Stroke is the third leading cause of death behind cardiovascular disease and cancer.It is also a leading cause of serious,long-term disability.Current treatments for prevention of stroke-related morbidity are limited to thrombolytic agents,such as tissue plasminogen activator(t-PA)and surgery.Neuroprotection against stroke induced brain injury is still major unfulfilled medical needs.Many neuroprotectants were highly effective in preclinical animal models,but few agents have been successfully translated to human brain diseases.Although the reason for these failures is unclear,we think that understanding the means and mechanisms of stimuli that boosting endogenous neuroprotective mechanisms by which the brain protects itself against noxious stimuli and recovers from damage are being considerably studied.Compared to many years of important research to the pathological effects of ethanol abuse,the past several decades have seen the publication of a lot of peer-reviewed studies indicating beneficial effects of light-moderate,non-binge consumption of varied alcoholic beverages,as well as experimental demonstrations that moderate ethanol exposure can reduce risks of cerebrovascular(ischemic)stroke,coronary heart disease,and so on.Brain functional comparisons between older moderate alcohol consumers and non-drinkers have received more recent epidemiological study.A hallmark meta-analysis of epidemiologic studies spanning almost forty years,provided a detailed association between ethanol consumption and risk for total stroke,ischemic stroke,and hemorrhagic stroke.Experimental studies with experimental rodent models and cultures(cardiac myocytes,endothelial cells)indicate that moderate alcohol exposure can promote antiinflammatory processes involving adenosine receptors,protein kinase C(PKC),nitric oxide synthase,heat shock proteins,and others which could underlie cardioprotection.In over half of nearly 45 reports since the early 1990s,significantly reduced risks of cognitive loss or dementia in moderate,non-binge consumers of alcohol(wine,beer,liquor)have been observed,whereas increased risk has been seen in only a few studies.Cerebral preconditioning,which has been observed in multiple organisms,has been developed to enhance endogenous neuroprotective effects against stroke induced brain injury.It is a phenomenon that brief episodes of a sublethal insult induce robust protection against subsequent lethal injuries.Cerebral preconditioning is a procedure by which a noxious stimulus below the threshold of damage is applied to brain to make the brain develop tolerance to resistance subsequent seriously injury.A considerable body of animal studies suggest that the brain can be preconditioned to resist acute injuries,such as ischemic stroke,neonatal hypoxia/ischemia,surgical brain injury,trauma,and agents that are used in models of neurodegenerative diseases,such as Parkinsons disease and Alzheimers disease.Preconditioning brain to tolerate the effects of cerebral ischemiareperfusion injury can be initiated through the application of several different mechanical and pharmacological strategies.Inducing brief nonlethal episodes of ischaemia and reperfusion to the brain prior to an episode of sustained lethal cerebral ischemia has the capacity to dramatically reduce cerebral ischemic injury--a phenomenon termed ischemic preconditioning(IPC).If pharmacological agents was administrated to precondition the brain to allowing one to recapitulate the benefits of these neuroprotective phenomena--so-termed pharmacological preconditioning.The identification of the cellular basis of the signaling pathways which underlie the effects of IPC has provided a conceptual framework for developing novel therapeutic strategies aimed at mimicking the neuroprotective effects of preconditioning with pharmacological agents--so-termed pharmacological preconditioning.A number of endogenous pharmacological agents have been shown to mimic the cytoprotective effects of IPC including adenosine,nitric oxide,hydrogen sulfide,bradykininand erythropoietin(EPO),oxygen,temperature,physical exercise.In addition,exogenously administered drugs including several direct ATP-sensitive potassium channel(KATP)channel openers such as diazoxide,Large conductance,Ca2+-activated K+channels(BKCa)channel opener such as NS1619,moderate ethanol and grape polyphenolic compound resveratrol from red wine,and certain volatile anesthetics including isoflurane,have all been shown to reduce infarct size to an extent similar to that observed following IPC.Pharmacological preconditioning is a clinically feasible paradigm that can be elicited by a wide variety of drugs.The classification of pharmacological preconditioning versus pharmacological pretreatment is somewhat nebulous,with the major distinction