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

Singh, Alpana; Verma, Poonam; Balaji, Gillela; Samantaray, Supriti; Mohanakumar, Kochupurackal P.

doi:10.1016/j.neuint.2016.07.003

Cited by 56 publications

(51 citation statements)

References 78 publications

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“…The dosing regimen was chosen according to the literature (13,17,18). The clinical score was significantly attenuated in nimodipinetreated mice in both the typical and atypical EAE groups ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…By applying different doses of nimodipine to N9 and BV-2 cultures for 24 h, we were able to detect a dose-dependent loss of cells. Doses were chosen according to the literature (13,24,25). A dose of 1 μM nimodipine did not lead to a significant difference compared with vehicle-treated cells, but in both cell lines a dose of 5 μM significantly reduced the number of microglial cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Nimodipine is a well-known cardiovascular drug and typically is used for long-term treatment in patients. Most recently it was shown that patients undergoing long-term antihypertensive therapy with L-type calcium channel blockers had a reduced risk of suffering from Parkinson's disease (13). Because MS patients usually are young and have a robust circulatory system, the long-term application of nimodipine should be safe.…”

Section: Discussionmentioning

confidence: 99%

“…To ensure that the doses of nimodipine used both in vivo and in vitro in our study were clinically relevant, we followed the recommendations in published studies (6, 13, 18, 50, 51). All doses described in the quoted literature were able to attenuate cognitive deficits in models of neurodegenerative diseases and to trigger endogenous hormone responses, so it is likely that sufficient levels of the drug were achieved in the CNS (13,50,52). Furthermore, many studies on subarachnoidal hemorrhage have shown that the dosages used in animal studies are able to induce comparable effects in patients (51, 52).…”

Section: Methodsmentioning

confidence: 99%

“…Its influence on oxidative stress, neuronal survival, synaptic plasticity, and aging also are being investigated, especially within the hippocampus (10,12). In addition, it was recently shown that the risk of suffering from Parkinson's disease was decreased under treatment with dihydropyridines (13). These studies suggest that nimodipine might have beneficial effects in MS as well, although its role in neurodegenerative diseases that are mediated by inflammatory events has not been well established (6).…”

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confidence: 99%

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Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Despite continuous interest in multiple sclerosis (MS) research, there is still a lack of neuroprotective strategies, because the main focus has remained on modulating the immune response. Here we performed in-depth analysis of neurodegeneration in experimental autoimmune encephalomyelitis (EAE) and in in vitro studies regarding the effect of the well-established L-type calcium channel antagonist nimodipine. Nimodipine treatment attenuated clinical EAE and spinal cord degeneration and promoted remyelination. Surprisingly, we observed calcium channel-independent effects on microglia, resulting in apoptosis. These effects were cell-type specific and irrespective of microglia polarization. Apoptosis was accompanied by decreased levels of nitric oxide (NO) and inducible NO synthase (iNOS) in cell culture as well as decreased iNOS and reactive oxygen species levels in EAE. In addition, increased numbers of Olig2 + APC + oligodendrocytes were detected. Overall, nimodipine application seems to generate a favorable environment for regenerative processes and therefore could be a treatment option for MS, because it combines features of immunomodulation with beneficial effects on neuroregeneration.M ultiple sclerosis (MS) is the most prevalent neurological disease of the CNS in young adults and is characterized by inflammation, demyelination, and axonal pathology (1) that result in multiple neurological and cognitive deficits (1-3). Intensive MS research studies have investigated modulating the immune system (4). Common therapeutic strategies are effective in slowing disease progression and attenuating the symptoms, but they cannot cure the disease. The option of preventing neurodegeneration early on would be a valuable addendum to customary treatment (4). Here we suggest that application of nimodipine could be an elegant way to target both neuroinflammation and neurodegeneration. The dihydropyridine nimodipine is commonly known as a 1.2 voltagegated L-type calcium channel antagonist and is used to treat hypertension and other cardiovascular diseases (5, 6). It also is used to prevent vasospasms after subarachnoidal hemorrhage (5) because of its high affinity for the CNS (7-9). Current research trials are examining its effects on brain injury, epilepsy, cognitive performance, and behavioral effects (6,7,10,11). Its influence on oxidative stress, neuronal survival, synaptic plasticity, and aging also are being investigated, especially within the hippocampus (10, 12). In addition, it was recently shown that the risk of suffering from Parkinson's disease was decreased under treatment with dihydropyridines (13). These studies suggest that nimodipine might have beneficial effects in MS as well, although its role in neurodegenerative diseases that are mediated by inflammatory events has not been well established (6). So far, nimodipine-mediated effects in the CNS have been claimed to result mainly from the modulation of neuronal activity, and studies on the potential effects of nimodipine on (micro)glia have not yet been conduct...

