title: Nimodipine, an L-type calcium channel blocker attenuates mitochondrial dysfunctions to protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced Parkinsonism in mice.
abstract: Parkinson's disease (PD), the most common progressive neurodegenerative movement disorder, results from loss of dopaminergic neurons of substantia nigra pars compacta. These neurons exhibit Cav1.3 channel-dependent pacemaking activity. Epidemiological studies suggest reduced risk for PD in population under long-term antihypertensive therapy with L-type calcium channel antagonists. These prompted us to investigate nimodipine, an L-type calcium channel blocker for neuroprotective effect in cellular and animal models of PD. Nimodipine (0.1-10 μM) significantly attenuated 1-methyl-4-phenyl pyridinium ion-induced loss in mitochondrial morphology, mitochondrial membrane potential and increases in intracellular calcium levels in SH-SY5Y neuroblastoma cell line as measured respectively employing Mitotracker green staining, TMRM, and Fura-2 fluorescence, but only a feeble neuroprotective effect was observed in MTT assay. Nimodipine dose-dependently reduced 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian syndromes (akinesia and catalepsy) and loss in swimming ability in Balb/c mice. It attenuated MPTP-induced loss of dopaminergic tyrosine hydroxylase positive neurons in substantia nigra, improved mitochondrial oxygen consumption and inhibited reactive oxygen species production in the striatal mitochondria measured using dichlorodihydrofluorescein fluorescence, but failed to block striatal dopamine depletion. These results point to an involvement of L-type calcium channels in MPTP-induced dopaminergic neuronal death in experimental parkinsonism and more importantly provide evidences for nimodipine to improve mitochondrial integrity and function.
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology Kolkata, 4, Raja Subodh Mullick Road, Jadavpur, 700032, India.
authors.forename: Alpana
authors.initials: A
authors.lastname: Singh
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology Kolkata, 4, Raja Subodh Mullick Road, Jadavpur, 700032, India.
authors.forename: Poonam
authors.initials: P
authors.lastname: Verma
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology Kolkata, 4, Raja Subodh Mullick Road, Jadavpur, 700032, India.
authors.forename: Gillela
authors.initials: G
authors.lastname: Balaji
authors.affiliation: Department of Neurosciences, Medical University of South Carolina, Charleston, SC, 29425, USA.
authors.forename: Supriti
authors.initials: S
authors.lastname: Samantaray
authors.affiliation: Laboratory of Clinical and Experimental Neuroscience, Division of Cell Biology and Physiology, CSIR-Indian Institute of Chemical Biology Kolkata, 4, Raja Subodh Mullick Road, Jadavpur, 700032, India; Inter University Centre for Biomedical Research & Super Specialty Hospital, Mahatma Gandhi University Campus at Thalappady, Rubber Board PO, Kottayam, 686009, Kerala State, India. Electronic address: iucbr@mgu.ac.in.
authors.forename: Kochupurackal P
authors.initials: KP
authors.lastname: Mohanakumar
mesh_terms: D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine / Q000494:pharmacology; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use*; D020746:Calcium Channels, L-Type / Q000502:physiology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D006801:Humans; D020267:MPTP Poisoning / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control*; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018696:Neuroprotective Agents; D017382:Reactive Oxygen Species; D009553:Nimodipine; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
keywords: Dopaminergic neuroprotection; Intracellular calcium levels; Mitochondrial membrane potential; Motor functions in mice; SH-SY5Y cell line