Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson’s Disease: Therapeutic Rationale and Current Status

Swart, T.; Hurley, Michael J.

doi:10.1007/s40263-016-0393-9

Cited by 36 publications

(21 citation statements)

References 84 publications

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“…Curiously, users of dihydropyridine calcium channel-blocker drugs-which target the L-type voltage-sensitive Cav1.3 channels expressed by dopaminergic neurons of the SN-are at decreased risk for PD [289][290][291][292][293]. This might reflect the fact that, whereas healthy mitochondria can buffer the episodic flux of calcium through these channels-which function as rhythmically-activated pacemakers in dopaminergic neurons of the SN-maintaining a basal dopaminergic tone-impaired mitochondria does so less effectively, leaving neurons exposed to toxic intracellular calcium levels [294].…”

Section: Controlling Intracellular Calcium With Calcium Channel-blockmentioning

confidence: 99%

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

McCarty

Lerner

2020

IJMS

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Parkinson’s disease (PD) is a chronic low-grade inflammatory process in which activated microglia generate cytotoxic factors—most prominently peroxynitrite—which induce the death and dysfunction of neighboring dopaminergic neurons. Dying neurons then release damage-associated molecular pattern proteins such as high mobility group box 1 which act on microglia via a range of receptors to amplify microglial activation. Since peroxynitrite is a key mediator in this process, it is proposed that nutraceutical measures which either suppress microglial production of peroxynitrite, or which promote the scavenging of peroxynitrite-derived oxidants, should have value for the prevention and control of PD. Peroxynitrite production can be quelled by suppressing activation of microglial NADPH oxidase—the source of its precursor superoxide—or by down-regulating the signaling pathways that promote microglial expression of inducible nitric oxide synthase (iNOS). Phycocyanobilin of spirulina, ferulic acid, long-chain omega-3 fatty acids, good vitamin D status, promotion of hydrogen sulfide production with taurine and N-acetylcysteine, caffeine, epigallocatechin-gallate, butyrogenic dietary fiber, and probiotics may have potential for blunting microglial iNOS induction. Scavenging of peroxynitrite-derived radicals may be amplified with supplemental zinc or inosine. Astaxanthin has potential for protecting the mitochondrial respiratory chain from peroxynitrite and environmental mitochondrial toxins. Healthful programs of nutraceutical supplementation may prove to be useful and feasible in the primary prevention or slow progression of pre-existing PD. Since damage to the mitochondria in dopaminergic neurons by environmental toxins is suspected to play a role in triggering the self-sustaining inflammation that drives PD pathogenesis, there is also reason to suspect that plant-based diets of modest protein content, and possibly a corn-rich diet high in spermidine, might provide protection from PD by boosting protective mitophagy and thereby aiding efficient mitochondrial function. Low-protein diets can also promote a more even response to levodopa therapy.

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Section: Controlling Intracellular Calcium With Calcium Channel-blockmentioning

confidence: 99%

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

McCarty

Lerner

2020

IJMS

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“…Previous work has demonstrated the utility of immunotherapy to reduce aSyn levels in the CNS (Masliah et al, 2005 ) and prevent possible trans-synaptic spread of toxic aSyn species (Bae et al, 2012 ). A retrospective analysis demonstrated that the use of dihydropyridines correlates with decreased probability of developing PD (Pasternak et al, 2012 ), and an LTCC antagonist isradipine is currently in phase III clinical trials as a disease-modifying therapy for PD (Swart and Hurley, 2016 ). Combining these approaches with drugs that reduce toxic DA species might provide additional benefits.…”

Section: Concluding Remarks and Future Directionsmentioning

confidence: 99%

Can Interactions Between α-Synuclein, Dopamine and Calcium Explain Selective Neurodegeneration in Parkinson's Disease?

2018

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Several lines of evidence place alpha-synuclein (aSyn) at the center of Parkinson's disease (PD) etiology, but it is still unclear why overexpression or mutated forms of this protein affect some neuronal populations more than others. Susceptible neuronal populations in PD, dopaminergic neurons of the substantia nigra pars compacta (SNpc) and the locus coeruleus (LC), are distinguished by relatively high cytoplasmic concentrations of dopamine and calcium ions. Here we review the evidence for the multi-hit hypothesis of neurodegeneration, including recent papers that demonstrate synergistic interactions between aSyn, calcium ions and dopamine that may lead to imbalanced protein turnover and selective susceptibility of these neurons. We conclude that decreasing the levels of any one of these toxicity mediators can be beneficial for the survival of SNpc and LC neurons, providing multiple opportunities for targeted drug interventions aimed at modifying the course of PD.

