Synergy between chronic corticosterone and sodium azide treatments in producing a spatial learning deficit and inhibiting cytochrome oxidase activity.
Previously, we developed a rat model of persistent mitochondrial dysfunction based upon the chronic partial inhibition of the mitochondrial enzyme cytochrome oxidase (EC 1.9.3.1). Continuous systemic infusion of sodium azide at approximately 1 mg/kg per hr inhibited cytochrome oxidase activity and produced a spatial learning deficit. In other laboratories, glucocorticoids have been reported to exacerbate neuronal damage from various acute metabolic insults. Therefore, we tested the hypothesis that corticosterone, the primary glucocorticoid in the rat, would potentiate the sodium azide-induced learning deficit. To this end, we first identified nonimpairing doses of sodium azide (approximately 0.75 mg/kg per hr) and corticosterone (100-mg pellet, 3-week sustained-release). We now report that chronic co-administration of these individually 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 cytochrome oxidase activity. The latter result represents a previously unidentified effect of glucocorticoids that provides a candidate mechanism for glucocorticoid potentiation of neurotoxicity induced by metabolic insult. These results may have the clinical implication of expanding the definition of hypercortisolism in patient populations with compromised oxidative metabolism. Furthermore, they suggest that glucocorticoid treatment may contribute to pathology in disease or trauma conditions that involve metabolic insult.
Bennett
M C
MC
Department of Pharmacology, University of Colorado Health Sciences Center, Denver 80262, USA.
Mlady
G W
GW
Fleshner
M
M
Rose
G M
GM
D000704:Analysis of Variance; D000818:Animals; D001386:Azides / Q000008:administration & dosage / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D003345:Corticosterone / Q000008:administration & dosage / Q000494:pharmacology*; D004343:Drug Implants; D004357:Drug Synergism; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors*; D004924:Escape Reaction / Q000187:drug effects; D007263:Infusions, Parenteral; D007858:Learning / Q000187:drug effects*; D008297:Male; D008928:Mitochondria / Q000201:enzymology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D019810:Sodium Azide; D013028:Space Perception / Q000187:drug effects; D013570:Synaptic Membranes / Q000201:enzymology
D001386:Azides; D004343:Drug Implants; D019810:Sodium Azide; D003576:Electron Transport Complex IV; D003345:Corticosterone