SYNERGY BETWEEN CHRONIC CORTICOSTERONE AND SODIUM-AZIDE TREATMENTS INPRODUCING A SPATIAL-LEARNING DEFICIT AND INHIBITING CYTOCHROME-OXIDASE ACTIVITY

Previously, we developed a rat model of persistent mitochondrial dysfu nction based upon the chronic partial inhibition of the mitochondrial enzyme cytochrome oxidase (EC 1.9.3.1), Continuous systemic infusion o f sodium azide at approximate to 1 mg/kg per hr inhibited cytochrome o xidase activity and produced a spatial learning deficit, In other labo ratories, glucocorticoids have been reported to exacerbate neuronal da mage from various acute metabolic insults, Therefore, we tested the hy pothesis that corticosterone, the primary glucocorticoid in the rat, w ould potentiate the sodium azide-induced learning deficit, To this end , we first identified nonimpairing doses of sodium azide (approximate to 0.75 mg/kg per hr) and corticosterone (100-mg pellet, 3-week sustai ned-release). We now report that chronic co-administration of these in dividually nonimpairing treatments produced a severe learning deficit, Moreover, the low dose of corticosterone, which did not elevate serum corticosterone, acted synergistically with sodium azide to inhibit cy tochrome oxidase activity, The latter result represents a previously u nidentified effect of glucocorticoids that provides a candidate mechan ism for glucocorticoid potentiation of neurotoxicity induced by metabo lic insult, These results may have the clinical implication of expandi ng the definition of hypercortisolism in patient populations with comp romised oxidative metabolism, Furthermore, they suggest that glucocort icoid treatment may contribute to pathology in disease or trauma condi tions that involve metabolic Insult.