dihydropyridines and Parkinson-Disease

This review will focus on the principles underlying the hypothesis that neuronal physiological phenotype-how a neuron generates and regulates action potentials-makes a significant contribution to its vulnerability in Parkinson's disease (PD) and aging. A cornerstone of this hypothesis is that the maintenance of ionic gradients underlying excitability can pose a significant energetic burden for neurons, particularly those that have sustained residence times at depolarized membrane potentials, broad action potentials, prominent Ca(2+) entry, and modest intrinsic Ca(2+) buffering capacity. This energetic burden is shouldered in neurons primarily by mitochondria, the sites of cellular respiration. Mitochondrial respiration increases the production of damaging superoxide and other reactive oxygen species (ROS) that have widely been postulated to contribute to cellular aging and PD. Many of the genetic mutations and toxins associated with PD compromise mitochondrial function, providing a mechanistic linkage between known risk factors and cellular physiology that could explain the pattern of pathology in PD. Because much of the mitochondrial burden created by this at-risk phenotype is created by Ca(2+) entry through L-type voltage-dependent channels for which there are antagonists approved for human use, a neuroprotective strategy to reduce this burden is feasible.

Topics: Action Potentials; Aging; Animals; Calcium Channels, L-Type; Dihydropyridines; Disease Susceptibility; DNA, Mitochondrial; Dopamine; Energy Metabolism; Humans; Ions; Mitochondria; Neurons; Parkinson Disease; Phenotype; Reactive Oxygen Species; Sequence Deletion; Substantia Nigra

Dihydropyridines (DHPs) may have neuroprotective effects against Parkinson's disease (PD).. This study investigated the effects of DHPs on nigrostriatal dopaminergic denervation and longitudinal motor and cognitive outcomes in PD.. We classified 476 patients with drug-naive PD who had undergone dopamine transporter imaging into three groups. They were selected according to a prior diagnosis of hypertension and use of DHPs and were matched using propensity scores: patients without hypertension (HTN-; n = 50) and patients with hypertension treated without DHP (HTN+/DHP-; n = 50) or with DHP (HTN+/DHP+; n = 50). Multiple linear regression and linear mixed model analyses were performed to determine intergroup differences in baseline dopamine transporter availability and longitudinal changes in the levodopa-equivalent dose, respectively. Using Kaplan-Meier analyses, we compared the risks of levodopa-induced dyskinesia, wearing off, and dementia-free survival during the 5.06 years of the mean follow-up period. The Cox regression model determined the independent effects of DHPs on dementia conversion.. DHPs may be associated with better long-term cognitive outcomes in hypertensive patients with PD. © 2023 International Parkinson and Movement Disorder Society.

Topics: Antiparkinson Agents; Cognition; Dihydropyridines; Dopamine Plasma Membrane Transport Proteins; Dyskinesias; Humans; Hypertension; Levodopa; Parkinson Disease

Studies showed that JM-20, a benzodiazepine-dihydropyridine hybrid molecule, protects against rotenone and 6-hydroxydopamine neurotoxicity. However, its protective effects against cytotoxicity induced by endogenous neurotoxins involved in Parkinson's disease (PD) pathogenesis have never been investigated. In this study, we evaluated the ability of JM-20 to inhibit alpha-synuclein (aSyn) aggregation. We also evaluated the interactions of JM-20 with aSyn by molecular docking and molecular dynamics and assessed the protective effect of JM-20 against aminochrome cytotoxicity. We demonstrated that JM-20 induced the formation of heterogeneous amyloid fibrils, which were innocuous to primary cultures of mesencephalic cells. Moreover, JM-20 reduced the average size of aSyn positive inclusions in H4 cells transfected with SynT wild-type and synphilin-1-V5, but not in HEK cells transfected with synphilin-1-GFP. In silico studies showed the interaction between JM-20 and the aSyn-binding site. Additionally, we showed that JM-20 protects SH-SY5Y cells against aminochrome cytotoxicity. These results reinforce the potential of JM-20 as a neuroprotective compound for PD and suggest aSyn as a molecular target for JM-20.

Topics: alpha-Synuclein; Benzodiazepines; Dihydropyridines; Humans; Molecular Docking Simulation; Neuroblastoma; Parkinson Disease

Experimental evidence and case-control studies suggest that dihydropyridine calcium channel blockers (DiCCBs) may protect against Parkinson's disease. The authors conducted a historical cohort study in Denmark to investigate the association between DiCCB use and risk of Parkinson's disease (1998-2006). Individual-level data on filled drug prescriptions, diagnostic information, and covariates were linked between nationwide registries. Among DiCCB users, 173 incident cases of Parkinson's disease were detected during 461,984 person-years of follow-up, compared with 5,538 cases during 17,343,641 person-years of follow-up among nonusers. After adjustment for age, sex, year, propensity score, and use of other antihypertensive drugs and statins, DiCCB use was associated with a reduced risk of Parkinson's disease (rate ratio (RR) = 0.71, 95% confidence interval (CI): 0.60, 0.82). This association was not present in patients who had previously used DiCCBs (RR = 1.04, 95% CI: 0.87, 1.24). DiCCB users aged ≥65 years were at lower risk of Parkinson's disease than DiCCB users aged <65 years (RR = 0.59, 95% CI: 0.40, 0.85). Among patients with Parkinson's disease, DiCCB use was associated with reduced risk of death (adjusted RR = 0.66, 95% CI: 0.47, 0.91) but not dementia (adjusted RR = 0.97, 95% CI: 0.60, 1.56). In conclusion, DiCCB exposure was associated with a reduced risk of incident Parkinson's disease, particularly in older patients, and with reduced mortality among patients with Parkinson's disease.

