The Origins of Oxidant Stress in Parkinson's Disease and Therapeutic Strategies

Abstract

Parkinson's disease (PD) is a major world-wide health problem afflicting millions of the aged population. Factors that act on most or all cell types (pan-cellular factors), particularly genetic mutations and environmental toxins, have dominated public discussions of disease etiology. Although there is compelling evidence supporting an association between disease risk and these factors, the pattern of neuronal pathology and cell loss is difficult to explain without cell-specific factors. This article focuses on recent studies showing that the neurons at greatest risk in PD-substantia nigra pars compacta dopamine neurons-have a distinctive physiological phenotype that could contribute to their vulnerability. The opening of L-type calcium channels during autonomous pacemaking results in sustained calcium entry into the cytoplasm of substantia nigra pars compacta dopamine neurons, resulting in elevated mitochondrial oxidant stress and susceptibility to toxins used to create animal models of PD. This cellspecific stress could increase the negative consequences of pan-cellular factors that broadly challenge either mitochondrial or proteostatic competence. The availability of well-tolerated, orally deliverable antagonists for L-type calcium channels points to a novel neuroprotective strategy that could complement current attempts to boost mitochondrial function in the early stages of the disease.

Pyrimidine-2,4,6-triones are a new class of voltage-gated L-type Ca2+ channel activators

“…Column chromatography was performed using silica gel 60 (0.040-0.063 mm). The identity of both compounds was confirmed by 1 H-NMR, 13 C-NMR and ESI-mass spectrometry (MS). 1 H-and 13 C-NMR spectra were recorded from CDCl 3 solutions on a Varian Gemini 2000 (200 and 50 MHz, respectively) spectrometer using tetramethylsilane as internal standard.…”

“…L-type Ca 2 þ currents also contribute to the dendritic Ca 2 þ transients during the autonomous pacemaking in substantia nigra pars compacta (SNc) dopaminergic neurons 12 . These Ca 2 þ oscillations add to the increased level of mitochondrial oxidative stress responsible for the particular vulnerability of these neurons to neurodegeneration in Parkinson's disease (PD) 13 . LTCC blockers can protect these neurons from neurodegeneration in various mammalian PD models 3,14 , and epidemiological clinical studies associate the use of brain-permeable Ca 2 þ channel blockers in hypertensive patients with reduced PD risk 15,16 .…”

Pharmacological Chaperoning of Nicotinic Acetylcholine Receptors Reduces the Endoplasmic Reticulum Stress Response

“…1, A and B), but it is plausible to suggest that increasing the ER exit of nAChRs could reorganize the COPII vesicle population and relieve ER stress caused by other environmental or genetic factors. Dopaminergic neurons contain potentially toxic metabolites of dopamine (Ahmadi et al, 2008;Miyazaki and Asanuma, 2009) and relatively high intracellular Ca 2ϩ levels (Surmeier et al, 2011). These factors probably lead to increased levels of ER stress under physiological conditions (Egawa et al, 2011).…”

La taille de l’axone est un facteur majeur influençant la dépense énergétique et la vulnérabilité des neurones dopaminergiques dans la maladie de Parkinson

“…Une hypothèse récente [5] propose que la demande énergétique élevée et la vulnérabilité accrue des neurones dopaminergiques de la SNc puissent être expliquées par le fait que ces neurones déchargent (c'est-à-dire qu'ils émettent des potentiels d'action) de façon autonome (décharge de type « pacemaker »). Ce type de décharge serait associé à une élévation cyclique importante des niveaux de calcium intracellulaire dans le compartiment somatodendritique de ces neurones, une propriété qui dépend de la présence de canaux calciques voltage-dépendants de type L 1 de la famille Ca v 1.3.…”