dihydropyridines and Parkinsonian-Disorders

A study was undertaken to test the association between dihydropyridine calcium channel blocker use and the time to important milestones of disease progression among patients with parkinsonism.. Data were obtained from Ontario's health care administrative databases. Within a cohort of hypertensive individuals older than 65 years who developed parkinsonism, we examined the effect of the length of exposure to less brain-penetrant dihydropyridines (amlodipine) and more brain-penetrant dihydropyridines (eg, nifedipine, felodipine) on parkinsonism milestones as measured by time to requiring drug treatment for parkinsonism, nursing home admission, and death.. Among 4,733 hypertensive individuals with parkinsonism, longer treatment with any dihydropyridine was associated with a decreased risk of each of the 3 outcomes. There was no difference, however, between amlodipine (adjusted hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.42-0.50 for initiation of drug treatment; HR, 0.68; 95% CI, 0.63-0.73 for application for nursing home admission; and HR, 0.75; 95% CI, 0.70-0.80 for death) and nonamlodipine dihydropyridines (adjusted HRs [95% CIs], 0.45 [0.39-0.53], 0.74 [0.67-0.81], and 0.74 [0.64-0.85] for the 3 milestones, respectively).. We found no specific beneficial effect of treatment with brain-penetrant dihydropyridines on delaying parkinsonism progression milestones. Dihydropyridine calcium channel blockers are unlikely to have a clinically significant effect on the course of parkinsonism, particularly Parkinson disease, in the doses used to treat hypertension.

Topics: Aged; Aged, 80 and over; Calcium Channel Blockers; Cohort Studies; Dihydropyridines; Disease Progression; Female; Humans; Hypertension; Male; Parkinsonian Disorders; Retrospective Studies

The motor symptoms of Parkinson's disease (PD) are due to the progressive loss of dopamine (DA) neurons in substantia nigra pars compacta (SNc). Nothing is known to slow the progression of the disease, making the identification of potential neuroprotective agents of great clinical importance. Previous studies using the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD have shown that antagonism of L-type Ca2+ channels protects SNc DA neurons. However, this was not true in a 6-hydroxydopamine (6-OHDA) model. One potential explanation for this discrepancy is that protection in the 6-OHDA model requires greater antagonism of Cav1.3 L-type Ca2+ channels thought to underlie vulnerability and this was not achievable with the low affinity dihydropyridine (DHP) antagonist used. To test this hypothesis, the DHP with the highest affinity for Cav1.3L-type channels-isradipine-was systemically administered and then the DA toxin 6-OHDA injected intrastriatally. Twenty-five days later, neuroprotection and plasma concentration of isradipine were determined. This analysis revealed that isradipine produced a dose-dependent sparing of DA fibers and cell bodies at concentrations achievable in humans, suggesting that isradipine is a potentially viable neuroprotective agent for PD.

Topics: Animals; Calcium Channel Blockers; Calcium Channels, L-Type; Dihydropyridines; Disease Models, Animal; Isradipine; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Parkinsonian Disorders

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