The mechanism of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity: Role of intracellular calcium☆
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Admixing MPTP-resistant and MPTP-vulnerable mice enhances striatal field potentials and calbindin-D28K expression to avert motor behaviour deficits
2019, Behavioural Brain ResearchCitation Excerpt :Intriguingly, the lateral nigra in CD-1 revealed lesser calbindin, which also happened to be the site of MPTP-induced neuronal loss in CD-1 [16], thus affirming calbindin’s role in deciphering strain specific MPTP susceptibility. MPTP intoxication exacerbate excitotoxicity by releasing mitochondrial Ca2+, leading to cell death [82,83]. This was evident in C57BL/6J that revealed calbindin downregulation in concurrent to earlier reports [84].
Differential expression of calbindin in nigral dopaminergic neurons in two mice strains with differential susceptibility to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
2016, Journal of Chemical NeuroanatomyCitation Excerpt :Calbindin effectively sequesters excess calcium in an ATP-independent manner, thus reducing the vulnerability of DA neurons to mitochondrial toxins that are involved in pathogenesis of PD (Gerfen et al., 1985; Yamada et al., 1990; Damier et al., 1999b; Yuan et al., 2013). MPP+, the toxic metabolite of MPTP inhibits mitochondrial complex I (Nicklas et al., 1987), which stimulates the release of calcium ions from mitochondrial stores, disrupting the calcium ion homeostasis (Kass et al., 1988). This results in an elevation of intracellular Ca2+, leading to the activation of Ca2+-dependent enzymes, for example, protein kinase and calpains I and II, which disturbs the normal function, resulting in cellular damage.
Neuroprotection by minocycline caused by direct and specific scavenging of peroxynitrite
2011, Journal of Biological ChemistryCitation Excerpt :Glutamate excitotoxicity represents a classical model of elevated cytosolic Ca2+ levels (53), and in such models, minocycline concentrations in the low nanomolar range have been reported to be neuroprotective (11). Similar observations were made in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)/1-Methyl-4-phenylpyridinium (MPP+) models that are also characterized by disturbed cellular Ca2+ homeostasis (54). Further indirect evidence for a role of PON scavenging by minocycline comes from experiments in which cerebellar granule cells were treated with subtoxic concentrations of an •NO donor and MPP+ that together allow formation of PON (8).
Zonisamide attenuates MPTP neurotoxicity in marmosets
2010, Journal of Pharmacological SciencesThe homocysteine-inducible endoplasmic reticulum stress protein counteracts calcium store depletion and induction of CCAAT enhancer-binding protein homologous protein in a neurotoxin model of Parkinson Disease
2009, Journal of Biological ChemistryCitation Excerpt :Whether dysregulation of ER Ca2+ homeostasis contributes to PD initiation and progression has not yet been established. Disturbances in intracellular Ca2+ homeostasis could play a role in dopaminergic degeneration because treatment with various PD neurotoxins has been shown to perturb intracellular Ca2+ homeostasis (26–28). The MPP+-induced cell death was inhibited by co-expression of calbindin-D28K or co-treatment with BAPTA (1,2-bis-(o-aminophenoxy)-ethane-N,N,N′,N′-tetracidic acid), suggesting a critical role for intracellular Ca2+ loads in MPP+-induced toxicity (46).
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This work was supported by the Swedish Medical Research Council (Project 03X-2471), Council of Europe Fellowship 87.001, and a Gustavus A. Pfeiffer AFPE Fellowship (to G.E.N.K.), and a fellowship from I.R.C.C.S. Policlinico S. Matteo, Universitá di Pavia, Italy (to P.N.).
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Visiting scientist from Department of Pharmacology and Therapeutics, University of British Columbia, Vancouver, B.C., Canada V6T 1W5.