Effect Of Neuroprotectant Cocktails On Cerebral 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.Multiple research demonstrated that necrosis and apoptosis are the two ways of neuron death after ischmia.It interfered with initiatived and passived mechanism of neuron death.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.As we all known the bcl-2 family protein plays an important role in the apoptosis of neuron death,including the antiapoptotic protein bcl-2,bcl-xL, Mcl-1 and the proapoptotic protein bax,bix etc.Among these protein ,bcl-2 is an important antiapoptotic protein,it is expressed in the neurons that be destined to survive.Over the years,Multiple mechanisms of brain injury from ischemia have been identified.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 beencalled 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 animal modle are not effective in humans is unclear.The possible reason is that agents aimed at specific aspects 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 cocktail of neuroprotecants. The development of cocktails 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.For example,the NMDA receptor antagonist MK-801 shows marked potency in reducing damage from focal ischemia in animal modles,however MK-801 shows dose-related toxic effect in humans and was limited its application.The concept of synergistic neuroprotection with agents that act at distinct parts of injury process is supported by several recent studies.Ma et al.reported a synergistic effect between subtherapeutic doses of MK-801 and caspase inhibitors in a mouse modle of trainsient focal ischemia.Richard et al. reported singly and incombination ,the neuroprotective efficacy of FBP,MK-801,Ascorbate,2-chloroadenosine and 2%isoflurance in vitroischemia modle.The au...