dizocilpine-maleate and lomerizine

We examined the effects of a new Ca2+ channel blocker, lomerizine, on the intraocular hypertension-induced ischemia/reperfusion injury in rat retina and on the glutamate-induced neurotoxicity in rat cultured retinal neurons, and compared its effects with those of a Ca2+ channel blocker (flunarizine) and an N-methyl-D-aspartate receptor antagonist (MK-801). Morphometric evaluation at 7 days after ischemia/reperfusion showed that treatment with lomerizine (0.1 and 1 mg kg(-1), i.v.) prior to ischemia and again immediately after reperfusion dose-dependently reduced the retinal damage. Treatment with MK-801 (1 mg kg(-1), i.v.) before ischemia significantly reduced the resulting retinal damage. Flunarizine (0.1 and 1 mg kg(-1), i.v.) tended to reduce the retinal damage, but its effect did not reach statistical significance. In an in vitro study, pretreatment with lomerizine (0.1 and 1 microM) or flunarizine (1 microM) significantly reduced glutamate-induced neurotoxicity, the effects being concentration dependent. Lomerizine (1 microM) also exhibited protective effects against both the N-methyl-D-aspartate and kainate induced types of neurotoxicity. However, lomerizine (1 microM) had little effect on the neurotoxicity induced by ionomycin (1 microM) application. Glutamate-induced neurotoxicity was abolished by removing Ca2+ from the medium. These results indicate that lomerizine protects neuronal cells against retinal neurotoxicity both in vivo and in vitro, and that this Ca2+ channel blocker may be useful as a therapeutic drug against retinal diseases that cause neuronal injury, such as normal tension glaucoma (NTG).

Topics: Animals; Calcium Channel Blockers; Cells, Cultured; Dizocilpine Maleate; Dose-Response Relationship, Drug; Flunarizine; Glutamic Acid; Male; Neuroprotective Agents; Neurotoxicity Syndromes; Piperazines; Rats; Rats, Sprague-Dawley; Reperfusion Injury

NMDA receptor antagonists have been demonstrated to be neuroprotective in focal cerebral ischemia and are supposed to prevent neurotoxic intracellular calcium increase. Another mechanism of calcium influx during ischemia involves activation of voltage-activated calcium channels, although the efficacy of calcium channel blockers against ischemia-induced damage varies. The purpose of this study was to determine the contributions of the excitotoxic mechanism and of calcium channel activation to metabolic and functional damage to rabbit spinal cord after ischemia induced by occlusion of the abdominal aorta. All metabolic parameters determined (ATP, energy charge, and lactate) completely recovered at 4 days following 20 min of ischemia when NMDA receptor antagonist MK-801 (1 mg/kg given i.v.) or calcium channel blocker KB-2796 (50 mg/kg given i.p.) was administered either prior to or after ischemia. Significant metabolic recovery was also observed after 30 min of ischemia with MK-801 administered before occlusion and KB-2796 given early in recirculation. Similarly, neurologic functions followed by functional performance in the hindlimbs were completely recovered following 20 and 30 min of ischemia and 4 days of recovery. This study demonstrates that although MK-801 or KB-2796 does not prevent paraplegia due to spinal cord ischemia in the rabbit, both drugs can influence the rate of recovery after ischemic injury.

Topics: Adenosine Triphosphate; Animals; Calcium Channel Blockers; Dizocilpine Maleate; Energy Metabolism; Excitatory Amino Acid Antagonists; Hindlimb; Ischemia; Lactic Acid; N-Methylaspartate; Piperazines; Rabbits; Reperfusion; Spinal Cord