Cell-Permeable Calpain Inhibitor SJA6017 Provides Functional Protection to Spinal Motoneurons Exposed to MPP +
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ORIGINAL ARTICLE
Cell-Permeable Calpain Inhibitor SJA6017 Provides Functional Protection to Spinal Motoneurons Exposed to MPP+ Supriti Samantaray 1 & Varduhi H. Knaryan 1 & Angelo M. Del Re 2 & John J. Woodward 2 & Donald C. Shields 1 & Mitsuyoshi Azuma 3,4 & Jun Inoue 3 & Swapan K. Ray 5 & Naren L. Banik 1 Received: 23 June 2020 / Revised: 17 July 2020 / Accepted: 27 July 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract Extra-nigral central nervous system sites have been found to be affected in Parkinson’s disease (PD). In addition to substantia nigra, degeneration of spinal cord motor neurons may play a role in the motor symptoms of PD. To this end, hybrid rodent VSC 4.1 cells differentiated into motoneurons were used as a cell culture model following exposure to Parkinsonian neurotoxicant MPP+. SJA6017, a cell-permeable calpain inhibitor, was tested for its neuroprotective efficacy against the neurotoxicant. SJA6017 attenuated MPP+-induced rise in intracellular free Ca2+ and concomitant increases in the active form of calpain. It also significantly prevented increased levels of proteases and their activities, as shown by reduced levels of 145 kDa calpain-specific and 120 kDa caspase-3-specific spectrin breakdown products. Exposure to MPP+ elevated the levels of reactive oxygen species in VSC 4.1 motoneurons; this was significantly diminished with SJA6017. The motor proteins in spinal motoneurons, i.e., dynein and kinesin, were also impaired following exposure to MPP+ through calpain-mediated mechanisms; this process was partially ameliorated by SJA6017 pretreatment. Cytoprotection provided by SJA6017 against MPP+-induced damage to VSC 4.1 motoneurons was confirmed by restoration of membrane potential via whole-cell patch-clamp assay. This study demonstrates that calpain inhibition is a prospective route for neuroprotection in experimental PD; moreover, calpain inhibitor SJA6017 appears to be an effective neuroprotective agent against MPP+-induced damage in spinal motoneurons. Keywords Calpain . Parkinson’s . Motor proteins . Apoptosis . Oxidative stress
Abbreviations dVSC 4.1 Differentiated ventral spinal cord cells MTT 3-(4, 5-Dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide IR Immunoreactivity * Naren L. Banik [email protected] 1
Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas St., MSC606 Suite 301, Charleston, SC 29425, USA
2
Division of Neuroscience Research and Center for Drug & Alcohol Programs, Medical University of South Carolina, Charleston, SC, USA
3
Kobe Creative Center, Senju Pharmaceutical Corporation Limited, Kobe 651-2241, Japan
4
Department of Integrative Biosciences, Oregon Health & Science University, Portland, OR, USA
5
Department of Pathology, Microbiology & Immunology, University of South Carolina School of Medicine, Columbia, SC, USA
MPTP PD ROS SBDP SC
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine Parkinson’s disease Reactive oxygen species Spectrin breakdown products Spinal cord
Introduction Parkinson’
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