Mesenchymal stem cells reduce the oxaliplatin-induced sensory neuropathy through the reestablishment of redox homeostasis in the spinal cord

Aims: The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties. Main methods: Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 x 10(6)), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively. Key findings: OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1 beta and TNF-alpha spinal levels did not differ between mice with or without sensory neumpathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-beta, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment. Significance: MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.

Automated summary

The study found that MSC can completely reverse the mechanical allodynia and thermal hyperalgesia induced by OXL-induced sensory neuropathy. MSC increased the gene expression of antioxidant factors SOD and Nrf-2, elevated the levels of anti-inflammatory cytokines IL-10 and TGF-beta in the spinal cord of neuropathic mice, and decreased nitrite and MDA levels, possibly inducing the reversal of OXL-induced sensory neuropathy by activating anti-inflammatory and antioxidant pathways.