Open AccessCell-Permeable Calpain Inhibitor SJA6017 Provides Functional Protection to Spinal Motoneurons Exposed to MPP+
Author(s) -
Supriti Samantaray,
Varduhi H. Knaryan,
Angelo M. Del Re,
John J. Woodward,
Donald C. Shields,
Mitsuyoshi Azuma,
Jun Inoue,
Swapan K. Ray,
Naren L. Banik
Publication year - 2020
Publication title -
neurotoxicity research/neurotoxicity resarch
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.923
H-Index - 73
eISSN - 1476-3524
pISSN - 1029-8428
DOI - 10.1007/s12640-020-00264-3
Subject(s) - calpain , neuroprotection , motor neuron , substantia nigra , microbiology and biotechnology , neuroscience , chemistry , biology , spinal cord , biochemistry , dopamine , dopaminergic , enzyme
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 Ca 2+ 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.