Protective Effect of Nimodipine against Ischemic Neuronal Damage in Rat Hippocampus without Changing Postischemic Cerebral Blood Flow

Abstract

The purpose of the present study was to investigate the neuroprotective action of nimodipine. Furthermore, the influence of nimodipine on postischemic local CBF (LCBF) was examined. Forebrain ischemia of the rat was performed for 10 min by bilateral carotid clamping, administration of trimethaphan, and blood withdrawal to obtain an MABP of 40 mm Hg. LCBF was measured after 10 min of postischemic recirculation by injecting [14C]iodoantipyrine in saline solution. Nimodipine (0.1, 0.3, and 1.0 mg/kg) was suspended in miglyol oil and applied orally 60 min prior to ischemia. Histological evaluation was performed 7 days after ischemia. Hippocampal neuronal damage was determined as the percentage of necrotic neurons. After preischemic application of nimodipine, neuronal damage was significantly reduced in the hippocampal CA1 subfield. Postischemic LCBF was not affected by treatment with nimodipine. These findings show that nimodipine is able to protect neurons against ischemic damage. The neuroprotective effect of nimodipine was not mediated by a postischemic cerebral vasodilation, but by a direct action on the neurons.

In Vivo Protection against NMDA-induced Neurodegeneration by MK-801 and Nimodipine: Combined Therapy and Temporal Course of Protection

“…Agents that block the Ca 2+ entry through activated NMDA-channels have been demonstrated in several ischaemia model studies to decrease neuronal damage Meldrum & Garthwaite, 1990;Siesjö et al, 1992). Other reports indicate that also blockade of the VDCCs and notably the L-type channels by dihydropyridines provide a remarkable neuroprotection in experimental ischaemia (Bellemann et al, 1983;Langley & Sorkin, 1989;Nuglisch et al, 1990;Rami & Krieglstein 1994;Scriabine et al, 1989).…”

“…Both MK-801 (dizocilipine) and nimodipine (a 1,4-dihydropyridine derivate, BAY E 9736) have been demonstrated to attenuate brain injury following experimental ischaemia and excitotoxic insults Luiten et al, 1995;McDonald et al, 1990;Nakamura et al, 1993;Nuglisch et al, 1990).…”

Cerebral Ischemia: Pharmacological Bases of Drug Therapy

“…6). Nimodipine had no influence on postischemic LCBF under these conditions [18]. These results clearly demonstrate that the calcium antagonist nimodipine mediates its neuroprotectivc effect via an action directly on neurons.…”

Delayed Neuronal Death in Ischemic Stroke: Molecular Pathways

“…Calcium/calmodulin-dependent protein kinase kinase (CaM-KK) protects against delayed apoptosis following glutamate by activating Atk and CaM kinase IV (Yano et al, 2005), which both are anti-apoptotic players. Nimodipine (Mossakowski & Gadamski, 1990;Nuglisch et al, 1990), dantrolene (Wei & Perry, 1996), and the tetrapeptide Tyr-Val-Ala-Aspchloromethyl ketone (Ac-YVAD-cmk) (Gray et al, 2001) are all able to block damage due to high cytosolic Ca 2+ levels in a variety of stroke models and may be useful in preventing excitotoxic damage. Energy depletion plays a large role in excitotoxicity.…”