dihydropyridines and Nerve-Degeneration

Studies have suggested that neuronal loss in Parkinson's disease (PD) could be related to the pacemaker activity of the substantia nigra pars compacta generated by L-type Ca(v) 1.3 calcium channels, which progressively substitute voltage-dependent sodium channels in this region during aging. Besides this mechanism, which leads to increases in intracellular calcium, other factors are also known to play a role in dopaminergic cell death due to overproduction of reactive oxygen species. Thus, dihydropyridines, a class of calcium channel blockers, and resveratrol, a polyphenol that presents antioxidant properties, may represent therapeutic alternatives for the prevention of PD. In the present study, we tested the effects of the dihydropyridines, isradipine, nifedipine, and nimodipine and of resveratrol upon locomotor behavior in Drosophila melanogaster. As previously described, paraquat induced parkinsonian-like motor deficits. Moreover, none of the drugs tested were able to prevent the motor deficits produced by paraquat. Additionally, isradipine, nifedipine, resveratrol, and ethanol (vehicle), when used in isolation, induced motor deficits in flies. This study is the first demonstration that dyhidropyridines and resveratrol are unable to reverse the locomotor impairments induced by paraquat in Drosophila melanogaster.

Topics: Animals; Antioxidants; Calcium Channel Blockers; Calcium Channels; Dihydropyridines; Disease Models, Animal; Dopamine; Drosophila melanogaster; Nerve Degeneration; Paraquat; Parkinsonian Disorders; Resveratrol; Stilbenes; Substantia Nigra

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

We investigated the effects of calcium antagonists against ischemic injury in vivo and against excitotoxic damage in vitro. In vivo nimodipine protected significantly the CA1 hippocampal neurons from neurodegeneration after transient global ischemia in rats without changing the local cerebral blood flow. Furnidipine reduced the area of ischemia after permanent MCA-occlusion in mice. The results in vitro using the Ca(2+)-sensitive dye fura-2 showed that nimodipine reduced in a dose-dependent manner the elevation of [Ca2+]i in hippocampal neurons induced by K(+)-stimulation. The present in vitro and in vivo data show that calcium antagonists are potent agents in protecting neurons against the deleterious consequences of an excitotoxic or ischemic insult.

Topics: Animals; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Electroencephalography; Hippocampus; Ischemic Attack, Transient; Mice; Nerve Degeneration; Nimodipine; Rats; Time Factors

In the present study we investigated the effect of different Ca2+ entry blockers on the onset of neuronal damage induced by glutamate, kainate or alpha-amino-3-hydroxy-5-methyl-5-isoxazolo propionate (AMPA) in primary culture of rat cerebellar granule cells. We found that the dihydropyridine derivative, nifedipine used at 100 nM concentration, significantly counteracted the neuronal death induced by 15 min application of 50 microM glutamate. This effect was dependent on the presence of nifedipine before the exposure of granule cells to glutamate and was dose-related (IC50 = 10 nM). The nifedipine response was reproduced by isradipine and by verapamil with IC50 values of 9 and 100 nM, respectively. The activation of voltage sensitive Ca2+ channels elicited by 100 nM Bay K 8644, greatly enhanced glutamate-mediated neurotoxicity. Moreover, 100 nM isradipine was significantly active in blocking the neuronal death produced by 24 h exposure of cerebellar granule cells to 10 microM AMPA or 60 microM kainate. These results reveal a 'preventive' role of the Ca2+ entry blockers on the development of the neurodegeneration induced by overstimulation of various glutamate receptor subtypes.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Animals; Animals, Newborn; Calcium Channel Blockers; Cerebellum; Dihydropyridines; Excitatory Amino Acid Antagonists; Glutamates; Glutamic Acid; Ibotenic Acid; Isradipine; Kainic Acid; Nerve Degeneration; Nervous System Diseases; Nifedipine; Rats; Rats, Inbred Strains; Verapamil