The aspirin metabolite sodium salicylate causes focal cerebral hemorrhage and cell death in rats with kainic acid-induced seizures

Aspirin (acetylsalicylic acid), and its main metabolite sodium salicylate, have been shown to protect neurons from excitotoxic cell death in vitro. Th e objective of our study was to investigate the possible neuroprotective ef fects of sodium salicylate in vivo in rats with kainic acid-induced seizure s. a model for temporal lobe epilepsy in human patients, Male Sprague-Dawle y rats received intraperitoneal injections of kainic acid either alone, or with sodium salicylate given before and for 40 h after kainic acid injectio ns. The control group received either phosphate-buffered saline or sodium s alicylate without co-administration of kainic acid. Animals developed statu s epilepticus, which was aborted 1.5-2 h later with diazepam. On day 3 foll owing kainic acid-induced seizures? animals received bromodeoxyuridine to m easure cellular proliferation, and were killed under anesthesia 24 h later. Brains were removed, sectioned, and analysed for gross histological change s, evidence of hemorrhage, DNA fragmentation, cellular proliferation, and m icroglial immunohistochemistry. We report that sodium salicylate did not pr otect neurons from seizure-induced cell death, and to the contrary, it caus ed focal hemorrhage and cell death in the hippocampal formation and the ent orhinal/piriform cortex of rats with kainic acid-induced seizures. Hemorrha ge was never observed in animals that received vehicle, kainic acid or sodi um salicylate only which indicated that sodium salicylate exerted its effec t only in animals with seizures, and was confined to select regions of the brain that undergo seizure activity. Large numbers of cells displaying DNA fragmentation were detected in the hippocampal formation, entorhinal/pirifo rm cortex and the dorsomedial thalamic nucleus of rats that received kainic acid or kainic acid in combination with sodium salicylate. Bromodeoxyuridi ne immunohistochemistry revealed large numbers of proliferating cells in an d around the areas with most severe neural injury induced by kainic acid or kainic acid co-administered with sodium salicylate, These same brain regio ns displayed intense staining with a microglia-specific marker, an indicati on of microglial activation in response to brain damage. In all cases, the degree of cell death, cell proliferation and microglia staining was more se vere in animals that received the combination of kainic acid and sodium sal icylate when compared to animals that received kainic acid alone. We hypothesize that our findings are attributable to sodium salicylate-indu ced blockade of cellular mechanisms that protect cells from calcium-mediate d injury. These initial observations may have important clinical implicatio ns for patients with epilepsy who take aspirin while affected by these cond itions, and should promote further investigation of this relationship. (C) 2000 IBRO. Published by Elsevier Science Ltd. All rights reserved.