NEUROTOXICITY IN ORGANOTYPIC HIPPOCAMPAL SLICES MEDIATED BY ADENOSINE-ANALOGS AND NITRIC-OXIDE

Adenosine (ADO) and nitric oxide (NO) have been implicated in a variet y of neurophysiological actions, including induction of long-term pote ntiation, regulation of cerebral blood flow, and neurotoxicity/neuropr otection. ADO has been shown to promote NO release from astrocytes by a direct effect on A(1) and A(2) receptors, thus providing a link betw een actions of NO and adenosine in the brain. However, while adenosine acts as an endogenous neuroprotectant, NO is believed to be the effec tor of glutamate neurotoxicity. To resolve this apparent paradox, we h ave further investigated the effects of adenosine and NO on neuronal v iability in cultured organotypic hippocampal slices exposed to sub-let hal (20') in vitro ischemia. Up to a concentration of 500 mu M ADO did not cause toxicity while exposures to 100 mu M of the stable ADO anal ogue chloroadenosine (CADO) caused widespread neuronal damage when pai red to anoxia/hypoglycemia. CADO effects were significantly prevented by the ADO receptor antagonist theophylline and blockade of NO product ion by L-NA (100 mu M). Moreover, CADO effects were mimicked by the NO donor SIN-1 (100 mu M). Application of 100 mu M ADO following blockad e of adenosine deaminase (with 10 mu M EHNA) replicated the effects of CADO. CADO, ADO + EHNA but not ADO alone caused a prolonged and susta ined release of nitric oxide as measured by direct amperometric detect ion. We conclude that at high concentrations and/or following blockade of its enzymatic catabolism, ADO may cause neurotoxicity by triggerin g NO release from astrocytes. These results demonstrate for the first time that activation of pathways other than those involving neuronal g lutamate receptors can trigger NO-mediated neuronal cell death in the hippocampus. (C) 1997 Elsevier Science B.V.