This study was designed to investigate the potential neuronal damage mechanism of the okadaic acid (OA) in the brain tissues of zebrafish embryos by evaluating in terms of immunofluorescence of Nf KB, TLR-4, caspase 3, ERK ½, c-FOS and 8-OHdG signaling pathways. We also evaluated body malformations. For this purpose, zebrafish embryos were exposed to 0.5 μg/ml, 1 μg/ml and 2.5 μg/ml of OA for 5 days. After application, FITC/GFP labeled protein-specific antibodies were used in immunofluorescence assay for NfKB, TLR-4, caspase 3, ERK ½, c-FOS and 8-OHdG respectively. The results indicated that OA caused immunofluorescence positivity of NfKB, TLR-4, caspase 3, ERK ½, c-FOS and 8-OHdG in a dose-dependent manner in the brain tissues of zebrafish embryos. Pericardial edema (PE), nutrient sac edema (YSE) and body malformations, tail malformation, short tail and head malformation (BM) were detected in zebrafish embryos. These results suggest that OA induces neuronal damage by affecting the modulation of DNA damage, apoptotic, and inflammatory activities in the brain tissues of zebrafish embryos. The increase in signaling pathways shows that OA can cause damage in the structure and function of brain nerve cells. Our results provide a new basis for the comprehensive assessment of the neural damage of OA and will offer enable us to better understand molecular the mechanisms underlying the pathophysiology of OA toxicity.

The mutual interplay between neuroinflammation, synaptic plasticity, and autophagy has piqued researchers\' interest, particularly when it comes to linking their impact and relationship to cognitive deficits. Being able to reduce inflammation and apoptosis, melatonin has shown to have positive neuroprotective effects; that is why we thought to check the possible role of agomelatine (AGO) as a promising candidate that could have a positive impact on cognitive deficits. In the current study, AGO (40 mg/kg/day, p.o., 7 days) successfully ameliorated the cognitive and learning disabilities caused by lipopolysaccharide (LPS) in rats (250 μg/kg/day, i.p., 7 days). This positive impact was supported by improved histopathological findings and improved spatial memory as assessed using Morris water maze. AGO showed a strong ability to control BACE1 activity and to rein in the hippocampal amyloid beta (Aβ) deposition. Also, it improved neuronal survival, neuroplasticity, and neurogenesis by boosting BDNF levels and promoting its advantageous effects and by reinforcing the pTrkB expression. In addition, it upregulated the pre- and postsynaptic neuroplasticity biomarkers resembled in synapsin I, synaptophysin, and PSD-95. Furthermore, AGO showed a modulatory action on Sortilin-related receptor with A-type repeats (SorLA) pathway and adjusted autophagy. It is noteworthy that all of these actions were abolished by administering PD98059 a MEK/ERK pathway inhibitor (0.3 mg/kg/day, i.p., 7 days). In conclusion, AGO administration significantly improves memory and learning disabilities associated with LPS administration by modulating the ERK/SorLA/BDNF/TrkB signaling pathway parallel to its capacity to adjust the autophagic process.

Methyl mercury is a teratogenic and neurodevelopmental toxicant in the environment. MeHg affects several biological pathways critical for brain development. The present study validated the effect of Fisetin on developmental MeHg exposure induced alterations in mitochondrial apoptotic pathway and Rho GTPase mRNA expressions in hippocampus of F1 generation rats. Pregnant Wistar rats were grouped as Group I : administered with vehicle control, Group II: MeHg (1.5 mg/kg b.w), Group III: MeHg + Fisetin (10 mg/kg b.w), Group IV: MeHg + Fisetin (30 mg/kg b.w), Group V: MeHg + Fisetin (50 mg/kg b.w), Group VI: MeHg + Fisetin (70 mg/kg b.w), Group VII: Fisetin (30 mg/kg b.w) alone. Fisetin reduced mercury accumulation in offspring brain. In hippocampus, Fisetin preserved mitochondrial total thiol status, glutathione antioxidant system, mitochondrial metabolic integrity and respiratory chain activity. Fisetin ameliorated apoptotic signals by preventing Cytochrome c release, down regulating ERK 1/2 and Caspase 3 gene expression. Fisetin also upregulated mRNA expressions of RhoA/Rac1/Cdc42 in hippocampus. Predominant effect of Fisetin was to reduce mercury accumulation in offspring brain there by diminishing the toxic effect of MeHg. Hence we showed that, gestational intake of Fisetin (30 mg/kg b.w.) impedes developmental MeHg neurotoxicity by regulating mitochondrial apoptotic and Rho GTPase signalling molecules and by reducing the mercury accumulation in hippocampus of F1 generation rats.