dihydropyridines and Brain-Edema

Voltage-dependent Ca(2+) channels have been divided into at least 5 types (L-, N-, T-, P-, and Q-type). L/N-type Ca(2+) channel blocker cilnidipine could reduce the size of cerebral infarction in the rat focal brain ischemia. L-type Ca(2+) channel blocker amlodipine reduced cerebral edema and inhibit neuronal cell death. N-type Ca(2+) channel blocker omega-conotoxin reduce the size of cerebral infarction and inhibit delayed neuronal cell death in hippocampal CA1 area. It is suggested that calcium antagonist has neuroprotective effect.

Topics: Amlodipine; Animals; Brain Edema; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Channels, N-Type; Cell Death; Cerebral Infarction; Dihydropyridines; Hippocampus; Humans; Neurons; Neuroprotective Agents; omega-Conotoxins; Rats

Cerebral ischemia is a major leading cause of death and at the first place cause of disability all over the world. There are a lot of drugs that are in experimental stage for treatment of stroke. Among them are calcium channel blockers (CCBs) that have, in animal models, different effectiveness in healing of ischemic damage in brain. Mechanism of CCBs' action in cerebral ischemia is still unclear, but antioxidative property is supposed to be implicated. In the present study, we investigated antioxidative and neuroprotective properties of two CCBs, azelnidipine and amlodipine.. Male Wistar Kyoto rats were subjected to 90 min of transient middle cerebral artery occlusion (MCAO) by a nylon thread. Animals were divided into 3 groups, vehicle, azelnidipine and amlodipine group. In the azelnidipine and amlodipine groups, rats were treated with azelnidipine (1 mg/kg) and amlodipine (1 mg/kg) by gastric gavage for 2 weeks before MCAO. Vehicle group was treated by solution of methyl cellulose for 2 weeks. Rats were killed 24 h after MCAO. Physiological parameters (mean arterial pressure, heart rate, body weight), infarct volume, brain edema index, cerebral blood flow (CBF), oxidative stress markers which are HEL, 4-HNE, AGE and 8-OHdG, and evidence of apoptosis by TUNEL, were investigated.. There were no significant differences among groups in mean arterial pressure, heart rate and body weight. Treatment with azelnidipine and amlodipine reduced infarct volume and brain edema. Azelnidipine treated group showed more marked reduction of infarct volume and cerebral edema than amlodipine group. There was no attenuation of CBF in CCBs groups. The number of HEL, 4-HNE, AGE and 8-OHdG positive cells were significantly decreased in the CCBs treated groups. These molecules were again fewer in the azelnidipine group than in the amlodipine group. In TUNEL staining, the numbers of positive cells was smaller in the CCBs treated groups, especially in the azelnidipine group.. Pretreatment of azelnidipine and amlodipine had a neuroprotective effect in ischemic brain. Antioxidative property is one of the important profiles of CCBs that is implicated in brain protection.

Topics: Amlodipine; Animals; Antioxidants; Apoptosis; Azetidinecarboxylic Acid; Brain; Brain Edema; Brain Infarction; Calcium Channel Blockers; Dihydropyridines; Immunohistochemistry; In Situ Nick-End Labeling; Infarction, Middle Cerebral Artery; Male; Nerve Degeneration; Neuroprotective Agents; Oxidative Stress; Rats; Rats, Inbred WKY; Reperfusion Injury; Treatment Outcome

CV-159, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic++ + acid methyl 6-(5-phenyl-3-pyrazolyloxy)hexyl ester, is a dihydropyridine derivative that blocks the L-type Ca2+ channel and inhibits the calmodulin (CaM)-dependent pathway. In this study, we examined the effects of CV-159 on rat ischemic brain injury. CV-159 (5 and 10 mg/kg, p.o.) gave significant protection against delayed neuronal death in the hippocampal CA1 region after 15-min transient forebrain ischemia. In contrast, the Ca2+ antagonists nicardipine (1 and 10 mg/kg, p.o.) and nifedipine (1 mg/kg, i.p.) and the CaM antagonist N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7, 500 ng, i.c.v.) had no effect on this hippocampal neuronal death. CV-159 also diminished the size of the brain infarct after permanent middle cerebral artery (MCA) occlusion, although physiological variables, including regional cerebral blood flow, were not affected. The increase in the water content of the infarcted cortex induced by MCA occlusion was significantly reduced by CV-159. On the other hand, neither nicardipine nor nifedipine affected the brain infarct size, volume or increased water content induced by MCA occlusion, as previously reported (A. Sauter and M. Rudin, Am. J. Hypertens. 4 121S-127S, 1991). These findings indicate that Ca2+ antagonists, such as nicardipine and nifedipine, and W-7 have no effect on rat ischemic brain injury. The results suggest that CV-159 protects against ischemic brain injury. This might be mediated by both blocking the L-type Ca2+ channel and inhibiting CaM-dependent function via Ca2+/CaM binding at a different binding site from that of W-7 to CaM (H. Umekawa, K. Yamakawa, K. Nunoki, N. Taira, T. Tanaka, and H. Hidaka, Biochem. Pharmacol. 37 3377-3381, 1988).