Topics: Age Factors; Aged; Calcium Channel Blockers; Cohort Studies; Denmark; Dihydropyridines; Female; Humans; Incidence; Male; Middle Aged; Parkinson Disease; Poisson Distribution; Propensity Score; Risk Factors

An increase in neuronal burst activities in the subthalamic nucleus (STN) is a well-documented electrophysiological feature of Parkinson disease (PD). However, the causal relationship between subthalamic bursts and PD symptoms and the ionic mechanisms underlying the bursts remain to be established. Here, we have shown that T-type Ca(2+) channels are necessary for subthalamic burst firing and that pharmacological blockade of T-type Ca(2+) channels reduces motor deficits in a rat model of PD. Ni(2+), mibefradil, NNC 55-0396, and efonidipine, which inhibited T-type Ca(2+) currents in acutely dissociated STN neurons, but not Cd(2+) and nifedipine, which preferentially inhibited L-type or the other non–T-type Ca(2+) currents, effectively diminished burst activity in STN slices. Topical administration of inhibitors of T-type Ca(2+) channels decreased in vivo STN burst activity and dramatically reduced the locomotor deficits in a rat model of PD. Cd(2+) and nifedipine showed no such electrophysiological and behavioral effects. While low-frequency deep brain stimulation (DBS) has been considered ineffective in PD, we found that lengthening the duration of the low-frequency depolarizing pulse effectively improved behavioral measures of locomotion in the rat model of PD, presumably by decreasing the availability of T-type Ca(2+) channels. We therefore conclude that modulation of subthalamic T-type Ca(2+) currents and consequent burst discharges may provide new strategies for the treatment of PD.

Topics: Animals; Benzimidazoles; Cadmium; Calcium; Calcium Channels, T-Type; Cyclopropanes; Dihydropyridines; Disease Models, Animal; Electrophysiology; Male; Mibefradil; Movement; Naphthalenes; Neurons; Nickel; Nitrophenols; Organophosphorus Compounds; Parkinson Disease; Rats; Rats, Wistar

This study was undertaken to investigate L-type calcium channel blockers of the dihydropyridine class for association with Parkinson disease (PD), because some of these drugs traverse the blood-brain barrier, are potentially neuroprotective, and have previously been evaluated for impact on PD risk.. We identified 1,931 patients with a first-time diagnosis for PD between 2001 and 2006 as reported in the Danish national hospital/outpatient database and density matched them by birth year and sex to 9,651 controls from the population register. The index date for cases and their corresponding controls was advanced to the date of first recorded prescription for anti-Parkinson drugs, if prior to first PD diagnosis in the hospital records. Prescriptions were determined from the national pharmacy database. In our primary analyses, we excluded all calcium channel blocker prescriptions 2 years before index date/PD diagnosis.. Employing logistic regression analysis adjusting for age, sex, diagnosis of chronic pulmonary obstructive disorder, and Charlson comorbidity score, we found that subjects prescribed dihydropyridines (excludes amlodipine) between 1995 and 2 years prior to the index date were less likely to develop PD (odds ratio, 0.73; 95% confidence interval, 0.54-0.97); this 27% risk reduction did not differ with length or intensity of use. Risk estimates were close to null for the peripherally acting drug amlodipine and for other antihypertensive medications.. Our data suggest a potential neuroprotective role for centrally acting L-type calcium channel blockers of the dihydropyridine class in PD that should be further investigated in studies that can distinguish between types of L-type channel blockers.

Topics: Aged; Aged, 80 and over; Amlodipine; Antihypertensive Agents; Calcium Channel Blockers; Community Health Planning; Denmark; Dihydropyridines; Female; Humans; Logistic Models; Male; Middle Aged; Outpatients; Parkinson Disease; Prescription Drugs; Registries; Retrospective Studies

Parkinson's disease is a pervasive, ageing-related neurodegenerative disease the cardinal motor symptoms of which reflect the loss of a small group of neurons, the dopaminergic neurons in the substantia nigra pars compacta (SNc). Mitochondrial oxidant stress is widely viewed as being responsible for this loss, but why these particular neurons should be stressed is a mystery. Here we show, using transgenic mice that expressed a redox-sensitive variant of green fluorescent protein targeted to the mitochondrial matrix, that the engagement of plasma membrane L-type calcium channels during normal autonomous pacemaking created an oxidant stress that was specific to vulnerable SNc dopaminergic neurons. The oxidant stress engaged defences that induced transient, mild mitochondrial depolarization or uncoupling. The mild uncoupling was not affected by deletion of cyclophilin D, which is a component of the permeability transition pore, but was attenuated by genipin and purine nucleotides, which are antagonists of cloned uncoupling proteins. Knocking out DJ-1 (also known as PARK7 in humans and Park7 in mice), which is a gene associated with an early-onset form of Parkinson's disease, downregulated the expression of two uncoupling proteins (UCP4 (SLC25A27) and UCP5 (SLC25A14)), compromised calcium-induced uncoupling and increased oxidation of matrix proteins specifically in SNc dopaminergic neurons. Because drugs approved for human use can antagonize calcium entry through L-type channels, these results point to a novel neuroprotective strategy for both idiopathic and familial forms of Parkinson's disease.

