Efeito antinociceptivo da Epiisopiloturina (EPIT) em modelo de dor neuropática no nervo safeno

Abstract

This study evaluated the antinociceptive effect of the alkaloid Epiisopiloturine (EPIT), derived from Pilocarpus microphyllus, in an experimental saphenous nerve neuropathy model, establishing it as a promising phytodrug candidate for non-opioid neuropathic pain therapies. The study utilized male Rattus norvegicus (n=8). EPIT was administered at doses of 1.5, 3.0, and 4.5 mg/kg.p.o. EPIT treatment was demonstrated to be well-tolerated, inducing neither sedation nor motor impairment (rotarod p < 0.0001, comparable to the sham group). The 1.5 mg/kg p.o. dose stood out for its most effective and tolerable action, and was elected for molecular investigation. This choice was based on the superior performance of this dose in reducing hyperexcitability (decreasing rearing and self-grooming) and restoring exploratory activity to basal levels on day 3 (p = 0.0083), in addition to presenting the greatest preservation of organic integrity (renal and hepatic). The relevance of this dose was molecularly validated by restoring hepatic oxidative balance (with significant reduction of MDA, p = 0.0074; and preservation of GSH, p = 0.0451) and promoting central immunomodulation (increase of IL-10, p = 0.0071; and decrease of TNF-α). Molecular investigation demonstrated that EPIT (1.5 mg/kg p.o.) inhibited the TLR4/NF-kB pathway and ERK1/2 phosphorylation, and reversed central hyperexcitability, marked by the reduction of TRPV1 (p = 0.003$) and the restoration of Myelin Basic Protein (PBM) (p = 0.0095).In conclusion, Epiisopiloturine is a neuroprotective and neuronal restorative agent, whose antinociceptive action is primarily mediated by the inhibition of the TLR4/NF-kB pathway, justifying its potential as a non-opioid phytodrug.