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“…Recently, it was showed that the treatment with L-type CCBs, such as isradipine, reduces motor symptoms and attenuates progressive death of dopamine neurons from substantia nigra in animal model of Parkinson's disease [19]. It was showed that isradipine produces a dose-dependent sparing of dopaminergic fibers, and cell bodies at concentrations achievable in humans [20], suggesting that L-type CCBs are potentially viable neuroprotective agents for Parkinson's disease. A phase II clinical trial published in 2016 showed that treatment with isradipine was safely tolerated to reduce motor symptoms by patients with Parkinson's disease [20].…”

Section: + /Camp Signalling Interaction In Neuroprotectionmentioning

confidence: 99%

“…It was showed that isradipine produces a dose-dependent sparing of dopaminergic fibers, and cell bodies at concentrations achievable in humans [20], suggesting that L-type CCBs are potentially viable neuroprotective agents for Parkinson's disease. A phase II clinical trial published in 2016 showed that treatment with isradipine was safely tolerated to reduce motor symptoms by patients with Parkinson's disease [20]. In addition, a 10-year follow-up study (2000 to 2010), involving 82,107 hypertensive patients of more than 60 years of age, showed that use of L-type CCBs reduced blood pressure, and risk of dementia in hypertensives patients, suggesting that these drugs could be clinically used to treat AD [21].…”

Section: + /Camp Signalling Interaction In Neuroprotectionmentioning

confidence: 99%

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

Caricati‐Neto¹,

Bergantin²

2017

J Syst Integr Neurosci

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Alzheimer's disease (AD) is a debilitating neuropsychiatric disorder characterized by the multifaceted decline in cognitive and behavioral functions. Due to the multifaceted nature of AD pathology and our limited understanding on its etiology, AD is difficult to be treated with currently available pharmaceuticals. Then, new therapeutic strategies for AD have been proposed. Since 1975, several clinical studies have reported that L-type Ca 2+ channel blockers (CCBs) used in antihypertensive therapy produces increase of plasma catecholamine levels and tachycardia, typical symptoms of sympathetic hyperactivity. Despite these adverse effects of CCBs have been initially attributed to adjust reflex of arterial pressure, during almost four decades these enigmatic phenomena remained unclear. In 2013, we discovered that this paradoxical sympathetic hyperactivity produced by CCBs results from the increase of catecholamines release from sympathetic nerves and adrenal chromaffin cells due to its modulatory action on the interaction between intracellular signaling pathways mediated by Ca 2+ and cAMP (Ca 2+ /cAMP signalling interaction). In addition, we discovered that the modulation of this interaction may stimulate neuroprotective response due to activation of cell survival pathways mediated by cAMP-responsive element binding protein (CREB). Then, the pharmacological modulation of Ca 2+ /cAMP signalling interaction by combined use of L-type CCBs and cAMP-enhancer compounds could be a more efficient and safer therapeutic strategy to produce increase of cholinergic neurotransmission and neuroprotection, attenuating cognitive deficit in AD patients.

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Calcium Channel Antagonists as Disease-Modifying Therapy for Parkinson’s Disease: Therapeutic Rationale and Current Status

Abstract: Parkinson's disease is a disabling hypokinetic neurological movement disorder with unknown aetiology in the majority of cases. Current pharmacological treatments, though effective at restoring movement, are only symptomatic and do nothing to slow the progression of the disease.

Cited by 36 publications

References 84 publications

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

Nutraceuticals Targeting Generation and Oxidant Activity of Peroxynitrite May Aid Prevention and Control of Parkinson’s Disease

Can Interactions Between α-Synuclein, Dopamine and Calcium Explain Selective Neurodegeneration in Parkinson's Disease?

Pharmacological modulation of neural Ca2+/camp signaling interaction as therapeutic goal for treatment of Alzheimer´s disease

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