being that in the preconditioned state protection is afforded in a timeframe beyond agent elimination.Due to its ease of establishment compared to the more invasive or elaborate preconditioning protocols described above,pharmacological preconditioning has been accepted as a promising paradigm to combat cerebral ischemic injury in the clinic.However,many limitations still need to be overcome,such as understanding and thus titrating the indirect effects of the agent that elicits the preconditioned state.Potential mechanisms and downstream targets of pharmacological preconditioning will be discussed in the second component of this series.Physiological explanations for the apparent cardiac and CNS benefits of moderate alcohol consumption have invoked the concept of ethanol preconditioning(EtOH-PC)which refers to a phenomenon in which heart and brain tissues are protected from the deleterious effects of ischemia/reperfusion(I/R)by prior ingestion of ethanol at low to moderate levels.In our protocol,EtOH-PC was induced by gavaging animals with a moderate dose of ethanol [volume of ethanol in microliters calculated from the equation(body weight(in g)×0.6)+0.3] 24 h before ischemia and this dose as a bolus to animals achieved a peak plasma concentration of~45 mg/dl 30 min(equivalent to one to three alcoholic beverages)after gavage and returned to control levels within 60 min of alcohol ingestion).EtOH-PC may mimic the classical ischemic preconditioning(IPC)and resveratrol pharmacological preconditioning to protect against ischemia and reperfusion injury.There were many evidences that moderate consumption of ethanol alone exerts protective effects against injury due to myocardial ischemia.Chronic and low dose ethanol drinking actually resulted in a significant reduction of infarct size in the ex vivo heart rat model,a protective effect similar to that observed with IPC.It was shown that ethanol preconditioning,administered by gavage to gerbils with a moderate dose of ethanol as a single bolus(producing a peak plasma concentration of 42–46 mg/dl)24 h before ischemia,offered a number of beneficial effects against ischemic injuries,including reductions in behavioral deficit,delayed neuronal death,neuronal and dendritic degeneration,and oxidative DNA damage.Both pre-and posttreatment with intracerebroventricular infusion of ethanol(0.1%,60 min prior or 30 min after ischemia)attenuated transient focal ischemic infarct.In a study by Zhao et al.,it was found that low doses of ethanol administered one hour prior to middle cerebral artery occlusion(MCAO)reduced ischemic core water content,or cerebral edema,in Sprague-Dawley rats.Larger doses of ethanol were shown to intensify the damage ethanol-induced cardioprotection was documented by improved recovery of contractile function and reduced release of CK,an indicator of myocyte damage.Moderate alcohol consumption reduced myocardial infarct size and cardiomyocyte apoptosis and induced significant amount of oxidative stress to the hearts which was then translated into the induction of the expression of several cardioprotective oxidative stressinducible proteins including heat shock protein(HSP)70.Endothelial nitric oxide synthase(eNOS)is a key regulator of vascular homeostasis and myocardial functions through the controlled production of nitric oxide(NO).Alcohol-associated cardioprotection was mediated,in part,through modulation of the eNOS protein and activity in the cardiovascular system.Models of inflammatory neural diseases also benefit from pre-exposure to ethanol,which may allow some extrapolation to the inflammatory state in stroke or chronic neurodegeneration.In hippocampal–entorhinal cortical organotypic cultures,ethanol preexposure(20–30 mM,6 days)significantly decreased neuronal degeneration due to exposure of the neuroinflammatory HIV-1 envelope glycoprotein.These studies demonstrate a possible role for ethanol in effecting a preconditioned state against neuroinflammatory processes.Epidemiological studies focusing on Alzheimer disease(AD)risk factors have indicated that alcohol,if consumed in moderation,is inversely correlated with developing either cardiovascular disease or AD,two conditions that share many common risk factors.Specifically,1–6 drinks per week were associated with reduced risk for developing dementia.Concurring with these observations,rat brain cerebellar cultures and hippocampalentorhinal cortical organotypic cultures were protected against Aβ toxicity by moderate ethanol exposure prior to the insult.The exact molecular mechanism of ethanol preconditioning remains obscure.Attempts to confirm this mechanism will provide new directions in the study of pharmaceutical preconditioning and the development of new treatment approaches for reducing the extent of CNS disease.