Heba-Tallah Abd Elrahim Abd Elkader

Cortical grey matter pathology manifests early demyelinating diseases and is a primary driver of permanent neurological impairment. Our study investigated the neuroprotective effects of betaine against cuprizone (CPZ)‐induced damage to the cerebral cortex in rats, focusing on its ability to modulate the upstream WNT4/mTOR signalling pathway. Cortical tissues were collected for biochemical assessments of oxidative and inflammatory markers, real‐time PCR analysis for WNT4 , GFAP , and mTOR gene expressions, histopathological examination, and immunohistochemical analysis of vimentin, S100, and synaptophysin. Exposure to CPZ resulted in severe cortical damage with profound oxidative stress. This oxidative status triggered a pronounced neuroinflammatory response, leading to elevated levels of IL‐17A, IL‐1β, and TNF‐α, which in turn caused chronic, hyper‐reactive astrogliosis. This was confirmed by the upregulation of GFAP gene expression and enhanced immunohistochemical staining of vimentin and S100β, resulting in extensive loss of cortical synaptic integrity (depletion of synaptophysin). Importantly, treatment with betaine served as a molecular brake, significantly downregulating the aberrant gene expressions of WNT4 and mTOR . This targeted downregulation effectively reduced the overactive glial response, leading to a significant reduction in astrogliosis ( GFAP , vimentin, and S100β), alleviated the pro‐inflammatory cytokines, restored endogenous antioxidant functions, and ultimately preserved cortical synaptophysin expression and cellular structure. Overall, these results demonstrate that betaine exerts a neuroprotective effect against CPZ‐induced cortical injury, which is strongly associated with the attenuation of WNT4/mTOR signalling pathway hyperactivation, suppression of astrogliosis, and preservation of synaptic density. The preservation of cortical grey matter integrity is directly associated with alleviating cognitive deficits and long‐term physical disabilities in multiple sclerosis patients, emphasising the translational relevance of targetable neuroprotective therapies.

Organophosphate pesticides (OPPs) are widely used in agriculture and are associated with metabolic dysregulation and cognitive impairment. Emerging evidence links OPP exposure to insulin resistance and diabetes mellitus, a condition known to negatively impact brain function. Prior investigations in our laboratory identified significant dysregulation of arachidonic acid (AA) metabolites associated with the endocannabinoid system in both diabetic patients and those with chronic OPP exposure, with a marked reduction in serum AA levels in the OPP-exposed cohort. This study investigates the impact of OPP exposure and pre-diabetes on the hippocampal proteome and whether AA supplementation can mitigate the resulting neuronal proteomic alterations. Using a controlled rat model, high-resolution LC-MS/MS-based proteomics identified differentially expressed proteins across experimental groups. Both OPP exposure and pre-diabetes were associated with increased cognitive impairment and were associated with overlapping disruptions in pathways related to insulin resistance, mitochondrial function, synaptic plasticity, and neuronal development. AA supplementation mitigated cognitive decline and stabilized synaptic and metabolic proteins; however, residual pathway dysregulation highlights the complexity of these stressors. Our results reveal novel molecular intersections between environmental and metabolic drivers of cognitive impairment, establishing a rationale for further research into inexpensive, protective dietary interventions.

The dysregulation of autophagy plays a significant role in the onset of various pathologies, with emerging evidence indicating its potential involvement in chronic pain conditions. The cellular and molecular mechanisms underlying this pathology have been thoroughly investigated, with the endocannabinoid system (ECS) identified as a crucial factor in the progression of chronic neuropathic pain. This chapter highlights several plant-derived cannabinoids, including cannabidiol, cannabinol, Δ-9-tetrahydrocannabinol, which exhibit unique modulatory effects on the ECS. We discuss the roles of cannabinoid receptors, cannabinoid enzymes, and PPARγ as modulators in decreased levels of inflammatory cytokines, as well as a reduction in microglial activation, and inhibit the assembly of NLRP3 inflammasome complex, which potentially provides substantial neuroprotective effects in neuropathic pain. Since the discovery of the endocannabinoid system and the implications of mitochondrial dysfunction and autophagy impairment in neuropathic pain, there has been an increasing interest in the therapeutic potential of this system.

Arsenic is associated with various neurological disorders, notably affecting memory and cognitive functions. The current study examined the protective effects of vitamin D3 (Vit. D3) in countering oxidative stress, neuroinflammation and apoptosis induced by sodium arsenite (SA) in the cerebral cortex of rats. Male Wistar rats were subjected to a daily oral administration of sodium arsenite (NaAsO2, SA) at a dosage of 5 mg/kg, along with 500 IU/kg of Vit. D3, and a combination of both substances for four weeks. The results indicated that Vit. D3 effectively mitigated the SA-induced increase in oxidative stress markers, thiobarbituric acid reactive substances (TBARS) and nitric oxide (NO), the decrease in antioxidants (reduced glutathione; GSH, superoxide dismutase; SOD, catalase; CAT, and glutathione peroxidase; GPx), as well as the increase in pro-inflammatory markers including, tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and amyloid-beta (Aβ)1–42. Furthermore, Vit. D3 reversed the alterations in the neurochemicals acetylcholinesterase (AchE), monoamine oxidase (MAO), dopamine (DA), and acetylcholine (Ach) and ameliorated the histopathological changes in the cerebral cortex. Moreover, immunohistochemical analyses revealed that Vit. D3 reduced the SA-induced overexpression of cerebral cysteine aspartate-specific protease-3 (caspase-3) and glial fibrillary acidic protein (GFAP) in the cerebral cortex of male rats. Consequently, the co-administration of Vit. D3 can protect the cerebral cortex against SA-induced neurotoxicity, primarily through its antioxidant, anti-inflammatory, anti-apoptotic, and anti-astrogliosis effects.

Bisphenol A (BPA), a common endocrine-disrupting chemical, is found in a wide range of home plastics. Early-life BPA exposure has been linked to neurodevelopmental disorders; however, the link between neuroinflammation, pyroptosis, and the development of psychiatric disorders is rarely studied. The current study attempted to investigate the toxic effect of BPA on inflammatory and microglial activation markers, as well as behavioral responses, in the brains of male rats in a dose- and age-dependent manner. Early BPA exposure began on postnatal day (PND) 18 at dosages of 50 and 125 mg/kg/day. We started with a battery of behavioral activities, including open field, elevated plus- and Y-maze tests, performed on young PND 60 rats and adult PND 95 rats. BPA causes anxiogenic-related behaviors, as well as cognitive and memory deficits. The in vivo and in silico analyses revealed for the first time that BPA is a substantial activator of nuclear factor kappa B (NF-κB), interleukin (IL)-1β, -2, -12, cyclooxygenase-2, and the NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, with higher beclin-1 and LC3B levels in BPA rats' PFC and hippocampus. Furthermore, BPA increased the co-localization of caspase-1 immunoreactive neurons, as well as unique neurodegenerative histopathological hallmarks. In conclusion, our results support the hypothesis that neuroinflammation and microglial activation are involved with changes in the brain after postnatal BPA exposure and that these alterations may be linked to the development of psychiatric conditions later in life. Collectively, our findings indicate that BPA triggers anxiety-like behaviors and pyroptotic death of nerve cells via the NF-κB/IL-1β/NLRP3/Caspase-1 pathway.