March 29 2011 Lech Kiedrowski Ph D UIC Department of Psychiatry lkiedr psych uic edu Neuroprotective agents Objectives 1 Learn about the mechanisms of neurodegeneration caused by brain ischemia stroke heart attack 2 Learn about neuroprotective agents being tested to counteract ischemic brain damage Outline 1 High susceptibility of the brain to ischemia 2 Mechanisms of ischemic neuronal death and the role of Ca2 and Zn2 in triggering these mechanisms 3 Agents developed to protect the brain from ischemic damage Ischemic 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 American Heart Association 2004 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 min Stroke 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 therapy American Heart Association 2009 Stroke 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 PA High 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 Glucose and oxygen are supplied to the brain with blood How humans are affected when this supply is interrupted 126 volunteers Arch Neurol Psych 50 1943 510 528 Arch Neurol Psych 50 1943 510 528 The Kabat Rossen Anderson apparatus 7 seconds of brain ischemia will make you unconscious but will not damage your brain Arch Neurol Psych 50 1943 510 528 EEG is flat within 10 sec of global brain ischemia Ischemic depolarization high elevation in external K takes place about 2 min after the onset of ischemia Hansen Acta Physiol Scand 1978 102 324 329 Sagital section through rat brain Hippocampus Selective vulnerability of CA1 neurons to ischemia CA1 CA Cornu Ammonis Ammon s horn DG Dentate Gyrus Sham operated DG CA3 CA1 neurons die CA3 and DG neurons survive 3 days after 10 min ischemia 7 days after 10 min ischemia Yokota et al Stroke 1995 26 1901 1907 Ischemia has to last over 2 min to kill CA1 neurons 2 min of ischemia 3 min of ischemia Hippocampal CA1 region in gerbil brain 7 days after ischemia Kato et al Brain Res 1991 553 238 242 What kills the CA1 neurons The Pulsinelli et al experiment Which hippocampus was denervated the left or the right one Denervation protected the CA1 neurons from ischemic death Pulsinelli 1985 Prog Brain Res 63 29 37 Death Extracellular glutamate during ischemia and reperfusion Baseline 10 20 30 Ischemia 10 20 Reperfusion 10 20 30 60 120 Glutamate M sampled from various brain regions of the rat subjected to 20 min ischemia Globus et al 1988 J Neurochem 51 1455 1464 Glutamate is neurotoxic Olney 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 ate Gl ut am Re c ep to r Death In cultured spinal neurons glutamate deregulates Ca2 homeostasis in a Ca dependent manner Tymianski et al J Neurosci 13 1993 2085 2104 Some of these receptors are Ca permeable channels Glutamate NMDA AMPA Glu R2 Na Ca2 Na Ca2 out MK 801 AMPA Kainate Glu R2 Na NBQX NBQX Na mGluRs group 1 mGluRs group 2 and 3 NBQX in K K K K IP3 cAMP Fraction deregulated dead Blocking NMDA receptors prevents glutamate induced deregulation of Ca2 homeostasis and neuronal death Ca2 deregulation Dead Neurons APV NMDA receptor inhibitor CNQX AMPA kainate receptor inhibitor NIM voltage gated Ca channel inhibitor Conclusion Inhibiting NMDA receptors is sufficient to protect the neurons against glutamate induced death Tymianski et al J Neurosci 13 1993 2085 2104 Failure of clinical stroke trials with glutamate receptor antagonist Drugs Mode of action Result Selfotel Aptiganel MK 801 Dextrorfan competitive NMDA antagonist noncompetitive NMDA antagonist noncompetitive NMDA antagonist noncompetitive NMDA antagonist trial discontinued adverse effects adverse effects adverse effects GV150526 glycine site antagonist of NMDA rec no efficacy Eliprodil polyamine site antagonist of NMDA rec no efficacy NBQX competitive AMPA receptor antagonist trial discontinued adverse effects renal toxicity Cerebrovasc Dis 11 suppl 1 2001 60 70 Zinc specific fluorescence in rat hippocampus before ischemia The role of zinc in ischemic neuronal death CA1 region 3 days after 10 min ischemia CaEDTA but not ZnEDTA protects CA1 neurons against ischemic death Zinc specific fluorescence Fuchsin staining pink of degenerating neurons Koh et al Science 272 1996 1013 1016 The data indicate that preventing zinc translocation using CaEDTA prevents the ischemic death of CA1 neurons What changes occur in the brain during ischemia What role does zinc play in these changes Poly ADP ribose polymerase 1 PARP 1 gets activated in ischemic brain and may lead to neuronal death Kauppinen and Swanson Neuroscience 145 2007 1267 1272 PARP 1 called also PARS mediated NAD and ATPdepletion leads to cell death NO nitric oxide PARS Poly ADP ribose synthetase NAm nicotinamide NMN nicotinamide mononucleotide PRPP phosphoribosyl pyrophosphate PPi inorganic phosphate Zhang et al Science 263 1994 686 689 Does PARP play a role in ischemic neuronal death PARP plays a role in ischemic brain infarct formation in vivo PARP 1 knockout PARP 1 inhibition PBS phosphate buffered saline control 3 AB 3 aminobenzamide PARP inhibitor PARP knockout or PARP inhibition reduce the size of ischemic brain infarct caused by the middle cerebral artery occlusion MCAO Endres et al J Cereb Blood Flow Metab 17 1997 1143 1151 Inhibition of PARP with 3 AB prevents the MCAO induced NAD depletion PBS phosphate buffered saline used as a control Dark color
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