Improvement of Cerebellum Redox States and Cholinergic Functions Contribute to the Beneficial Effects of Silymarin Against Manganese-Induced Neurotoxicity

Abstract

Manganese (Mn) is a potent neurotoxin involved in the initiation and progression of various cognitive disorders. Oxidative stress is reported as one of accepted mechanisms of Mn toxicity. The present study was designed to explore the effects of silymarin, a natural antioxidant, in attenuating the toxicity induced by Mn in rat cerebellum. In this investigation, rats were treated orally with MnCl₂ (20 mg/ml) for 30 days, subsets of these animals were treated intraperitoneally daily with silymarin (100 mg/kg) along with respective controls. Mn exposure caused a marked oxidative stress in cerebellum as indicated by a significant decrease in the activities of enzymatic antioxidants like superoxide dismutase, catalase and glutathione peroxidase and in the levels of non-enzymatic antioxidants like reduced glutathione (GSH), total thiols and vitamin C. Conversely an increase was obtained in lipid and protein markers such as thiobarbituric reactive acid substances, lipid hydroperoxide and protein carbonyl products contents. A significant increase in acetylcholinesterase and a decrease in Na⁺/K⁺-ATPase activities were also shown, with a substantial rise in the expression of acetylcholinesterase and inducible nitric oxide synthase (iNOS), and nitric oxide levels. The potential effect of SIL to prevent Mn induced neurotoxicity was also reflected by histopathological observations. Rats exposed to Mn showed a reduced number and morphological alterations of cerebellar Purkinje cells. These phenomenons were completely reversed by SIL co-treatment. We concluded that silymarin may protect against Mn-induced oxidative stress in cerebellum by inhibiting both lipid and protein oxidation and by activating acetylcholinesterase and inducible nitric oxide synthase (iNOS) gene expression.

Silymarin and dimercaptosuccinic acid ameliorate lead-induced nephrotoxicity and genotoxicity in rats

“…The doses of silymarin and the course for 5 consecutive days for DMSA were based on the previous reports. 24,25 We found that Pb exposition caused a significant increase in the BLLs compared with the control group. DMSA administration caused a significant decrease in BLLs.…”

Altered biometal homeostasis is associated with CLN6 mRNA loss in mouse neuronal ceroid lipofuscinosis

“…6I), is a site of significant lipopigment accumulation at 52 weeks of age in CLN6 mice (Thelen et al, 2012b). Moreover, Purkinje cell loss was reported to be an early pathological feature in mouse models of infantile, late infantile and juvenile NCL diseases (Sleat et al, 2004; Macauley et al, 2009; Weimer et al, 2009), and oral treatment of rats with manganese for 30 days resulted in cerebellar Purkinje cell loss and morphological abnormalities (Chtourou et al, 2012). Importantly, Purkinje cells are essential for controlling motor and learning functions, and motor symptoms were the first to be detected in this model (Fig.…”

“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

“…Similarly, crude aqueous extracts of Melissa officinalis blunted the Mn-induced striatal and hippocampal lipid peroxidation [187]. Purified flavonoids, such as, silymarin (obtained from Silybum marianum , a plant with hepatoprotecive properties) protected neuroblastoma cells [188] and prevented Mn-induced oxidative stress in brain, liver, and kidney of rats [189–191]. Lycopene has also been reported to decrease the neurotoxicity of Mn in rats [192].…”