Biomarkers of methylmercury neurotoxicity and neurodevelopmental features: A systematic review.

The issue of MeHg contamination is a significant concern due to its detrimental impact on the environment. This study aimed to thoroughly investigate the effects of MeHg on neurodevelopmental biomarkers, as there is a lack of systematic reviews in this area. We conducted a comprehensive search of three databases (PubMed, Scopus, and Web of Science) and found 522 records, which were then meticulously reviewed by two independent reviewers. A total of 66 studies were included, with biomarkers related to oxidative stress, neurotransmission, inflammation, epigenetics, and apoptosis being the most prominent. The results of both in vitro and in vivo models indicate that antioxidant enzymes and other oxidative stress-related markers are indeed, altered following MeHg exposure. Moreover, MeHg exposure causes significant disruptions to neurotransmitter levels, activities of neurotransmitter synthesis enzymes, receptor densities, and proteins involved in synaptic function. Proinflammatory biomarkers are consistently overexpressed in both MeHg-treated cells and the brains of exposed rats. Furthermore, studies on DNA methylation and biomarker activity suggest that MeHg exposure may lead to neurotoxicity and neurodevelopmental issues via perturbations to epigenetic markers and the apoptosis pathway.

Genistein attenuates amyloid-beta-induced cognitive impairment in rats by modulation of hippocampal synaptotoxicity and hyperphosphorylation of Tau.

Alzheimer's disease is a progressive neurodegenerative disorder characterized by extracellular accumulation of amyloid-beta (Aß) peptide, which induces synaptic dysfunction, alteration of intracellular signaling pathways, hyperphosphorylation of the Tau protein, and cognitive impairment. Genistein, one of the major isoflavones present in soy and soy products, has been shown to modulate some of the pathogenic events associated with the neurodegeneration process. However, its underlying mechanisms remain to be clarified. Therefore, the objectives of the present study were to evaluate the ability of genistein to protect against Aß1-42-induced cognitive impairment in rats and to elucidate some of the possible mechanisms involved in its neuroprotective effects in the hippocampus. Male Wistar rats received bilateral intracerebroventricular infusions of Aß1-42 (2 nmol) and genistein 10 mg/kg orally for 10 days. The Aß-infused animals showed significant impairment of memory, which was accompanied by the following neurochemical alterations in the hippocampus: decreased levels of the synaptic proteins synaptophysin and postsynaptic density protein 95 (PSD-95), hyperphosphorylation of Tau with increased activation of glycogen synthase kinase-3ß and c-Jun N-terminal kinase, and inactivation of ERK. Treatment with genistein improved Aß-induced cognitive impairment by attenuation of synaptotoxicity, hyperphosphorylation of Tau, and inactivation of ERK. Furthermore, treatment with this soy isoflavone did not cause systemic toxicity. These findings provide further evidence of the neuroprotective effect of genistein in an in vivo model of Aß toxicity and, importantly, extend the current knowledge concerning the mechanisms associated with the neuroprotective effects of this compound in the hippocampus.

Genistein protects against amyloid-beta-induced toxicity in SH-SY5Y cells by regulation of Akt and Tau phosphorylation.

Alzheimer's disease is a neurodegenerative disorder characterized by extracellular deposition of amyloid-ß (Aß) peptide and hyperphosphorylation of Tau protein, which ultimately leads to the formation of intracellular neurofibrillary tangles and cell death. Increasing evidence indicates that genistein, a soy isoflavone, has neuroprotective effects against Aß-induced toxicity. However, the molecular mechanisms involved in its neuroprotection are not well understood. In this study, we have established a neuronal damage model using retinoic-acid differentiated SH-SY5Y cells treated with different concentrations of Aß25-35 to investigate the effect of genistein against Aß-induced cell death and the possible involvement of protein kinase B (PKB, also termed Akt), glycogen synthase kinase 3ß (GSK-3ß), and Tau as an underlying mechanism to this neuroprotection. Differentiated SH-SY5Y cells were pre-treated for 24 hr with genistein (1 and 10 nM) and exposed to Aß25-35 (25 µM), and we found that genistein partially inhibited Aß induced cell death, primarily apoptosis. Furthermore, the protective effect of genistein was associated with the inhibition of Aß-induced Akt inactivation and Tau hyperphosphorylation. These findings reinforce the neuroprotective effects of genistein against Aß toxicity and provide evidence that its mechanism may involve regulation of Akt and Tau proteins.