Topics: Animals; Body Temperature; Brain Edema; Calcium Channel Blockers; Calcium-Calmodulin-Dependent Protein Kinases; Cell Death; Cerebral Infarction; Dihydropyridines; Hemodynamics; Hippocampus; Ischemic Attack, Transient; Male; Neurons; Neuroprotective Agents; Nicardipine; Nifedipine; Rats; Rats, Sprague-Dawley; Sulfonamides; Time Factors; Water

SM-6586 (SM) is a new derivative of dihydropyridine with potent calcium blocking activity and inhibitory activity of the Na+/H+ and Na+/Ca++ exchange transport. The effect of SM on survival rate, brain edema and metabolites was evaluated using two different models in spontaneously hypertensive rat (SHR). Global ischemia was induced by bilateral common carotid artery ligation (BLCL) and focal ischemia was induced by middle cerebral artery occlusion. The survival rate after BLCL was higher in the SM-treated group. The brain water content was lower, the ATP level was higher and lactate level was lower in the SM-treated group compared to the control group. In focal ischemia models, the SM-treated group showed a reduction of T1 relaxation time. The brain water content was significantly decreased in the SM-treated group. These results indicate that SM was effective in ameliorating the ischemic insult in global and focal cerebral ischemia models.

Topics: Animals; Blood-Brain Barrier; Brain Damage, Chronic; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Energy Metabolism; Male; Oxadiazoles; Rats; Rats, Inbred SHR; Water-Electrolyte Balance

Acute cerebral ischemia was produced in rats by injection of arachidonic acid (AA) into the internal carotid artery. Evans blue (EB) was intravenously injected and its extravasation into the brain was determined as an indicator of disturbances in the blood-brain barrier and endothelial cells. Control animals showed severe cerebral edema and marked blue staining of the brain. Benidipine (30 micrograms/kg, i.p.) suppressed the increase in cerebral water content and the extravasation of EB. Similarly nicardipine (100 micrograms/kg, i.p.) suppressed the elevation of water content and the extravasation of EB. Furthermore, both benidipine (30 micrograms/kg, i.p.) and nicardipine (100 micrograms/kg, i.p.) improved the neuronal injuries following AA-injection. An antiplatelet agent, ticlopidine (100 mg/kg, i.p.), and a thromboxane A2 synthetase inhibitor, OKY-1581 (3 mg/kg, i.p.), also suppressed the elevation of cerebral water content. A lipoxygenase inhibitor, AA-561 (200 mg/kg, p.o.), and a cyclooxygenase inhibitor, indomethacin (10 mg/kg, i.p.), did not prevent the increase in cerebral water content. Neither benidipine (3-30 micrograms/kg, i.v.) nor nicardipine (100 micrograms/kg, i.v.) inhibited the AgNO3-induced thrombus formation of the abdominal aorta, whereas ticlopidine (100 mg/kg, p.o.) and OKY-1581 (3 mg/kg, i.v.) prevented the thrombus formation. From the present results, it is suggested that benidipine, as well as nicardipine, may protect against AA-induced acute cerebral infarction via a mechanism independent of antithrombotic action.

Topics: Animals; Arachidonic Acid; Benzoquinones; Blood-Brain Barrier; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Cerebral Infarction; Dihydropyridines; Evans Blue; Lipoxygenase Inhibitors; Male; Methacrylates; Nicardipine; Rats; Rats, Inbred Strains; Thromboxane-A Synthase; Ticlopidine