Calcium channel blocker use and risk of Parkinson's disease: a meta-analysis

Lang, Yakun; Gong, Dandan; Fan, Yu

doi:10.1002/pds.3781

Cited by 34 publications

(25 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CaV 1.3-mediated dendritic calcium oscillations, characterizing rhythmic activity of SNpc DAergic neurons, have previously been suggested to determine the vulnerable phenotype of these neurons (Guzman et al, 2009; Ilijic et al, 2011; Surmeier and Schumacker, 2013). In agreement, clinical studies and meta-analyses indicate that users of brain-permeable L-type VGCC blockers have a 30% reduced risk of developing PD (Ritz et al, 2010; Lang et al, 2015). Our results indicate that L-type calcium channels are activated by normal subthreshold synaptic activity and become hyperactivated in SNpc DAergic neurons following pharmacological Ih suppression.…”

Section: Discussionmentioning

confidence: 69%

The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

Carbone

Costa

Provensi

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

Differential vulnerability between Substantia Nigra pars compacta (SNpc) and Ventral Tegmental Area (VTA) dopaminergic (DAergic) neurons is a hallmark of Parkinson’s disease (PD). Understanding the molecular bases of this key histopathological aspect would foster the development of much-needed disease-modifying therapies. Non-heterogeneous DAergic degeneration is present in both toxin-based and genetic animal models, suggesting that cellular specificity, rather than causing factors, constitutes the background for differential vulnerability. In this regard, we previously demonstrated that MPP+, a neurotoxin able to cause selective nigrostriatal degeneration in animal rodents and primates, inhibits the Hyperpolarization-activated current (Ih) in SNpc DAergic neurons and that pharmacological Ih antagonism causes potentiation of evoked Excitatory post-synaptic potentials (EPSPs). Of note, the magnitude of such potentiation is greater in the SNpc subfield, consistent with higher Ih density. In the present work, we show that Ih block-induced synaptic potentiation leads to the amplification of somatic calcium responses (SCRs) in vitro. This effect is specific for the SNpc subfield and largely mediated by L-Type calcium channels, as indicated by sensitivity to the CaV 1 blocker isradipine. Furthermore, Ih is downregulated by low intracellular ATP and determines the efficacy of GABAergic inhibition in SNpc DAergic neurons. Finally, we show that stereotaxic administration of Ih blockers causes SNpc-specific neurodegeneration and hemiparkinsonian motor phenotype in rats. During PD progression, Ih downregulation may result from mitochondrial dysfunction and, in concert with PD-related disinhibition of excitatory inputs, determine a SNpc-specific disease pathway.

show abstract

Section: Discussionmentioning

confidence: 69%

The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

Carbone

Costa

Provensi

et al. 2017

Front. Cell. Neurosci.

View full text Add to dashboard Cite

show abstract

“…; Gudala et al . ; Lang et al ). This PD‐protective effect is assumed (but not yet clearly demonstrated) to be caused by inhibition of LTCCs in SN DA neurons, most likely of Cav1.3 channels, which in turn abolishes dendritic Ca 2+ oscillations and associated oscillatory metabolic stress in mice (Guzman et al .…”

Section: Ion Channels Define Activity Pattern and Ca2+ Homeostasis Ofmentioning

confidence: 98%

“…LTCCs in SN DA neurons, particularly those of the Cav1.3 subtype, have received much attention in recent years, since blood-brain barrier (BBB) permeable LTCC blockers of the dihydropyridine-type [DHPs, like isradipine (Striessnig et al 1998)] apparently reduce the risk for developing PD by about 30% in humans, as epidemiologic data of retrospective studies indicate (Becker et al 2008;Ritz et al 2010;Marras et al 2012;Pasternak et al 2012;Gudala et al 2015;Lang et al 2015). This PD-protective effect is assumed (but not yet clearly demonstrated) to be caused by inhibition of LTCCs in SN DA neurons, most likely of Cav1.3 channels, which in turn abolishes dendritic Ca 2+ oscillations and associated oscillatory metabolic stress in mice Kang et al 2013;Surmeier and Schumacker 2013;Huang et al 2014;Ortner et al 2014).…”

Section: Pd-protective Effects Of Voltage-gated L-type Ca 2+ Channel mentioning

confidence: 99%

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

Duda¹,

Pötschke²,

Liss³

2016

Journal of Neurochemistry

137

131

View full text Add to dashboard Cite

Dopamine-releasing neurons within the Substantia nigra (SN DA) are particularly vulnerable to degeneration compared to other dopaminergic neurons. The age-dependent, progressive loss of these neurons is a pathological hallmark of Parkinson's disease (PD), as the resulting loss of striatal dopamine causes its major movement-related symptoms. SN DA neurons release dopamine from their axonal terminals within the dorsal striatum, and also from their cell bodies and dendrites within the midbrain in a calcium-and activity-dependent manner. Their intrinsically generated and metabolically challenging activity is created and modulated by the orchestrated function of different ion channels and dopamine D2-autoreceptors. Here, we review increasing evidence that the mechanisms that control activity patterns and calcium homeostasis of SN DA neurons are not only crucial for their dopamine release within a physiological range but also modulate their mitochondrial and lysosomal activity, their metabolic stress levels, and their vulnerability to degeneration in PD. Indeed, impaired calcium homeostasis, lysosomal and mitochondrial dysfunction, and metabolic stress in SN DA neurons represent central converging trigger factors for idiopathic and familial PD. We summarize double-edged roles of ion channels, activity patterns, calcium homeostasis, and related feedback/feed-forward signaling mechanisms in SN DA neurons for maintaining and modulating their physiological function, but also for contributing to their vulnerability in PD-paradigms. We focus on the emerging roles of maintained neuronal activity and calcium homeostasis within a physiological bandwidth, and its modulation by PD-triggers, as well as on bidirectional functions of voltage-gated L-type calcium channels and

show abstract

“…Further support for a potential therapeutic role for DHPs comes from case-control and cohort studies. These studies reported a significantly reduced risk for a first-time diagnosis of PD in users of brainpermeable CCBs (odds or rate ratios of 0.71-0.78) (Becker et al, 2008;Ritz et al, 2010;Pasternak et al, 2012;Lang et al, 2015). Neuroprotection by CCBs, in particular by DHPs, can be rationalized by inhibition of dendritic Ca 2+ entry during action potentials of rhythmic activity or during burst firing (Putzier et al, 2009), which occurs in response to reward-predicting stimuli (Liss and Roeper, 2008).…”

Section: +mentioning

confidence: 99%

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Zamponi¹,

Striessnig²,

Koschak³

et al. 2015

Pharmacol Rev

903

992

View full text Add to dashboard Cite

Calcium channel blocker use and risk of Parkinson's disease: a meta-analysis

Cited by 34 publications

References 33 publications

The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

The Hyperpolarization-Activated Current Determines Synaptic Excitability, Calcium Activity and Specific Viability of Substantia Nigra Dopaminergic Neurons

Converging roles of ion channels, calcium, metabolic stress, and activity pattern of Substantia nigra dopaminergic neurons in health and Parkinson's disease

The Physiology, Pathology, and Pharmacology of Voltage-Gated Calcium Channels and Their Future Therapeutic Potential

Contact Info

Product

Resources

About