Sinapic Acid Mitigates Pentylenetetrazol-induced Acute Seizures By Modulating the NLRP3 Inflammasome and Regulating Calcium/calcineurin Signaling: In Vivo and In Silico Approaches

Abstract

Sinapic acid (SA) is a naturally occurring carboxylic acid found in citrus fruits and cereals. Recent studies have shown that SA has potential anti-seizure properties due to its anti-inflammatory, antioxidant, and anti-apoptotic effects. The present study investigated the neuroprotective role of SA at two different dosages in a pentylenetetrazol (PTZ)-induced acute seizure model. Mice were divided into six groups: normal control, PTZ, SA (20 mg/kg), SA (20 mg/kg) + PTZ, SA (40 mg/kg), and SA (40 mg/kg) + PTZ. SA was orally administered for 21 days, followed by a convulsive dose of intraperitoneal PTZ (50 mg/kg). Seizures were estimated via the Racine scale, and animals were behaviorally tested using the Y-maze. Brain tissues were used to assess the levels of GABA, glutamate, oxidative stress markers, calcium, calcineurin, (Nod)-like receptor protein-3 (NLRP3), interleukin (IL)-1β, apoptosis-associated speck-like protein (ASC), Bcl-2–associated death protein (Bad) and Bcl-2. Molecular docking of SA using a multistep in silico protocol was also performed. The results showed that SA alleviated oxidative stress, restored the GABA/glutamate balance and calcium/calcineurin signaling, downregulated NLRP3 and apoptosis, and improved recognition and ambulatory activity in PTZ-treated mice. In silico results also revealed that SA strongly interacts with the target proteins NLRP3 and ASC. Overall, the results suggest that SA is a promising antiseizure agent and that both doses of SA are comparable, with 40 mg/kg SA being superior in normalizing glutathione, calcium and IL-1β, in addition to calcineurin, NLRP3, ASC and Bad. Graphical Abstract

Pharmacological Activities and Molecular Mechanisms of Sinapic Acid in Neurological Disorders

“…In addition to its antioxidant properties, SA demonstrates metal-chelating potential, anti-inflammatory effects, antiapoptotic properties, and neuroprotective qualities, with the last attributed to the inhibition of inducible nitric oxide synthase (iNOS) expression and nitric oxide blockade. Moreover, SA demonstrates promise in safeguarding against lysosomal dysfunction and mitigating carbon tetrachloride-induced inflammation in rats, potentially via nuclear factor κ light chain enhancement of activated B cells (NF-kB) activation and the modulation of proinflammatory cytokines. ,, …”