Effects of a new diphenylpiperazine calcium antagonist, KB-2796, on cerebral ischemic neuronal damage in rats.
1. The effects of KB-2796, a new diphenylpiperazine calcium antagonist, on the mitochondrial dysfunction and energy metabolism deficits were examined in the ischemic rat brain. 2. KB-2796 (30 mg/kg, p.o.), administered 60 min prior to decapitation, improved the reduced respiratory activity of mitochondria obtained from rat brain 5 min after decapitative ischemia. 3. KB-2796 (30 mg/kg, p.o.), administered 60 min prior to ischemic insult, improved both the reductions in pyruvate and ATP and prevented increases in the lactate/pyruvate ratio induced by 30-min forebrain ischemia in rats with 4-vessel occlusion (4-VO). 4. The effect of KB-2796 on local cerebral glucose utilization (LCGU) was examined by a quantitative autoradiographic 2-[14C]deoxyglucose method in normal and 4-VO rats. 5. Postischemic LCGU measured 24 hr after reperfusion in the forebrain, in particular in the cortex, thalamus, geniculate body, hippocampus, caudate-putamen, nucleus accumbens, colliculus, and corpus callosum, was below the normal control value. 6. KB-2796 (1 mg/kg, i.v.), administered 1 min prior to the injection of 2-[14C]deoxyglucose, improved the reductions in LCGU that were produced by cerebral ischemia in the cortex, thalamus, geniculate body, caudate-putamen, nucleus accumbens and substantia nigra, but did not affect LCGU in normal rats. 7. These findings suggest that KB-2796 minimized the deficits in brain energy metabolism produced by ischemia; this agent may therefore be a valuable therapeutic drug in cerebrovascular-related disorders.
Yamashita
A
A
Department of Pharmacology, New Drug Research Laboratories, Kanebo Ltd, Osaka, Japan.
Ozaki
A
A
Ikegami
A
A
Hayashi
A
A
Hara
H
H
Sukamoto
T
T
Ito
K
K
D000818:Animals; D001921:Brain / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004734:Energy Metabolism / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D002121:Calcium Channel Blockers; D010879:Piperazines; C052424:lomerizine; D005947:Glucose