Topics: Animals; Biological Clocks; Brain; Calcium; Calcium Channel Blockers; Calcium Channels, L-Type; Calcium Signaling; Cyclophilins; Dihydropyridines; Dopamine; Gene Deletion; Ion Channels; Iridoid Glycosides; Iridoids; Male; Mice; Mice, Transgenic; Mitochondria; Mitochondrial Proteins; Neurons; Oncogene Proteins; Oxidative Stress; Parkinson Disease; Peptidyl-Prolyl Isomerase F; Peroxiredoxins; Protein Deglycase DJ-1; Purines; Superoxides; Uncoupling Protein 1

Pacemaking activity in adult substantia nigra (SN) dopamine neurons relies on L-type Ca2+ channels, but a surprising study in Nature by Chan et al. demonstrates that blockade of these channels by dihydropyridines re-establishes the pacemaking driven by sodium and HCN channels found in juvenile SN. This shift protects SN neurons in chemical models of Parkinson's disease (PD), suggesting that elevated intracellular Ca2+ participates in SN cell loss and that dihydropyridines may provide therapy in PD.

Topics: Animals; Antiparkinson Agents; Biological Clocks; Calcium Channels, L-Type; Cyclic Nucleotide-Gated Cation Channels; Dihydropyridines; Humans; Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; Parkinson Disease; Parkinson Disease, Secondary; Potassium Channels; Substantia Nigra

The results of this study demonstrate that the equilibrium nonspecific binding of DHP Ca2+ channel blockers to the membrane bilayer is highly dependent on cholesterol content. The molecular explanation for this observation appears to be related to the fact that cholesterol and DHPs occupy a similar molecular location in the membrane hydrocarbon core (Fig. 4). The membrane location of amlodipine may also be critical for subsequent receptor recognition and binding to voltage-sensitive Ca2+ channels in peripheral and CNS tissue. Finally, changes in the cholesterol content of neural plasma membranes isolated from diseased cortical regions of subjects with AD were reported and may be indicative of a general defect in lipid metabolism. Further studies are underway to characterize in greater detail possible changes in cholesterol content with aging and AD. The implication of these changes for structure/function relationships in the membrane is also being explored.

Topics: Aged; Aging; Alzheimer Disease; Amlodipine; Brain Chemistry; Calcium Channel Blockers; Cell Membrane; Cholesterol; Dihydropyridines; Female; Humans; In Vitro Techniques; Lipid Bilayers; Male; Membrane Lipids; Membrane Proteins; Nerve Tissue Proteins; Neurons; Parkinson Disease; Phospholipids; Solubility; X-Ray Diffraction

Topics: Aged; Aged, 80 and over; Antihypertensive Agents; Antiparkinson Agents; Dihydropyridines; Drug Therapy, Combination; Female; Humans; Hypertension; Male; Neurologic Examination; Nitrobenzenes; Parkinson Disease; Parkinson Disease, Secondary; Piperazines

Disruptions of normal calcium (Ca2+) homeostasis in human aging processes, are well documented. The existence of at least four distinct types of Ca2+ channels, L-, T-, P-, and N-, have been reported in the central nervous system. Binding sites for clinically useful dihydropyridines (DHP) and phenylalkylamines (PA) are located on the L-type Ca2+ channels. In the present study, DHP/[3H]PN200-110 and PA/[3H](-)-D-888 binding parameters were determined in various brain areas obtained at autopsy from Alzheimer's (AD), Parkinson's (PD), Huntington's (HD) disease patients, and healthy age-matched controls as a means to assess the integrity of L-type channels in these neurological disorders often associated with the aging brain. DHP and PA receptor binding parameters (KD and Bmax) were not significantly altered in any of the brain regions studied in AD and PD. However, a significant decrease in the maximal binding capacity of [3H]PN200-110 was observed in the striatum of HD patients. Taken together, this suggests that DHP and PA binding sites associated to L-type Ca2+ channels are mostly preserved in AD and PD brains. Accordingly, the use of DHP- and/or PA-related drugs in these neurological disorders should not be hindered by deficits in their related Ca2+ channel binding proteins.

Topics: Aged; Alzheimer Disease; Autopsy; Binding Sites; Brain; Calcium; Calcium Channels; Dihydropyridines; Female; Humans; Huntington Disease; Isradipine; Male; Middle Aged; Organ Specificity; Parkinson Disease; Reference Values; Verapamil