Geraniin Mitigates Neuropathic Pain Through Antioxidant, Anti-Inflammatory, and Nitric Oxide Modulation in a Rat Model of Chronic Constriction Injury

Neuropathic pain (NPP) remains therapeutically challenging, with oxidative/nitrosative stress and neuroinflammation-amplified by nitric oxide (NO)-as key drivers. This study investigated geraniin (GRN), a naturally occurring hydrolyzable ellagitannin widely distributed in various plant species, including <i>Phyllanthus</i> spp. and <i>Nephelium lappaceum</i> (rambutan), in a rat model of sciatic nerve chronic constriction injury (CCI), focusing on NO-pathway involvement. Male Wistar rats (n = 8/group) received intraperitoneal GRN (3, 10, 30, or 100 mg/kg) or vehicle (1% DMSO in saline) daily for 21 days. Behavioral (thermal hyperalgesia, mechanical allodynia, sciatic functional index), electrophysiological (nerve conduction velocity), and biochemical markers-oxidative/nitrosative stress (nitrite, MDA), antioxidant defenses (GSH, SOD, CAT), inflammation (TNF-α, IL-1β, IL-6, MPO), and apoptosis (caspase-3)-were quantified. L-arginine or L-NAME was co-administered to probe NO signaling. GRN at 30 and 100 mg/kg produced significant antinociceptive and neuroprotective effects; 30 mg/kg was selected for detailed analysis. By day 21, GRN improved pain thresholds and nerve conduction, enhanced antioxidant capacity, suppressed inflammatory mediators, and reduced caspase-3 activity. L-arginine reversed, whereas L-NAME potentiated these effects, confirming NO-dependent modulation. Collectively, GRN mitigates CCI-induced NPP via coordinated antioxidant, anti-inflammatory, and anti-apoptotic actions, supporting its potential as a multi-target candidate for pharmacokinetic and translational development.