Anesthesiologists frequently manage patients at risk of cerebral ischemia, and anesthetics have long been studied as potential neuroprotectants. Because the changes provoked by cerebral ischemia are cellular mechanisms, simplified model systems complement animal studies by allowing analysis of cellular mechanisms. Defining the cellular effects of anesthetics on brain cells during ischemia will lead to a better understanding of the pathophysiology of ischemic brain injury. New therapeutic options will likely result from improved understanding of the cell biology of ischemia. Recently, brain protection from ischemia by prior induction of a stress response was reported. First described in response to heat, """"""""heat shock"""""""" or """"""""stress"""""""" protein production reflects a coordinated change in gene expression in response to diverse environmental stresses, including ischemia. This response, in the case of heat, is due to activation of a transcription factor (HSF) which leads to coordinated activation of stress genes. The known ability of neurons and astrocytes to mount a stress response is proposed to modulate their vulnerability to injury. However, the mechanism of stress response induction in the brain and its role in protection is not clearly defined.Furthermore, the effect of anesthetics on the cellular stress response is virtually unknown. The applicants propose to address these problems in primary cultures of neurons and astrocytes studying hsp70 as representative of the stress response. (1) The mechanisms of induction of transcription in neurons and astrocytes by OGD (in vitro ischemia) will be determined. (2) Whether some anesthetics alone induce hsp70 and whether they alter hsp70 production in astrocytes or neurons in response to ischemia will be determined. (3) Pretreatment with heat protects brain cells from subsequent ischemia; the importance of hsp70 in this protection will be evaluated using antisense RNA to block hsp70 production. (4) The relative efficacy of specific types of injury to induce hsp70 will be determined. These studies will help define the mechanism of induction of hsp70 and its possible importance in protecting neurons and astrocytes from OGD injury.
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