Sex-dependent metal accumulation and immunoexpression of Hsp70 and Nrf2 in rats' brain following manganese exposure.

Manganese (Mn), although important for multiple cellular processes, has posed environmental health concerns due to its neurotoxic effects. In recent years, there have been extensive studies on the mechanism of Mn-induced neuropathology, as well as the sex-dependent vulnerability to its neurotoxic effects. Nonetheless, cellular mechanisms influenced by sex differences in susceptibility to Mn have yet to be adequately characterized. Since oxidative stress is a key mechanism of Mn neurotoxicity, here, we have probed Hsp70 and Nrf2 proteins to investigate the sex-dependent changes following exposure to Mn. Male and female rats were administered intraperitoneal injections of MnCl2 (10 mg/kg and 25 mg/kg) 48 hourly for a total of eight injections (15 days). We evaluated changes in body weight, as well as Mn accumulation, Nrf2 and Hsp70 expression across four brain regions; striatum, cortex, hippocampus and cerebellum in both sexes. Our results showed sex-specific changes in body-weight, specifically in males but not in females. Additionally, we noted sex-dependent accumulation of Mn in the brain, as well as in expression levels of Nrf2 and Hsp70 proteins. These findings revealed sex-dependent susceptibility to Mn-induced neurotoxicity corresponding to differential Mn accumulation, and expression of Hsp70 and Nrf2 across several brain regions.

ERK/MAPK signalling in the developing brain: Perturbations and consequences.

The extracellular regulated kinase/microtubule-associated protein kinase (ERK/MAPK) signalling pathway transduces signals that cause an alteration in the ongoing metabolic pathways and modifies gene expression patterns; thus, influencing cellular behaviour. ERK/MAPK signalling is essential for the proper development of the nervous system from neural progenitor cells derived from the embryonic mesoderm. Several signalling molecules that regulate the well-coordinated process of neurodevelopment transduce developmental information through the ERK/MAPK signalling pathway. The ERK/MAPK is a potential novel therapeutic target in several neurodevelopmental disorders, however, despite years of study, there is still significant uncertainty about the exact mechanism by which the ERK/MAPK signalling pathway elicits specific responses in neurodevelopment. Here, we will review the evidence highlighting the role of ERK/MAPK signalling in neurodevelopment. We will also discuss the structural implication and behavioural deficits associated with perturbed ERK/MAPK signalling pathway in cortical development, whilst examining its contribution to the neuropathology of several neurodevelopmental disorders, such as Autism Spectrum Disorder, Schizophrenia, Fragile X, and Attention Deficit Hyperactive Disorder.

Impact of environmental toxicants on p38- and ERK-MAPK signaling pathways in the central nervous system.

There are several candidate signalling pathways that mediate the response of the central nervous system (CNS) cells to environmental toxins. However, much is still to be learned on how these pathways modulate neurotoxicity. The mitogen-activated protein kinases (MAPKs) signalling pathways, which include the extracellular signal-regulated protein kinase (ERK) and the p38-MAPK, are potentially key pathways to regulate CNS responses to environmental toxins. The pathways play leading roles in the transmission of extracellular signals into the cell nucleus, leading to cell differentiation, cell growth, and apoptosis, to name a few. Moreover, exposure to environmental toxins induces p38- and ERK-MAPK activation, which leads to oxidative stress, inflammation, and apoptosis in the CNS. Here, we provide a concise review of the recent evidence demonstrating the role of p38- and ERK-MAPK signaling pathways and their downstream targets in the CNS following exposure to environmental toxicants such as metals, organophosphorus and persistent organic pollutants.

Epigenetic influence of environmentally neurotoxic metals.

Continuous globalization and industrialization have ensured metals are an increasing aspect of daily life. Their usefulness in manufacturing has made them vital to national commerce, security and global economy. However, excess exposure to metals, particularly as a result of environmental contamination or occupational exposures, has been detrimental to overall health. Excess exposure to several metals is considered environmental risk in the aetiology of several neurological and neurodegenerative diseases. Metal-induced neurotoxicity has been a major health concern globally with intensive research to unravel the mechanisms associated with it. Recently, greater focus has been directed at epigenetics to better characterize the underlying mechanisms of metal-induced neurotoxicity. Epigenetic changes are those modifications on the DNA that can turn genes on or off without altering the DNA sequence. This review discusses how epigenetic changes such as DNA methylation, post translational histone modification and noncoding RNA-mediated gene silencing mediate the neurotoxic effects of several metals, focusing on manganese, arsenic, nickel, cadmium, lead, and mercury.

Metal-induced neurotoxicity in a RAGE-expressing C. elegans model.

Environmental and occupational metal exposure poses serious global concerns. Metal exposure have severally been associated with neurotoxicity and brain damage. Furthermore, receptor for advanced glycation end products (RAGE) is also implicated in neurological disorders, particularly those with altered glucose metabolism. Here, we examine potential compounding effect of metal exposure and RAGE expression on dopamine (DA) and serotonin (SER) neurons in C. elegans. In addition, we evaluate the effect of RAGE expression on DA and SER neurons in hyperglycemic conditions. Newly generated RAGE-expressing C. elegans tagged with green fluorescent proteins (GFP) in DAergic and SERergic neurons were treated with cadmium (Cd) or manganese (Mn). Additionally, the RAGE-expressing worms were also exposed to high glucose conditions. Results showed metals induced neurodegeneration both in the presence and absence of RAGE expression, but the manner of degeneration differed between Cd and Mn treated nematodes. Furthermore, RAGE-expressing worms showed significant neurodegeneration in both DAergic and SERergic neurons. Our results indicate co-occurrence of metal exposure and RAGE expression can induce neurodegeneration. Additionally, we show that RAGE expression can exacerbate hyperglycemic induced neurodegeneration.

Potential neurological impact of coronaviruses: implications for the novel SARS-CoV-2.

Coronaviruses (CoV) are viruses widely known to cause severe respiratory distress due to the prominent clinical symptoms presented. These symptoms, which include fever and dry cough, are frequently found in individuals with CoV infection. Neurological manifestations of CoV have often been neglected; however, recent studies have reported neurological consequences of CoV infection. Here, we review these literatures and discuss the neurologic impact of CoV while highlighting potential implications of the novel SARS-CoV-2 in the nervous system. We also discuss the possible routes by which these viruses invade the nervous system and the mechanism by which they may induce neurological damage.