Developmental methylmercury toxicity in a 6- hydroxydopamine Parkinsonian rat model: evaluating Searsia chirindensis as a potential neuroprotectant.

Abstract

Methylmercury (MeHg) pollution in South Africa has escalated due to increased demand from industrial sources such as coal-fired power stations. This had led to a growing interest in the effects of this metal toxin on human health. Prenatal MeHg exposure has been suggested to be a silent neurotoxicant, which may display its effects when triggered by a further neurotoxic insult. MeHg exposure during the perinatal period leads to neurodevelopmental deficits resulting in motor and cognitive dysfunction. This suggests that developmental MeHg exposure may predispose to the development of neurodegenerative diseases such as Parkinson’s disease (PD). In this study, we investigate the effects of prenatal MeHg exposure at adolescence and furthermore when subjected to an additional neurotoxic insult in a parkinsonian rat model. Behavioural tests were conducted to assess motor deficits with neurochemical assessment of trace element levels, total antioxidant capacity, dopamine and cytokine concentrations as well as gene expression profiling. We also investigated a novel plant extract Searsia chirindensis (SC) as a potential neuroprotectant by alleviating neurotoxicity. Overall the results of our study show that prenatal MeHg exposure disrupts trace element homeostasis at adolescence asymptomatically however, these imbalances are exaggerated following a further neurotoxic insult leading to motor deficits. Treatment with SC reduced motor deficits in MeHg-exposed offspring as reflected by higher dopamine levels. Contrastingly, treatment in the absence of MeHg exacerbated motor deficits with higher copper levels and upregulation of antioxidant genes fth1 and nqo1 in response to the neurotoxic effect. Therefore the overall total antioxidant capacity was not affected by SC. We also investigated the effect of SC on normal body parameters to assess for toxicity. Our findings showed that SC did not affect either liver or renal function and therefore does not affect the homeostasis of other body systems. Therefore conclusively our study showed that developmental MeHg exposure results in altered trace element homeostasis which may predispose to the development of neurodegenerative diseases such as Parkinson’s. We also showed that SC stem-bark extract reduced motor deficits caused by 6-hydroxydopamine in MeHg-exposed offspring but exacerbated neurotoxicity in its absence. SC also did not have any adverse effect on the homeostasis of other body systems. Overall, this suggests that SC has potential as a neuroprotectant however further studies must be conducted to fully elucidate the mechanisms involved in its effect.