Reestablishment of Redox Homeostasis in the Nociceptive Primary Afferent as a Mechanism of Antinociception Promoted by Mesenchymal Stem/Stromal Cells in Oxaliplatin-Induced Chronic Peripheral Neuropathy

Abstract

Painful neuropathy is a common adverse effect of oxaliplatin (OXL), a platinum-derivative chemotherapeutic agent. Oxidative stress and mitochondrial dysfunction are key factors contributing to the development of OXL-induced peripheral neuropathy (OIPN). Based on the antioxidant and antinociceptive properties of mesenchymal stem/stromal cells (MSC), the present study tested the hypothesis that MSC induce antinociceptive effects during OIPN by promoting regulation of redox environment and mitochondrial homeostasis in the nociceptive primary afferents. C57Bl/6 mice submitted to the OXL-chronic neuropathy induction protocol by repeated intravenous administration of OXL (1 mg/kg) were evaluated to determine the paw mechanical and thermal nociceptive thresholds using the von Frey filaments and cold plate tests, respectively. Two weeks after the neuropathy induction, mice were treated with bone marrow-derived MSC ( 1 × 10 6 ), vehicle, or gabapentin (GBP, 70 mg/kg). Four weeks later, mitochondrial morphology, gene expression profile, and oxidative stress markers in the sciatic nerve and dorsal root ganglia (DRG) were evaluated by transmission electron microscopy, RT-qPCR, and biochemical assays, respectively. OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia. The behavioral painful neuropathy was completely reverted by a single administration of MSC, while the daily treatment with GBP induced only a short-lived antinociceptive effect. The ultrastructural analysis of the sciatic nerve and DRG of OIPN mice revealed a high proportion of atypical mitochondria in both myelinated and unmyelinated fibers. Importantly, this mitochondrial atypia was strongly reduced in MSC-treated neuropathic mice. Moreover, MSC-treated neuropathic mice showed upregulation of Sod and Nrf2 mRNA in the sciatic nerve and DRG. In line with this result, MSC reduced markers of nitrosative stress and lipid peroxidation in the sciatic nerve and DRG from OIPN mice. Our data suggest that the reestablishment of redox homeostasis in the nociceptive primary afferents is a mechanism by which MSC transplantation reverts the OXL-induced chronic painful neuropathy.

Mesenchymal stem cells improve redox homeostasis and mitochondrial respiration in fibroblast cell lines with pathogenic MT-ND3 and MT-ND6 variants

“…The above results demonstrate that MSC co-culture leads to a durable improvement of mitochondrial function in cell lines with mtDNA mutations. Of note, there are numerous studies in mouse models that already investigated the in vivo effects of MSC-based treatment approaches for disease conditions such as acute lung injury [14], nonalcoholic fatty liver disease [30] and peripheral neuropathy [31]. Moreover, application of MSC products to treat graft-versus-host disease is already part of clinical patient care [32].…”

Alpha-Lipoic Acid as an Antioxidant Strategy for Managing Neuropathic Pain

“…Oxaliplatin, a widely used chemotherapy agent, can induce mitochondrial atypia that is related to sensory alterations in mice [ 35 ]. Other platinum-based drugs also promote mitochondrial dysfunction, affecting cellular respiration and leading to ROS accumulation [ 36 ].…”

Platinum-Induced Peripheral Neuropathy (PIPN): ROS-Related Mechanism, Therapeutic Agents, and Nanosystems

“…MSCs increased the levels of anti-inflammatory cytokines [IL-10 and transforming growth factor-β (TGF-β)] and the gene expression of antioxidant factors (SOD and Nrf-2) in the spinal cord of neuropathic mice, as well as reduced the nitrite and MDA spinal levels, thus, reestablishing the redox homeostasis in the spinal cord ( Dos Santos et al, 2021 ). In addition, the mitochondrial atypia that was observed in sciatic nerve and DRG of PIPN mice was markedly decreased after MSC treatment ( Oliveira et al, 2021 ). Besides activating anti-inflammatory and antioxidant pathways, MSCs can also serve as a promising drug carrier and, thus, be further developed to improve therapeutic effect toward PIPN.…”