Study Of The Combination Of Neuroprotectants On Ischemic Volume And Apoptosis Of Neurons And The Expression Of Caspase-3 Of Focal Ischemia In Rats

Ischemic stroke is a major cause of death and disability in the world.But effective agent for ischemic stroke is uncertain till now. Although the thrombolysis therapy have made great progress in recent years,more than half patients still have serious disability and therapy is limited by the short time window.Multiple research demonstrated that necrosis and apoptosis are the two ways of neuron death after ischmia. It is not only the ischemia but the series response in biochemistry that decide the fate of ischemic neurons . In the acute phase of cerebral ischemia there exists necrosis and apoptosis at the same time,necrosis is the main way of cell death in the core of cerebral ischemia and apoptosis is the main way of cell death in the penumbral region where cells are not so rapidly and severely damaged.On the other hand apoptosis is the main way of cell death in the delayed damage phase of cerebral ischemia.So apoptosis may contribute to the final infarct size.Apoptotic cell death is a initiatived way under physiology and pathology conditions.It is a biology process controlled by genes and factors.Caspasefamily is the specific death initiating signaling transmission molecul.It is regarded the operator of apoptosis.And caspase-3 in the most important key effect protease in the caspase injury cascade.It is called the" killer protein" .It is the ischemic injury cascade that decide the fate of the ischemic neuron. These include production of oxygen free radicals(lipid peroxidation),release of excitatory amino acids(glutamate and aspartate),release of mediators of inflammation,involvement of calcium,failure of energy metabolism,and other mechanisms. The excited toxicity mediated by glutamate and the overload of intracellular calcium are the main cause and the final common path of neuron death.The strategies aimed at specific aspects of the injury cascade which have been called neuroprotant have been studied in the past.For example,free radical scavengers,excitatory amino acid antagonists,calcium channel blockers,energy metabolisms supporters and others have been investigated for years.But what remains curious is that although many of the agents appear quite effective in preclinical studies with small-animal modles of ischemia,nearly none of these have been proven conclusively to be effective in humans On the other hands,some agents(such as NMDA antagonists MK-801)were limited for toxic side effects.This fact limites the application and the effect of neuroprotectant in clinical.Why neuroprotecants that are effective in animalmodle are not effective in humans is unclear.The possible reason is that agents aimed at specific aspect of the injury cascade can not fully break in the injury cascade from ischemia.So it is important to know if synergistic effects can be achieved by combining several effective agents in the same strategy. The development of combination for neuroprotection from ischemic insult is attractive now for several reasons.Firstly,A combination of agents which individually inhibit different parts of the ischemic injury cascade may provide much more protection than any single agent.This goal is much significant since no single strategy has showed an universally protective in brain ischemia of human.Secondly,by combining agents it might be possible to use agents at lower dose than required in single use .So it is possible to avoid dose-related toxic effect.The purpose of this study was to investigate combinations of agents for synergistic effects.We use the MCAO modle in rats to test the benefits of several proposed neuroprotection agents ,including preventing ATP loss with FDP ,antagonism of NMDA receptors with MK-801,scavenging free radicals with NAC.With the use of MCAO modle we studied the effect of the combination of neuroprotectants on infarct size with TTC stain ,apoptosis of neurons with TUNEL and expression of apoptotic protein caspase-3 with immunohistochemistry and western blot.Part 1 Effect of the combination of neuroprotectants onischemic volum...