Slide 1OutlineIschemic brain damage may occur after:Heart attack and brain damageStroke and brain damageHigh energy requirements of the brainSlide 7Slide 8Slide 9Slide 10Slide 11Slide 12Slide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26What early events ?Early Stages of Global Brain Ischemia Oxygen DepletionIn the presence of oxygen and glucose, Ca2+ accumulates in the mitochondriaSlide 30Slide 31Slide 32Many in vitro studies were performed in the absence of Mg2+.Early events of brain ischemiaEarly Event of Global Brain Ischemia Low pH inhibits NMDA receptorsSlide 36Early Stages of Brain Ischemia ANOXIC DEPOLARIZATIONSlide 38Early Stages of Brain IschemiaHow do the early ischemic ionic fluxes affect the plasmalemmal Na/Ca (NCX) and Na/Ca+K (NCKX) exchange operation?Slide 41Slide 42Slide 43Slide 44Slide 45NCX and NCKX reverse during anoxic depolarizationHow high do NCX and NCKX elevate [Ca2+]c?Very shortly after the onset of ischemia, in hippocampal CA1 neurons in vivo, [Ca2+]i elevates to ~50 mMSlide 49Slide 50Slide 51Slide 52Slide 53What is calpain?Slide 55Slide 56Slide 57Slide 58Slide 59Slide 60Slide 61Slide 62Slide 63ReadingsApril 4, 2007L. Kiedrowski, Ph.D.UICDepartment of [email protected] agentsOutline1. Extreme vulnerability of brain to ischemia2. Early stages of brain ischemia3. Delayed neuronal death after ischemia4. Neuroprotective agents and strategiesAmerican Heart Association 2004Ischemic brain damage may occur after: •Heart attack (global ischemia)•Stroke (focal ischemia)–ischemic (occlusion of a blood vessel) 88%–hemorrhagic (bleeding in the brain) 12%American Heart Association 2004Heart attack and brain damage•Brain damage can start to occur just 4-6 min after the heart stops pumping blood•Survival rate is only 2% if heart is arrested for more than 12 minStroke and brain damage•600,000 new cases each year•Every 45 seconds someone in the USA has a stroke and every 3 min someone dies of it•Stroke is the third leading cause of death, behind heart disease and cancer•Stroke is the leading cause of long-term disability (60% of survivors become handicapped)•In 2004, the overall cost of stroke-induced brain injury was over $53.6 billion•Lack of effective neuroptotective agents•The only currently available therapy: intravenous injection of t-PA (Tissue Plasminogen Activator, a clot-dissolving agent)High energy requirements of the brain•The human brain constitutes only 2% of the body weight, yet it utilizes approximately 25% of total glucose and almost 20% of oxygen.Arch. Neurol. Psych. 50 (1943) 510-528“This is the first controlled investigation on the effects of acute arrest of the circulation to the human brain.”Arch. Neurol. Psych. 50 (1943) 510-528Humans become unconscious within 7 seconds of brain ischemiaWhere does the consciousness reside?ILN – intralaminar nuclei of thalamusMRF – mesencephalic reticular formationConsciousness requires MRF activityPermanent post-stroke coma results from bilateral lesions within MRFfrom Hansen, (1978) Acta Physiol. Scand. EEG is flat within 10 sec of global brain ischemiaIschemic depolarization (high elevation in external K+) takes place about 2 min after the onset of ischemia.Sagital section of rat brainHippocampusSelective vulnerability of hippocampal CA1 neurons to ischemia From Yokota et al. Stroke (1995) 26: 1901-1907.Sham operated3 days after 10-min ischemia7 days after 10-min ischemiaCA1 neurons dieCA3 and DG neurons surviveCA = Cornu Ammonis (Ammon’s horn)DG = Dentate GyrusDGCA1CA3Ischemia2 min3 minFrom Kato et al. Brain Res. (1991) 238-242Hippocampal CA1 regionin gerbil brain 7 days after ischemiaIschemia has to last over 2 min to kill CA1 neuronsDenervation protected CA1 neurons from ischemic death.This indicates that CA1 neurons are damaged indirectly. from Pulsinelli (1985) Prog Brain Res 63:29-37.???Death10 20 30 10 20 10 20 30 60 120 Baseline Ischemia ReperfusionExtracellular glutamate during ischemia and reperfusionGlutamate (µM) sampled from various brain regions of the rat subjected to 20-min ischemia.From Globus et al. (1988) J Neurochem 51:1455-1464.Glutamate is neurotoxicOlney, J.W., Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science, 1969. 164: p. 719-721.A single subcutaneous injection of glutamate (4 mg/g) produces brain lesions and kills 2 – 9 day-old mice within 1 to 48 hours.GlutamateReceptorDeath?In cultured spinal neurons, application of glutamate deregulates Ca2+ homeostasis. This deregulation depends on extracellular Ca2+ concentrationFrom Tymianski et al. J. Neurosci. 13 (1993) 2085-2104The data imply that Ca2+ homeostasis is deregulated by glutamate-induced Ca2+ influxTwo classes of glutamate receptors: ionotropic and metabotropicGlutamateNMDAAMPA(-Glu-R2)AMPA(+Glu-R2)KainatemGluRsgroup 1mGluRsgroup 2 and 3inoutIonotropic receptorsMetabotropic receptorsSome ionotropic glutamate receptors mediate Ca2+ influx inoutGlutamateNMDAAMPA(-Glu-R2)AMPA(+Glu-R2)KainatemGluRsgroup 1mGluRsgroup 2 and 3IP3 cAMP Na+ Ca2+Na+Na+Na+ Ca2+K+K+K+K+MK-801 and NBQX inhibit NMDA and AMPA/kainate receptors, respectivelyinoutGlutamateNMDAAMPA(-Glu-R2)AMPA(+Glu-R2)KainatemGluRsgroup 1mGluRsgroup 2 and 3IP3 cAMP NBQXCNQXNBQXCNQXNBQXCNQXMK-801APVFrom Tymianski et al. J. Neurosci. 13 (1993) 2085-2104Ca2+ deregulationDead NeuronsFraction deregulated/deadAPV – NMDA receptor inhibitorCNQX – AMPA/kainate receptor inhibitorNIM – voltage-gated Ca channel inhibitorBlocking NMDA receptors prevents glutamate-induced deregulation of Ca2+ homeostasis and neuronal deathConclusion: Inhibiting NMDA receptors is sufficient to protect the neurons against glutamate-induced deathFailure of clinical trials with glutamate receptor antagonistDrugs Mode of action ResultSelfotel competitive NMDA antagonist trial discontinued Aptiganel noncompetitive NMDA antagonist adverse effectsMK-801 noncompetitive NMDA antagonist adverse effectsDextrorfan noncompetitive NMDA antagonist adverse effects Racemide noncompetitive NMDA antagonist phase III planedGV150526 glycine site antagonist of NMDA rec. no efficacyEliprodil polyamine site antagonist of NMDA rec. no efficacyNBQX competitive AMPA receptor antagonist trial discontinuedadverse effectsrenal toxicityCerebrovasc. Dis. 11, suppl 1 (2001) 60-70!What
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