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Neurotoxicity: Calpain and 1-Methyl-4-phenylpyridinium (MPP+)

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Handbook of Neurotoxicity

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Abstract

MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is commonly utilized in animal models of Parkinson’s disease. This compound is metabolized in the central nervous system to produce 1-methyl-4-phenylpyridinium (MPP+) which interacts with neuronal mitochondria to suppress cellular energy production, generate reactive oxygen species, increase cytosolic calcium levels, and ultimately promote apoptotic cell death. Dopaminergic neurons are critically affected by this mitochondrial dysfunction. Calcium-activated neutral proteinase (calpain) is also pathologically activated by the increased intracellular calcium levels. Hyperactivated calpain cleaves alpha-synuclein into truncated subunits (prone to aggregation) as found in Lewy bodies. Calpain activation following MPTP administration also plays a role in neuroinflammation with T cell activation, cytokine production, and cell signaling pathways. Dopaminergic neuronal apoptosis is also observed in relation to calpain-mediated Bax/Bcl-2 disruption. In addition to mesencephalic neuronal degeneration, these MPP+-induced calpain-mediated effects have also been identified in extranigral neurons such as spinal motoneurons. Thus, derangements in nigral dopamine production and apoptotic neuronal death in other nervous system sites can contribute to the multiple symptoms experienced by Parkinsonian patients. Moreover, administration of calpain inhibitors and anti-inflammatory agents (e.g., estrogen and melatonin) in these animal models demonstrates significant attenuation of neuronal degeneration and resulting Parkinsonian symptoms.

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Abbreviations

6-OHDA:

6-hydroxydopamine

AIF:

Apoptosis inducing factor

Ca2+:

Calcium

Cdk5:

Cyclin-dependent kinase 5

MPP+:

1-Methyl-4-phenylpyridinium

MPTP:

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine

NOS:

Nitric oxide synthase

PD:

Parkinson’s disease

ROS:

Reactive oxygen species

SN:

Substantia nigra

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Authors and Affiliations

  1. Department of Neurosurgery, Medical University of South Carolina, Charleston, SC, USA

    Donald C. Shields & Naren L. Banik

  2. Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, USA

    Azizul Haque & Naren L. Banik

  3. Ralph H. Johnson Veterans Administration Medical Center, Charleston, SC, USA

    Naren L. Banik

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  1. Donald C. Shields
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  2. Azizul Haque
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  3. Naren L. Banik
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Correspondence to Naren L. Banik .

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  1. Department of Biomedical Sciences, Quillen College of Medicine East Tennessee State University, Johnson City, TN, USA

    Richard M. Kostrzewa

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Shields, D.C., Haque, A., Banik, N.L. (2022). Neurotoxicity: Calpain and 1-Methyl-4-phenylpyridinium (MPP+). In: Kostrzewa, R.M. (eds) Handbook of Neurotoxicity. Springer, Cham. https://doi.org/10.1007/978-3-031-15080-7_188

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