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Schampel

Volovitch

Koeniger

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Identification of Sclareol As a Natural Neuroprotective Ca_v1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery

et al. 2022

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Parkinson's disease (PD) results from selective loss of substantia nigra dopaminergic (SNc DA) neurons, and is primarily caused by excessive activity‐related Ca2+ oscillations. Although L‐type voltage‐gated calcium channel blockers (CCBs) selectively inhibiting Cav1.3 are considered promising candidates for PD treatment, drug discovery is hampered by the lack of high‐throughput screening technologies permitting isoform‐specific assessment of Cav‐antagonistic activities. Here, a synthetic‐biology‐inspired drug‐discovery platform enables identification of PD‐relevant drug candidates. By deflecting Cav‐dependent activation of nuclear factor of activated T‐cells (NFAT)‐signaling to repression of reporter gene translation, they engineered a cell‐based assay where reporter gene expression is activated by putative CCBs. By using this platform in combination with in silico virtual screening and a trained deep‐learning neural network, sclareol is identified from a essential oils library as a structurally distinctive compound that can be used for PD pharmacotherapy. In vitro studies, biochemical assays and whole‐cell patch‐clamp recordings confirmed that sclareol inhibits Cav1.3 more strongly than Cav1.2 and decreases firing responses of SNc DA neurons. In a mouse model of PD, sclareol treatment reduced DA neuronal loss and protected striatal network dynamics as well as motor performance. Thus, sclareol appears to be a promising drug candidate for neuroprotection in PD patients.

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Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis

Desai

Davies

Rossi

et al. 2020

Annals of Neurology

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Objective Treatment of relapses in multiple sclerosis (MS) has not advanced beyond steroid use, which reduces acute loss of function, but has little effect on residual disability. Acute loss of function in an MS model (experimental autoimmune encephalomyelitis [EAE]) is partly due to central nervous system (CNS) hypoxia, and function can promptly improve upon breathing oxygen. Here, we investigate the cause of the hypoxia and whether it is due to a deficit in oxygen supply arising from impaired vascular perfusion. We also explore whether the CNS‐selective vasodilating agent, nimodipine, may provide a therapy to restore function, and protect from demyelination in 2 MS models. Methods A variety of methods have been used to measure basic cardiovascular physiology, spinal oxygenation, mitochondrial function, and tissue perfusion in EAE. Results We report that the tissue hypoxia in EAE is associated with a profound hypoperfusion of the inflamed spinal cord. Treatment with nimodipine restores spinal oxygenation and can rapidly improve function. Nimodipine therapy also reduces demyelination in both EAE and a model of the early MS lesion. Interpretation Loss of function in EAE, and demyelination in EAE, and the model of the early MS lesion, seem to be due, at least in part, to tissue hypoxia due to local spinal hypoperfusion. Therapy to improve blood flow not only protects neurological function but also reduces demyelination. We conclude that nimodipine could be repurposed to offer substantial clinical benefit in MS. ANN NEUROL 2020 ANN NEUROL 2020;88:123–136

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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

Cited by 56 publications

References 78 publications

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Identification of Sclareol As a Natural Neuroprotective Ca_v1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery

Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis

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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

Cited by 56 publications

References 78 publications

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Nimodipine fosters remyelination in a mouse model of multiple sclerosis and induces microglia-specific apoptosis

Identification of Sclareol As a Natural Neuroprotective Cav1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery

Nimodipine Reduces Dysfunction and Demyelination in Models of Multiple Sclerosis

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Identification of Sclareol As a Natural Neuroprotective Ca_v1.3‐Antagonist Using Synthetic Parkinson‐Mimetic Gene Circuits and Computer‐Aided Drug Discovery