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

• Published in: Inflammation 2024-12, Vol.47 (6), p.1969-1986
• Main Authors: Ali, Shimaa O., Ghaiad, Heba R., Elmasry, Ghada F., Mehana, Noha A.
• Format: Article
• Language: English
• Subjects: Animals; Anticonvulsants - pharmacology; Anticonvulsants - therapeutic use; Apoptosis; Bcl-2 protein; Biomedical and Life Sciences; Biomedicine; Calcineurin; Calcineurin - metabolism; Calcium - metabolism; Calcium Signaling - drug effects; Calcium signalling; Carboxylic acids; Cereals; Computer Simulation; Coumaric Acids - pharmacology; Coumaric Acids - therapeutic use; Down-regulation; Glutathione; Immunology; Inflammasomes; Inflammasomes - metabolism; Internal Medicine; Male; Mice; Molecular Docking Simulation; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Oral administration; Oxidative stress; Oxidative Stress - drug effects; Pathology; Pentylenetetrazole; Pharmacology/Toxicology; Proteins; Rheumatology; Seizures; Seizures - chemically induced; Seizures - drug therapy; Seizures - metabolism; Signal Transduction - drug effects; Sinapic acid; γ-Aminobutyric acid
• ISSN: 0360-3997; 1573-2576; 1573-2576
• DOI: 10.1007/s10753-024-02019-0

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