Morin-Loaded PLGA-Chitosan Nanoparticles Attenuate PTZ-Induced Seizure-Related Behavioral, Biochemical, and Transcriptional Changes in Male Rats

Aims: Morin is a flavonoid with potential neuroprotective and anti-inflammatory properties. This study evaluated the anticonvulsant and anxiolytic effects of morin-loaded PLGA-chitosan nanoparticles (Morin-PLGA-CS NPs) in male Wistar rats. Methods: Morin-PLGA-CS NPs were synthesized using a modified single emulsion-solvent evaporation method followed by CS coating. NPs were characterized by dynamic light scattering (DLS), scanning electron microscopy (SEM), and in vitro drug release analysis. Adult male Wistar rats received intraperitoneal injections of free morin (25 mg/kg), Morin-PLGA-CS NPs, diazepam (1 mg/kg), blank NPs, or vehicle. Behavioral assessments included the open-field test (OFT), elevated-plus maze (EPM), novel object recognition (NOR) test, and pentobarbital-induced sleep test. Anticonvulsant activity was evaluated using PTZ-induced seizure latency. Cytokine concentrations in cortical and hippocampal tissue lysates were quantified by ELISA at 12 h post-PTZ. Hippocampal relative mRNA expression of Nrf2, HO-1, GFAP, and Iba1 was quantified by quantitative real-time PCR (qRT-PCR). Results: Morin-PLGA-CS NPs demonstrated a hydrodynamic diameter of 221.6 nm, a zeta potential of +23.3 mV, and an encapsulation efficiency of 81%. FTIR spectroscopy showed spectral changes compatible with morin incorporation and possible hydrogen-bonding interactions. The NPs exhibited approximately 81.4% morin release over 72 h in vitro. Compared to free morin, Morin-PLGA-CS NPs increased center-zone exploration in the OFT and open-arm behavior in the EPM, but also reduced total distance traveled in the OFT, indicating that motor suppression or sedation may have contributed to the behavioral profile (p < 0.001). It also improved the discrimination index (DI) in the NOR test and elevated sleep duration in the pentobarbital test (p < 0.001). The NPs also prolonged seizure latency (137.2 s vs. 114.5 s for free morin; p < 0.001) and markedly reduced IL-1β, IL-6, and TNF-α levels in both the cortex and hippocampus. At the molecular level, Morin-PLGA-CS NPs were associated with significantly increased hippocampal Nrf2 and HO-1 mRNA transcript levels and decreased GFAP and Iba1 transcript levels relative to free morin and the PTZ-challenged vehicle control group. Conclusions: Morin-PLGA-CS NPs produced greater behavioral, anticonvulsant, inflammatory, and redox effects than free morin in male rats. Molecular data revealed changes in hippocampal mRNA expression, including increased Nrf2 and HO-1 transcripts and decreased GFAP and Iba1 transcripts. However, these transcript-level findings are preliminary and require protein-level validation.