Slide 1ObjectivesOutlineIschemic brain damage may occur after:Heart attack and brain damageStroke and brain damageSlide 7High energy requirements of the brainSlide 9Slide 10Slide 11The Kabat-Rossen-Anderson apparatusSlide 13Slide 14Slide 15Slide 16Slide 17Slide 18Slide 19Slide 20Slide 21Slide 22Slide 23Slide 24Slide 25Slide 26Slide 27Slide 28Slide 29Slide 30Slide 31Slide 32Slide 33Slide 34Slide 35Slide 36Slide 37Slide 38Slide 39Slide 40Slide 41Slide 42Slide 43Slide 44Slide 45Slide 46Slide 47Slide 48Slide 49Slide 50Slide 51Slide 52Slide 53Slide 54Slide 55Slide 56Slide 57Slide 58Slide 59Slide 60Slide 61Slide 62Slide 63Slide 64Slide 65Slide 66Slide 67Slide 68Slide 69Slide 70Slide 71ReadingsMarch 31, 2010Lech Kiedrowski, Ph.D.UICDepartment of [email protected] agentsObjectives1. Learn about the mechanisms of neurodegeneration caused by brain ischemia (stroke, heart attack).2. Learn about neuroprotective agents being developed to counteract ischemic brain damage.Outline1. High susceptibility of brain to ischemia2. Mechanisms of ischemic neuronal death and the role of Ca2+ and Zn2+ in triggering these mechanisms3. Agents developed to protect the brain from ischemic damageAmerican Heart Association 2004Ischemic brain damage may occur after: •Heart attack (global ischemia)•Stroke (focal ischemia)–ischemic (occlusion of a blood vessel) 87%–hemorrhagic (bleeding in the brain) 13%Heart attack and brain damage•Brain damage can start to occur just 4-6 minutes after the heart stops pumping blood•Survival rate is only 2% if heart is arrested for more than 12 minStroke and brain damage•About 795,000 cases each year•Every 40 seconds someone in the USA has a stroke and every 3 min someone dies of it•Stroke is the third leading cause of death, after heart disease and cancer•Stroke is the leading cause of long-term disability (60% of survivors become handicapped)•The estimated direct and indirect cost of stroke for 2009 was $68.9 billion. •Lack of effective neuroprotective therapyAmerican Heart Association 2009Stroke and brain damage The only FDA-approved therapy for stroke is intravenous injection of t-PA (Tissue Plasminogen Activator, a clot-dissolving agent) However, t-PA must be applied during the first 3 hours of stroke and during this time it has to be determined that the stroke is not hemorrhagic Often stroke victims arrive at the hospital or are diagnosed too late to apply t-PAHigh energy requirements of the brain The human brain constitutes only 2% of the body’s weight, yet it utilizes approximately 25% of total glucose and almost 20% of oxygen Both glucose and oxygen are supplied to the brain with bloodWhat happens when the blood supply to the brain is interrupted?Arch. Neurol. Psych. 50 (1943) 510-528Arch. Neurol. Psych. 50 (1943) 510-528The Kabat-Rossen-Anderson apparatusDramatic SymptomsArch. Neurol. Psych. 50 (1943) 510-5287 seconds of brain ischemia will make you unconscious, but will not damage your brainArch. Neurol. Psych. 50 (1943) 510-528Hansen, Acta Physiol. Scand. (1978) 102: 324-329.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 through rat brainHippocampusSelective vulnerability of CA1 neurons to ischemia 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 GyrusDGCA1CA32 min of ischemia3 min of ischemiaKato et al. Brain Res. (1991) 553: 238-242.Hippocampal CA1 regionin gerbil brain 7 days after ischemiaIschemia has to last over 2 min to kill CA1 neuronsWhat kills the CA1 neurons?The Pulsinelli et al. experimentDenervation protected the CA1 neurons from ischemic deathPulsinelli (1985) Prog Brain Res 63: 29-37Which hippocampus was denervated, the left or the right one????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.Globus et al. (1988) J Neurochem 51:1455-1464Glutamate 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 hoursGlutamateReceptorDeath?In cultured spinal neurons, glutamate deregulates Ca2+ homeostasis in a Ca-dependent mannerTymianski et al. J. Neurosci. 13 (1993) 2085-2104Glutamate activates a number of receptorsGlutamateNMDAAMPA(-Glu-R2)AMPA(+Glu-R2)KainatemGluRsgroup 1mGluRsgroup 2 and 3inoutIonotropic receptorsMetabotropic receptorsSome of these receptors are Ca-permeable channelsinoutGlutamateNMDAAMPA(-Glu-R2)AMPA(+Glu-R2)KainatemGluRsgroup 1mGluRsgroup 2 and 3IP3 cAMP Na+ Ca2+Na+Na+Na+ Ca2+K+K+K+K+NBQX NBQXNBQXMK-801Some of these receptors are Ca-permeable channelsinoutGlutamateNMDAAMPA(-Glu-R2)AMPA(+Glu-R2)KainatemGluRsgroup 1mGluRsgroup 2 and 3IP3 cAMP Na+ Ca2+Na+Na+Na+ Ca2+K+K+K+K+NBQX NBQXNBQXMK-801Tymianski 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 stroke 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 GV150526 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!Zinc-specific fluorescence in rat hippocampus before ischemiaCA1 region 3 days after 10-min ischemiaZinc-specific fluorescenceFuchsin staining (pink) of degenerating neuronsKoh et al. Science 272 (1996) 1013-1016CaEDTA but
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