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Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice

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Abstract

Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, resulting in dopaminergic (DA) neuronal loss in the substantia nigra pars compacta (SNpc) and damage to the extranigral spinal cord neurons. Current therapies do not prevent the disease progression. Hence, developing efficacious therapeutic strategies for treatment of PD is of utmost importance. The goal of this study is to delineate the involvement of calpain-mediated inflammation and neurodegeneration in SN and spinal cord in MPTP-induced parkinsonian mice (C57BL/6 N), thereby elucidating potential therapeutic target(s). Increased calpain expression was found localized to tyrosine hydroxylase (TH+) neurons in SN with significantly increased TUNEL-positive neurons in SN and spinal cord neurons in MPTP mice. Inflammatory markers Cox-2, caspase-1, and NOS-2 were significantly upregulated in MPTP mouse spinal cord as compared to control. These parameters correlated with the activation of astrocytes, microglia, infiltration of CD4+/CD8+ T cells, and macrophages. We found that subpopulations of CD4+ cells (Th1 and Tregs) were differentially expanded in MPTP mice, which could be regulated by inhibition of calpain with the potent inhibitor calpeptin. Pretreatment with calpeptin (25 μg/kg, i.p.) attenuated glial activation, T cell infiltration, nigral dopaminergic degeneration in SN, and neuronal death in spinal cord. Importantly, calpeptin ameliorated MPTP-induced altered gait parameters (e.g., reduced stride length and increased stride frequency) as demonstrated by analyses of spatiotemporal gait indices using ventral plane videography. These findings suggest that calpain plays a pivotal role in MPTP-induced nigral and extranigral neurodegenerative processes and may be a valid therapeutic target in PD.

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Abbreviations

DA:

Dopaminergic

deNFP:

Dephosphorylated neurofilament protein

GFAP:

Glial fibrillary acidic protein

IR:

Immunoreactivity

L-DOPA:

L-3,4-dihydroxyphenylalanine

MPTP:

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

PD:

Parkinson disease

SN:

Substantia nigra

TH:

Tyrosine hydroxylase

SBDP:

Spectrin break down product

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Acknowledgments

Authors thank Dr. Ajit Kale of Mouse Specifics for helpful suggestions during analysis of gait parameters. This study was funded in part by the RO1 grants from National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS-NIH; NS-62327-01A2; NS-56176 and NS-65456) and the Veterans Administration (I01 BX001262 and I01 BX002349).

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Authors have no conflicts of interest to declare.

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Authors and Affiliations

  1. Department of Neurosurgery and Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 309 CSB, MSC 606, Charleston, SC, 29425, USA

    Supriti Samantaray, Varduhi H. Knaryan, April A. Cox & Naren L. Banik

  2. Department of Neurosurgery, The George Washington University, 2150 Pennsylvania Avenue, NW, Suite 7-420, Washington, DC, 20037, USA

    Donald C. Shields

  3. Department of Microbiology and Immunology, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, 29425, USA

    Azizul Haque

  4. Ralph H. Johnson Veterans Medical Center, Charleston, SC, 29425, USA

    Naren L. Banik

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  1. Supriti Samantaray
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Correspondence to Naren L. Banik.

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Samantaray, S., Knaryan, V.H., Shields, D.C. et al. Inhibition of Calpain Activation Protects MPTP-Induced Nigral and Spinal Cord Neurodegeneration, Reduces Inflammation, and Improves Gait Dynamics in Mice. Mol Neurobiol 52, 1054–1066 (2015). https://doi.org/10.1007/s12035-015-9255-6

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