Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs

Domoki, Ferenc and Bari, Ferenc and Nagy, K. and Siklós, László (2004) Diazoxide prevents mitochondrial swelling and Ca2+ accumulation in CA1 pyramidal cells after cerebral ischemia in newborn pigs. BRAIN RESEARCH, 1019 (1-2). pp. 97-104. ISSN 0006-8993

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Abstract

Diazoxide (DIAZ), an opener of mitochondrial ATP-sensitive K+ channels (mK(ATP)), protects neurons against hypoxic/ischemic stress in vivo, however, direct evidence showing mitochondrial effects of DIAZ in postischemic neurons is lacking. We investigated if DIAZ affects mitochondrial alterations after global ischemia/reperfusion (I/R) in CA1 pyramidal neurons by using oxalate-pyroantimonate electron cytochemistry. Anesthetized piglets were either non-treated, or treated with DIAZ (3 mg/kg, iv), I/R, DIAZ+I/R, or 5-hydroxy-decanoate (5HD)+DIAZ+I/R(n=6, 6, 11, 5, 7, respectively). Ischemia(10 min)was induced by intracranial pressure (ICP) elevation. After 5-30min of reperfusion, the brains were fixed for ultrastructural studies. Relative volumes of Ca2+-containing deposits and mitochondria in CA1 pyramidal cells were determined by point counting on electron micrographs. I/R resulted in maximal increases in mitochondrial volume (from 7.14 +/- 0.63% to 9.74 +/- 0.57%*), and Ca2+ levels (from 5.86 +/- 1.11% to 11.39 +/- 1.35%*; mean S.E.M., *p<0.05) at 10-15-min reperfusion time. In this interval, pretreatment with DIAZ virtually abolished mitochondrial swelling (6.88 +/- 0.49%) and Ca2+ accumulation (5.15 +/- 0.82%) evoked by I/R. The protective effect of DIAZ was reduced by 5HD, an inhibitor of mK(ATB) resulting in a calcium accumulation similar to that after IR (10.44 +/- 1.98%). Thus, DIAZ might preserve mitochondrial integrity in CA1 pyramidal cells after I/R, at least in part mediated by mK(ATP).

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