Bicuculline Methiodide Preserves Neuromuscular Integrity and Skeletal Muscle Bioenergetics Through Neuroimmune Modulation in Experimental Sepsis

Background: Sepsis-induced systemic inflammation triggers profound metabolic and inflammatory alterations in skeletal muscle, leading to oxidative damage, mitochondrial dysfunction, and muscle wasting. However, the mechanisms linking endotoxemia to skeletal muscle metabolic failure and neuromuscular-associated alterations remain incompletely understood. The present study investigated the effects of bicuculline methiodide (BMI), a GABAA receptor antagonist, on inflammatory responses, oxidative stress, energy metabolism, and selected neural-associated markers in a lipopolysaccharide (LPS)-induced rat model of sepsis. Methods: Adult male Sprague–Dawley rats were allocated into Control, LPS, Bicuculline, and LPS + Bicuculline groups. Twenty-four hours after treatment, gastrocnemius muscle tissues were analyzed for TNF-alpha, IL-10, GABA, and malondialdehyde (MDA) levels, while ATP-related metabolites were quantified by HPLC. NeuN and synaptophysin immunoreactivity were also assessed in muscle sections. Results: LPS administration increased TNF-alpha and MDA levels, altered IL-10 concentrations, and disrupted high-energy phosphate metabolism, accompanied by changes in NeuN and synaptophysin immunoreactivity. Bicuculline co-administration reduced MDA levels, was associated with higher IL-10 concentrations than the LPS group, and markedly increased phosphocreatine levels. Conclusions: These findings indicate that BMI was associated with attenuation of selected inflammatory and oxidative alterations and with changes in skeletal muscle energy metabolites in this experimental model. Because cholinergic markers, alpha7 nicotinic acetylcholine receptor activity, vagal activity, and receptor-specific pharmacological controls were not assessed, the present findings do not establish direct activation of the cholinergic anti-inflammatory pathway or a GABAergic-cholinergic mechanism. The observed effects should therefore be considered exploratory and hypothesis-generating.