CaMKII and CaV3.2 T-type calcium channel mediate Connexin-43-dependent inflammation by activating astrocytes in vincristine-induced neuropathic pain.

Abstract

Vincristine (VCR), an alkaloid isolated from vinca, is a commonly used chemotherapeutic drug. However, VCR therapy can lead to dose-dependent peripheral neurotoxicity, mainly manifesting as neuropathic pain, which is one of the dominant reasons for limiting its utility. Experimentally, we discovered that VCR-induced neuropathic pain (VINP) was accompanied by astrocyte activation; the upregulation of phospho-CaMKII (p-CaMKII), CaV3.2, and Connexin-43 (Cx43) expression; and the production and release of inflammatory cytokines and chemokines in the spinal cord. Similar situations were also observed in astrocyte cultures. Interestingly, these alterations were all reversed by intrathecal injection of KN-93 (a CaMKII inhibitor) or L-Ascorbic acid (a CaV3.2 inhibitor). In addition, KN-93 and L-Ascorbic acid inhibited the increase in [Ca2+]i associated with astrocyte activation. We also verified that knocking down or inhibiting Cx43 level via intrathecal injection of Cx43 siRNA or Gap27 (a Cx43 mimetic peptide) relieved pain hypersensitivity and reduced the release of inflammatory factors; however, they did not affect astrocyte activation or p-CaMKII and CaV3.2 expression. Besides, the overexpression of Cx43 through the transfection of the Cx43 plasmid did not affect p-CaMKII and CaV3.2 expressions in vitro. Therefore, CaMKII and CaV3.2 may activate astrocytes by increasing [Ca2+]i, thereby mediating Cx43-dependent inflammation in VINP. Moreover, we demonstrated that the CaMKII signalling pathway was involved in VCR-induced inflammation, apoptosis, and mitochondrial damage. Collectively, our findings show a novel mechanism by which CaMKII and CaV3.2 mediate Cx43-dependent inflammation by activating astrocytes in neuropathic pain induced by VCR.

• Authors: Gui-Zhou Li, Ya-Hui Hu, Yi-Ni Lu, Qing-Yan Yang, Di Fu, Feng Chen, Yun-Man Li
• Journal: Cell biology and toxicology (Cell Biol Toxicol) Vol. 39 Issue 3 Pg. 679-702 (06 2023) ISSN: 1573-6822 [Electronic] Switzerland
• PMID: 34286406 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to Springer Nature B.V.

Chemical References

• Connexin 43
• KN 93
• Vincristine
• Calcium Channels, T-Type
• Calcium-Calmodulin-Dependent Protein Kinase Type 2

Topics

• Humans
• Connexin 43 (genetics, metabolism)
• Vincristine (pharmacology, metabolism, therapeutic use)
• Calcium Channels, T-Type (metabolism, therapeutic use)
• Astrocytes (metabolism)
• Calcium-Calmodulin-Dependent Protein Kinase Type 2 (metabolism, therapeutic use)
• Neuralgia (chemically induced, drug therapy, metabolism)