Mechanistic insights into the neuroprotective effect of syringic acid on methotrexate-induced neurotoxicity in rats via Sirt1/AKT/HO-1 pathway.

Syringic acid (SA), a naturally occurring derivative of benzoic acid, is widely distributed in many plants and fruits. It has been believed to exhibit potent anti-inflammatory, antioxidant, antiapoptotic, anticarcinogenic, and immunomodulatory effects. This study was designed to explore the protective role of syringic acid versus methotrexate (MTX)-induced neurotoxicity. Rats were randomly assigned into four experimental groups: Group 1: Normal control group; Group 2: MTX group (20 mg/kg, i.p.) single dose on the sixth day; Group 3 & 4: Syringic acid groups (50 and 100 mg/kg, orally) for 10 continuous days and one dosage of MTX (20 mg/kg, i.p.) on the sixth day. Treatment with syringic acid markedly improved behavioral parameters relative to the MTX group, reflecting attenuation of MTX-induced cognitive and locomotor impairments. Moreover, syringic acid restored redox balance by elevating GSH levels, reducing MDA accumulation, and activating PKC-dependent CDC42 signaling with upregulation engagement of the AKT/SIRT1/HO-1 axis, thereby attenuating MTX-induced oxidative stress. In addition, it reduced inflammation via decreasing TNF-α, NF-κB, IL-6 and IL-18 and prevented neuronal death (apoptosis) by suppressing caspase-3. Syringic acid treatment significantly ameliorated the pathological brain changes in rats, showing restoration of normal neuronal structure. In conclusion, syringic acid effectively mitigated methotrexate-induced neurotoxicity by improving behavioral performance and preserving neuronal integrity. These protective effects were mediated through enhancement of antioxidant defenses, reduction of oxidative stress and inflammation, and suppression of apoptotic signaling.