April 4 2007 L Kiedrowski Ph D UIC Department of Psychiatry lkiedr psych uic edu Neuroprotective agents Outline 1 2 3 4 Extreme vulnerability of brain to ischemia Early stages of brain ischemia Delayed neuronal death after ischemia Neuroprotective agents and strategies Ischemic 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 2004 Heart 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 min American Heart Association 2004 Stroke 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 This is the first controlled investigation on the effects of acute arrest of the circulation to the human brain Arch Neurol Psych 50 1943 510 528 Humans become unconscious within 7 seconds of brain ischemia Arch Neurol Psych 50 1943 510 528 Where does the consciousness reside ILN intralaminar nuclei of thalamus MRF mesencephalic reticular formation Consciousness requires MRF activity Permanent post stroke coma results from bilateral lesions within MRF 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 from Hansen 1978 Acta Physiol Scand Sagital section of rat brain Hippocampus Selective vulnerability of hippocampal 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 From Yokota et al Stroke 1995 26 1901 1907 Ischemia has to last over 2 min to kill CA1 neurons Ischemia 2 min 3 min Hippocampal CA1 region in gerbil brain 7 days after ischemia From Kato et al Brain Res 1991 238 242 Denervation protected CA1 neurons from ischemic death This indicates that CA1 neurons are damaged indirectly from 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 From 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 application of glutamate deregulates Ca2 homeostasis This deregulation depends on extracellular Ca2 concentration The data imply that Ca2 homeostasis is deregulated by glutamate induced Ca2 influx From Tymianski et al J Neurosci 13 1993 2085 2104 Two classes of glutamate receptors ionotropic and metabotropic Glutamate Ionotropic receptors NMDA AMPA Glu R2 AMPA Kainate Glu R2 Metabotropic receptors mGluRs group 1 out in mGluRs group 2 and 3 Some ionotropic glutamate receptors mediate Ca2 influx Glutamate NMDA Na Ca2 AMPA Glu R2 Na Ca2 AMPA Kainate Glu R2 Na Na mGluRs group 1 K K IP3 mGluRs group 2 and 3 out in K K cAMP MK 801 and NBQX inhibit NMDA and AMPA kainate receptors respectively Glutamate NMDA out MK 801 APV AMPA Glu R2 NBQX CNQX AMPA Kainate Glu R2 NBQX CNQX NBQX CNQX mGluRs group 1 mGluRs group 2 and 3 in 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 From Tymianski et al J Neurosci 13 1993 2085 2104 Failure of clinical trials with glutamate receptor antagonist Drugs Mode of action Result Selfotel Aptiganel MK 801 Dextrorfan Racemide competitive NMDA antagonist noncompetitive NMDA antagonist noncompetitive NMDA antagonist noncompetitive NMDA antagonist noncompetitive NMDA antagonist trial discontinued adverse effects adverse effects adverse effects phase III planed GV150526 Eliprodil glycine site antagonist of NMDA rec polyamine site antagonist of NMDA rec no efficacy no efficacy NBQX competitive AMPA receptor antagonist trial discontinued adverse effects renal toxicity Cerebrovasc Dis 11 suppl 1 2001 60 70 What methodological problems Answer Many in vitro studies underestimated the impact of early ischemic events on the mechanism of toxic Ca2 influx What early events 1 Oxygen depletion 2 Drop in pH 3 Plasma membrane depolarization by K efflux 4 Cytosolic Na elevation These events affect the mechanism by which glutamate kills neurons Early Stages of Global Brain Ischemia Oxygen Depletion From Halsey et al Microvasc Res 1977 In the presence of oxygen and glucose Ca2 accumulates in the mitochondria m ATP s si ly co ly G pu Ca Glucose p pla s Pyruvate Glutamate Ca2 Ca phosphate Ca2 ATP Pi 180 mV endoplasmic reticulum ma lem ma mito ch ond rion Krebs cycle O2 4NADH eH 2H2O H H In the absence of oxygen and glucose Ca2 accumulates in the cytosol p s si ly co ly G p a C um Pyruvate Glutamate Ca2 2 Ca Ca Ca phosphate 2 Pi 180 mV calpain Krebs cycle 4NADH e Lactate Mg2 blocks NMDA channel Na Ca2 out NMDA rec Glu Mg in Na influx via AMPA channel depolarizes the plasma membrane and removes the Mg2 block Na Ca2 out in NMDA rec Glu Na Glu Depolarization AMPA rec Many in vitro studies were performed in the absence of Mg2 s si ly co ly G Glucose Pyruvate Glutamate Ca2 Ca phosphate Ca2 Pi NMDA channel not blocked by Mg2 180 mV Krebs cycle O2 4NADH eH 2H2O H H Under Mg free conditions the Ca2 influx via NMDA receptors is artificially enhanced Early events of
View Full Document
Unlocking...