Kaurenoic Acid from Annona senegalensisAttenuates Hippocampal NMDA Receptor Overexpression and Enhances Cognitive Function in a Rat Model of PTZ-Induced Seizures

Background: Overactivation of N-methyl-D-aspartate receptors (NMDARs) is implicated in seizure-induced excitotoxicity and neurodegeneration. Kaurenoic acid, a diterpenoid from Annona senegalensis, has shown anticonvulsant potential, but its modulatory effect on NMDARs in epilepsy remains unclear. This study investigates the neuroprotective and cognitive effects of kaurenoic acid and its impact on hippocampal NMDAR expression in a PTZ-induced seizure model in rats. Methods: Kaurenoic acid (KNA) was isolated from the ethyl acetate fraction of A. senegalensis leaves. Thirty male Wistar rats were divided into five groups (n=6): control, PTZ only, KNA (400 or 800 mg/kg, p.o) + PTZ, and phenobarbital (PB, 10 mg/kg, i.p) + PTZ. Seizure activity was scored using Racine’s scale. Cognitive performance was assessed via the Open Field and Novel Object Recognition tests. Hippocampal NMDAR levels were measured using ELISA. Data were analyzed with ANOVA and Tukey’s post hoc test. Results: KNA significantly increased seizure thresholds in myoclonic (173±33 s) and tonic-clonic seizures (444±41 s), comparable to PB (233±43 s and 534±42 s), p<0.0001. KNA improved thigmotaxis (98%) and preserved cognitive function with a positive discrimination index (44±17%), whereas PB impaired cognition (−61±18%). Locomotor activity decreased with both KNA and PB. PTZ elevated NMDAR expression (27±1 µmol) compared to control (22.8±0.2 µmol), while both KNA and PB reduced NMDAR levels (17±3 and 23±1 µmol, respectively). Conclusion: Kaurenoic acid demonstrated strong anticonvulsant and neuroprotective effects, effectively lowering hippocampal NMDAR expression and preserving cognitive function better than phenobarbital. These findings support its therapeutic potential as a safer alternative for seizure management.