K-ATP channel openers, adenosine agonists and epileptic preconditioning are stress signals inducing hippocampal neuroprotection

Many models of induced ischemic and epileptic tolerance have now been descr ibed in the brain. Although detailed mechanisms underlying such protections still remain largely unknown, induction of heat shock proteins is amongst the endogenous responses believed to play an important role in cellular def ense mechanisms. This study reveals that the development of epileptic toler ance also coincides with the induction of the 70,000 mel. wt heat shock pro tein expression within the time window of protection. Adenosine agonists or ATP-sensitive potassium channel openers have also been shown to exert stro ng neuroprotective effects when injected shortly prior to a severe ischemic or epileptic insult. The present work shows that adenosine receptor activa tion and ATP-sensitive potassium channel opening induce 70,000 mel. wt heat shock protein expression in the rat hippocampus and are able to mimic neur oprotection driven by preconditioning. R-phenylisopropyladenosine, a purine agonist, or (-)cromakalim, an ATP-sensitive potassium channel opener, was administered three days prior to a lethal ischemic or epileptic episode to mimic preconditioning. Neurodegeneration was assessed using Cresyl Violet s taining and cellular DNA fragmentation visualized by the terminal deoxynucl eotidyl transferase-mediated 2'-deoxyuridine 5'-triphosphate-biotin nick en d labeling method. 70,000 mel. wt heat shock protein expression was analyse d by western blotting and immunohistochemistry. The results show a long-las ting neuroprotection induced by activation of adenosine receptors or ATP-se nsitive K+ channels as early as three days prior to induction of a severe i schemic or epileptic challenge. This protective effect is associated with e nhanced 70,000 mel. wt heat shook protein expression also occurring three d ays following administration of R-phenylisopropyladenosine or (-)cromakalim . These findings support the idea that preconditioning doses of R-phenylisopr opyladenosine and (-)cromakalim act as mild cellular stresses inducing neur oprotection in a manner similar to a mild kainate treatment prior to a leth al ischemic or severe epileptic insult three days later. They also suggest that a delayed 70,000 mel. wt heat shock protein expression induced by exci tatory neuronal stresses such as short ischemia, mild kainic acid treatment or activation of adenosine receptors and ATP sensitive potassium channels is predictive of neuronal survival against a subsequent lethal injury. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.