Combined therapy with dizocilpine and levemopamil does not reduce ischemic neuronal injury in rats.
Excessive intracellular accumulation of calcium has been postulated to result in ischemic neuronal death. Reduction of intracellular calcium entry should therefore be expected to reduce ischemic neuronal injury. Two pathways through which extracellular calcium ions can enter neurons are voltage-sensitive and N-methyl-D-aspartate receptor-linked cation pores. Combined blockade of both these types of channels might be more effective in reducing intracellular calcium accumulation than the blockade of either channel alone. We therefore evaluated the cerebroprotective effects of dizocilpine, an N-methyl-D-aspartate receptor antagonist, and levemopamil, a phenylalkylamine calcium channel blocker, administered singly or in combination, in a model of forebrain ischemia in the rat. Four groups of rats (n = 8 each) were studied. In the first group, dizocilpine, 5 mg/kg, was administered before ischemia. In the second group, levemopamil, 5 mg/kg, was given both preischemia and 2 h postischemia. In the third group, both dizocilpine (5 mg/kg) and levemopamil (5 mg/kg) were given preischemia and levemopamil (5 mg/kg) was given postischemia. The control group received saline placebo. The rats were subjected to forebrain ischemia by bilateral carotid artery occlusion for 10 min with simultaneous hypotension to 35 mm Hg. Neuronal injury was evaluated 3 days after ischemia. Dizocilpine reduced postischemia neuronal injury in the ventral hippocampus (p = 0.045). Levemopamil and the combination of levemopamil and dizocilpine did not protect neurons from ischemic injury. The present study does not provide support for the strategy of combined therapy with dizocilpine (administered before ischemia) and levemopamil (administered before and after ischemia) to protect neurons from injury produced by severe incomplete forebrain ischemia.
Sano
T
T
University of California at San Diego, La Jolla 92093-0629.
Patel
P M
PM
Drummond
J C
JC
Cole
D J
DJ
D000818:Animals; D002121:Calcium Channel Blockers / Q000627:therapeutic use*; D016291:Dizocilpine Maleate / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D007511:Ischemia / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009474:Neurons / Q000473:pathology*; D051381:Rats; D011921:Rats, Inbred WKY; D014700:Verapamil / Q000031:analogs & derivatives* / Q000627:therapeutic use
D002121:Calcium Channel Blockers; D016291:Dizocilpine Maleate; D014700:Verapamil; C052752:emopamil