsy attempt to rename strokes "brain attacks" THIS DEATH TAKES SEVERAL FORMS: Pumps run out of energy, releasing a flood of neurotransmitters Glutamate release causes excitotoxicity via classical NMDA and AMPA channels Release of other neurotransmitters probably explains "near-death" and "out of body" experiences as simple hallucinations Breakdown of ionic pumps also causes influx of water into the cell, causing swelling and membrane rupture Reperfusion: collateral circulation often quickly resumes oxygen supply, but this can cause increased formation of free radicals, membrane damage, and apoptosis Inflammation: Unlike AD, WBCs infiltrate the brain after stroke, often worsening damage RBCs can also cause neurotoxicity through introduction of iron UNDERSTANDING GLUTAMATE EXCITOTOXICITY First, we DON'T understand glutamate excitotoxicity NOR is such excitotoxicity the ONLY form of ischemic brain damage The glutamatergic synapse - glutamate synthesis Glutamate neurotransmission involves very close cooperation between the neuron and surrounding glial cells - the astrocytes Glutamine is supplied TO the neuron BY the astrocyte Glutamine is converted to glutamate by the mitochondrial enzyme GLUTAMINASE Then stored in vesicles prior to release Glutamate reuptake: Only means of turning system off Uses TWO reuptake pumps, one on neuron, the other on the astrocyte Curiously, the astrocyte converts the glutamate back to glutamine and ships it to the neuron to be changed back to glutamate The NMDA receptor: just ONE of three glutamate- activated ion channels known to be involved in excitotoxicity (AMPA and Kainate are the other 2) A ligand-gated calcium channel Like the GABA channel, has SEVERAL binding sites: + Mg++ site INSIDE the channel, blocks Ca++ + PCP site INSIDE the channel - blocks Ca++ + Glycine site on receptor - excitatory + Zinc site on receptor - excitatory + Polyamine site on receptor - excitatory Calcium, free radicals and excitotoxicity: Over-excitation releases a flood of intracellular Calcium Calcium does literally hundreds of things in the cell, many of which MIGHT be involved in excitotoxicity Much interest has focused on the possibility that calcium ingress activates enzymes which produce free radicals, and these cause cell death TREATMENT OF ISCHEMIC BRAIN DAMAGE All treatments are still experimental, but many hold great promise in animal models, including: Compounds which block glutamate excitotoxicity Free radical scavengers Sodium and calcium channel blockers Anti-inflammatory agents Hypothermia: one of the most effective and least- used treatments!