In inflammatory neuropathies, oxidative stress results in neuronal and Schwann cell (SC) death promoting early neurodegeneration and clinical disability. Treatment with the short-chain fatty acid propionate showed a significant immunoregulatory and neuroprotective effect in multiple sclerosis patients. Similar effects have been described for patients with chronic inflammatory demyelinating polyneuropathy (CIDP). Therefore, Schwann cell’s survival and dorsal root ganglia (DRG) outgrowth were evaluated in vitro after propionate treatment and application of H2O2 or S-nitroso-N-acetyl-D-L-penicillamine (SNAP) to evaluate neuroprotection. In addition, DRG resistance was evaluated by the application of oxidative stress by SNAP ex vivo after in vivo propionate treatment. Propionate treatment secondary to SNAP application on DRG served as a neuroregeneration model. Histone acetylation as well as expression of the free fatty acid receptor (FFAR) 2 and 3, histone deacetylases, neuroregeneration markers, and antioxidative mediators were investigated. β-hydroxybutyrate was used as a second FFAR3 ligand, and pertussis toxin was used as an FFAR3 antagonist. FFAR3, but not FFAR2, expression was evident on SC and DRG. Propionate-mediated activation of FFAR3 and histone 3 hyperacetylation resulted in increased catalase expression and increased resistance to oxidative stress. In addition, propionate treatment resulted in enhanced neuroregeneration with concomitant growth-associated protein 43 expression. We were able to demonstrate an antioxidative and neuroregenerative effect of propionate on SC and DRG mediated by FFAR3-induced histone acetylases expression. Our results describe a pathway to achieve neuroprotection/neuroregeneration relevant for patients with immune-mediated neuropathies.

Neurodegeneration and oxidative stress are central drivers of immune-mediated neuropathies. Capsaicin, the active ingredient in chili pepper and a direct agonist of the transient receptor potential vanilloid (TRPV1) channel, is used clinically to treat neuropathic pain. We previously demonstrated immunomodulatory and antioxidative effects of capsaicin in experimental autoimmune neuritis in vivo and Schwann cells (SC) in vitro. However, the molecular mechanisms underlying the maintenance of axonal integrity in dorsal root ganglion (DRG) and SC homeostasis remain unclear. In this study, we described the effects of capsaicin on DRG and SC in vitro under both naïve and S-Nitroso-N-acetyl-DL-penicillamine (SNAP)-induced oxidative stress conditions. Capsaicin induced an upregulation of the antioxidative cascade involving Nrf2, Ho-1, and Nqo1 in naïve DRG neurons and restored axonal growth under preventive and therapeutic settings. Preventive treatment enhanced catalase expression, whereas treatment increased regeneration-associated Gap43 and Atf3. Inhibition of TRPV1 with capsazepine partly attenuated the protective effect of axonal outgrowth, indicating TRPV1-mediated neuroprotection. In SC, capsaicin increased mitochondrial ATP production and spare respiratory capacity, inducing a transient Nrf2-dependent antioxidant response. Capsaicin suppressed expression of myelination markers under basal conditions but promoted expression of myelination- and repair-associated markers under oxidative stress. The findings support capsaicin as a regulator of neuronal and Schwann cell oxidative stress adaptation.