The anticancer estrogen receptor antagonist tamoxifen impairs consolidation of inhibitory avoidance memory through estrogen receptor alpha.

Over two-thirds of women with breast cancer have positive tumors for hormone receptors, and these patients undergo treatment with endocrine therapy, tamoxifen being the most widely used agent. Despite being very effective in breast cancer treatment, tamoxifen is associated with side effects that include cognitive impairments. However, the specific aspects and mechanisms underlying these impairments remain to be characterized. Here, we have investigated the effects of tamoxifen and interaction with estrogen receptors on formation of memory for inhibitory avoidance conditioning in female rats. In the first experiment, Wistar female rats received a single oral dose of tamoxifen (1, 3, or 10 mg/kg) or saline by gavage immediately after training and were tested for memory consolidation 24 h after training. In the second experiment, rats received a single dose of 1 mg/kg tamoxifen or saline by gavage 3 h after training and were tested 24 h after training for memory consolidation. In the third experiment, rats received a subcutaneous injection with estrogen receptor α agonist or estrogen receptor beta agonist 30 min before the training. After training, rats received a single oral dose of tamoxifen 1 mg/kg or saline and were tested 24 h after training. In the fourth experiment, rats were trained and tested 24 h later. Immediately after test, rats received a single dose of tamoxifen (1 mg/kg) or saline by gavage and were given four additional daily test trials followed by a re-instatement. Tamoxifen at 1 mg/kg impaired memory consolidation when given immediately after training and the estrogen receptor alpha agonist improved the tamoxifen-related memory impairment. Moreover, tamoxifen impairs memory consolidation of the test. These findings indicate that estrogen receptors regulate the early phase of memory consolidation and the effects of tamoxifen on memory consolidation.

Alterations on Na⁺,K⁺-ATPase and acetylcholinesterase activities induced by amyloid-ß peptide in rat brain and GM1 ganglioside neuroprotective action.

Alzheimer's disease (AD) is a neurodegenerative disorder whose pathogenesis involves production and aggregation of amyloid-ß peptide (Aß). Aß-induced toxicity is believed to involve alterations on as Na(+),K(+)-ATPase and acetylcholinesterase (AChE) activities, prior to neuronal death. Drugs able to prevent or to reverse these biochemical changes promote neuroprotection. GM1 is a ganglioside proposed to have neuroprotective roles in AD models, through mechanisms not yet fully understood. Therefore, this study aimed to investigate the effect of Aß1-42 infusion and GM1 treatment on recognition memory and on Na(+),K(+)-ATPase and AChE activities, as well as, on antioxidant defense in the brain cortex and the hippocampus. For these purposes, Wistar rats received i.c.v. infusion of fibrilar Aß1-42 (2 nmol) and/or GM1 (0.30 mg/kg). Behavioral and biochemical analyses were conducted 1 month after the infusion procedures. Our results showed that GM1 treatment prevented Aß-induced cognitive deficit, corroborating its neuroprotective function. Aß impaired Na(+),K(+)-ATPase and increase AChE activities in hippocampus and cortex, respectively. GM1, in turn, has partially prevented Aß-induced alteration on Na(+),K(+)-ATPase, though with no impact on AChE activity. Aß caused a decrease in antioxidant defense, specifically in hippocampus, an effect that was prevented by GM1 treatment. GM1, both in cortex and hippocampus, was able to increase antioxidant scavenge capacity. Our results suggest that Aß-triggered cognitive deficit involves region-specific alterations on Na(+),K(+)-ATPase and AChE activities, and that GM1 neuroprotection involves modulation of Na(+),K(+)-ATPase, maybe by its antioxidant properties. Although extrapolation from animal findings is difficult, it is conceivable that GM1 could play an important role in AD treatment.