Resveratrol Activates Antioxidant Defense Pathways, Restores the Expression of Two Pore Domain Potassium Channels and Prevents Allodynia in Experimental Model of Oxaliplatin-Induced Neuropathic Pain

P.R. BRUMOVSKY; M.F. CORONEL; C.A. MIGUEL; M.J. VILLAR; M.V. NOYA-RIOBÓ; C.G. ACOSTA

Washington

Congreso; IASP World Congress on Pain; 2021

Background and AimsChemotherapy-induced peripheral neuropathic pain (CIPNP) is a frequent and devastating side effect of cancer therapy (1,2). No preventative strategies are currently available (1,3,4). The aim of our work was to evaluate the use of resveratrol (RESV) in the prevention of CIPNP. We also evaluated the expression of different antioxidant defense system components and leak potassium channels as possible target molecules underlying RESV actions.MethodsMale rats were injected with oxaliplatin (OXA, 2 mg/kg/day, 3 injections on alternate days, cumulative dose 6 mg/kg, ip) and received daily RESV (7-14 mg/kg/day) or vehicle in their drinking water, starting 4 days before OXA administration and thereafter, until the end of the experiment. Mechanical and thermal allodynia were assessed by performing von Frey and Choi Tests respectively, and the expression of antioxidant mediators (nuclear factor erythroid 2-related factor 2, Nrf2; NAD(P)H quinone oxidorreductase 1, NQO-1; heme oxygenase 1, HO-1), two pore domain potassium channels (TWIKrelated potassium channel 1, TREK1; TWIK-related arachidonic acid-stimulated potassium channel, TRAAK) and neuronal injury (activating transcription factor 3, ATF3) / activation (the proto-oncogene c-fos) markers were evaluated at lumbar dorsal root ganglia (DRGs) and spinal cord (SC) levels by using real time- RT-PCR.ResultsWhen compared to control animals (CTL, receiving only vehicles), those receiving OXA developed both mechanical and thermal hypersensitivity and allodynia (p< 0.01 vs CTL for mechanical and thermal thresholds from day 1 and thereafter), while animals treated with OXA+RESV showed patterns of response similar to those detected in CTL animals (p >0.05 at every time point). A significant decrease in the expression of the potassium channels TREK1 and TRAAK (p< 0.01 vs CTL in both cases), as well as a significant increase in the mRNA levels of the antioxidant and detoxifying enzymes NQO-1 and HO-1 and the neuronal injury marker ATF3 (p< 0.01 vs CTL for NQO-1, p< 0.05 vs CTL for HO-1, p< 0.001 vs CTL for ATF3) were detected in lumbar DRGs of OXA animals. A concomitant upregulation of the neuronal activation marker c-fos and the transcription factor Nrf2, main regulator of antioxidant defense mechanisms, was observed in the dorsal SC (p< 0.01 vs CTL for both markers). RESV early and sustained administration was able to restore TREK1 and TRAAK expression levels (p< 0.05 vs OXA for both channels, while inducing a further increase in the expression of Nrf2, NQO-1, HO-1 (p< 0.01 vs OXA, p0.05 vs CTL in both cases).ConclusionsThese results show that RESV systemic administration induces the expression of different anti-oxidant mediators while preventing the downregulation of leak potassium channels, thus preventing OXAinduced neuronal injury/ hyperactivity and neuropathic pain.