{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T04:06:29Z","timestamp":1789445189898,"version":"build-2803163510"},"reference-count":77,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2025,8,24]],"date-time":"2025-08-24T00:00:00Z","timestamp":1755993600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Veterans Administration","award":["BX006101"],"award-info":[{"award-number":["BX006101"]}]},{"name":"Veterans Administration","award":["BX001262"],"award-info":[{"award-number":["BX001262"]}]},{"name":"Veterans Administration","award":["SCIRF #2016 I-03"],"award-info":[{"award-number":["SCIRF #2016 I-03"]}]},{"name":"Veterans Administration","award":["SCIRF #2018 I-01"],"award-info":[{"award-number":["SCIRF #2018 I-01"]}]},{"name":"Veterans Administration","award":["IK6BX005964"],"award-info":[{"award-number":["IK6BX005964"]}]},{"name":"Veterans Administration","award":["1R21NS118393-01"],"award-info":[{"award-number":["1R21NS118393-01"]}]},{"name":"South Carolina State Spinal Cord Injury Research Fund","award":["BX006101"],"award-info":[{"award-number":["BX006101"]}]},{"name":"South Carolina State Spinal Cord Injury Research Fund","award":["BX001262"],"award-info":[{"award-number":["BX001262"]}]},{"name":"South Carolina State Spinal Cord Injury Research Fund","award":["SCIRF #2016 I-03"],"award-info":[{"award-number":["SCIRF #2016 I-03"]}]},{"name":"South Carolina State Spinal Cord Injury Research Fund","award":["SCIRF #2018 I-01"],"award-info":[{"award-number":["SCIRF #2018 I-01"]}]},{"name":"South Carolina State Spinal Cord Injury Research Fund","award":["IK6BX005964"],"award-info":[{"award-number":["IK6BX005964"]}]},{"name":"South Carolina State Spinal Cord Injury Research Fund","award":["1R21NS118393-01"],"award-info":[{"award-number":["1R21NS118393-01"]}]},{"name":"Department of Veterans Administration","award":["BX006101"],"award-info":[{"award-number":["BX006101"]}]},{"name":"Department of Veterans Administration","award":["BX001262"],"award-info":[{"award-number":["BX001262"]}]},{"name":"Department of Veterans Administration","award":["SCIRF #2016 I-03"],"award-info":[{"award-number":["SCIRF #2016 I-03"]}]},{"name":"Department of Veterans Administration","award":["SCIRF #2018 I-01"],"award-info":[{"award-number":["SCIRF #2018 I-01"]}]},{"name":"Department of Veterans Administration","award":["IK6BX005964"],"award-info":[{"award-number":["IK6BX005964"]}]},{"name":"Department of Veterans Administration","award":["1R21NS118393-01"],"award-info":[{"award-number":["1R21NS118393-01"]}]},{"name":"National Institutes of Health","award":["BX006101"],"award-info":[{"award-number":["BX006101"]}]},{"name":"National Institutes of Health","award":["BX001262"],"award-info":[{"award-number":["BX001262"]}]},{"name":"National Institutes of Health","award":["SCIRF #2016 I-03"],"award-info":[{"award-number":["SCIRF #2016 I-03"]}]},{"name":"National Institutes of Health","award":["SCIRF #2018 I-01"],"award-info":[{"award-number":["SCIRF #2018 I-01"]}]},{"name":"National Institutes of Health","award":["IK6BX005964"],"award-info":[{"award-number":["IK6BX005964"]}]},{"name":"National Institutes of Health","award":["1R21NS118393-01"],"award-info":[{"award-number":["1R21NS118393-01"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Parkinson\u2019s disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra, and key pathways such as neuroinflammation, oxidative stress, and autophagy are believed to significantly contribute to the mechanisms of neurodegeneration. Calpain activation plays a critical role in neuroinflammation and neurodegeneration, as demonstrated by its impact on microglial activation, reactive oxygen species (ROS) production, and neuronal survival. In this study, we investigated the effects of calpain inhibition using calpeptin (CP) and calpain-2-specific inhibitors in cellular and murine models of neuroinflammation and PD. In BV2 microglial cells, LPS-induced production of pro-inflammatory cytokines (TNF-\u03b1, IL-6) and chemokines (MCP-1, IP-10) were significantly reduced by CP treatment with a concomitant decrease in ROS generation. Similarly, in VSC-4.1 motoneuron cells, calpain inhibition attenuated IFN-\u03b3-induced ROS production and improved cell viability, demonstrating its neuroprotective effects. Moreover, in a murine MPTP model of PD, calpain inhibition reduced astrogliosis, ROCK2 expression, and levels of inflammatory cytokines (TNF-\u03b1, IL-1\u03b2, IL-6, IL-7, and IL12p70) and chemokines (MCP-1 and IP-10) in the dorsal striatum and plasma. The specific role of calpain-2 in immune modulation was further highlighted in human microglia, SV-40 cells. With respect to immune modulation in these cells, siRNA-mediated knockdown of calpain-2, but not calpain-1, significantly reduced antigen presentation to CD4+ T cells. Thus, calpain-2 is likely involved in regulating antigen presentation and activation of inflammatory CD4+ T cells. These findings underscore the therapeutic potential of calpain-2 inhibition in mitigating neuroinflammation and neurodegeneration, particularly in PD, by targeting microglial activation, ROS production, and neuronal survival pathways.<\/jats:p>","DOI":"10.3390\/cells14171310","type":"journal-article","created":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:09:32Z","timestamp":1756080572000},"page":"1310","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Neuroprotective Effects of Calpain Inhibition in Parkinson\u2019s Disease: Insights from Cellular and Murine Models"],"prefix":"10.3390","volume":"14","author":[{"given":"Vandana","family":"Zaman","sequence":"first","affiliation":[{"name":"Ralph H. Johnson Veterans Administration Medical Center, 109 Bee St, Charleston, SC 29401, USA"},{"name":"Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amy","family":"Gathings","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey P.","family":"Drasites","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA"},{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donald C.","family":"Shields","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Narendra L.","family":"Banik","sequence":"additional","affiliation":[{"name":"Ralph H. Johnson Veterans Administration Medical Center, 109 Bee St, Charleston, SC 29401, USA"},{"name":"Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6386-9390","authenticated-orcid":false,"given":"Azizul","family":"Haque","sequence":"additional","affiliation":[{"name":"Ralph H. Johnson Veterans Administration Medical Center, 109 Bee St, Charleston, SC 29401, USA"},{"name":"Department of Neurosurgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC 29425, USA"},{"name":"Department of Pharmacology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, Charleston, SC 29425, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,8,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1136\/jnnp-2019-322338","article-title":"Parkinson\u2019s disease: Etiopathogenesis and treatment","volume":"91","author":"Jankovic","year":"2020","journal-title":"J. Neurol. Neurosurg. 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