title: Manganese-exposed developing rats display motor deficits and striatal oxidative stress that are reversed by Trolox.
abstract: While manganese (Mn) is essential for proper central nervous system (CNS) development, excessive Mn exposure may lead to neurotoxicity. Mn preferentially accumulates in the basal ganglia, and in adults it may cause Parkinson's disease-like disorder. Compared to adults, younger individuals accumulate greater Mn levels in the CNS and are more vulnerable to its toxicity. Moreover, the mechanisms mediating developmental Mn-induced neurotoxicity are not completely understood. The present study investigated the developmental neurotoxicity elicited by Mn exposure (5, 10 and 20 mg/kg; i.p.) from postnatal day 8 to PN27 in rats. Neurochemical analyses were carried out on PN29, with a particular focus on striatal alterations in intracellular signaling pathways (MAPKs, Akt and DARPP-32), oxidative stress generation and cell death. Motor alterations were evaluated later in life at 3, 4 or 5 weeks of age. Mn exposure (20 mg/kg) increased p38(MAPK) and Akt phosphorylation, but decreased DARPP-32-Thr-34 phosphorylation. Mn (10 and 20 mg/kg) increased caspase activity and F2-isoprostane production (a biological marker of lipid peroxidation). Paralleling the changes in striatal biochemical parameters, Mn (20 mg/kg) also caused motor impairment, evidenced by increased falling latency in the rotarod test, decreased distance traveled and motor speed in the open-field test. Notably, the antioxidant Trolox™ reversed the Mn (20 mg/kg)-dependent augmentation in p38(MAPK) phosphorylation and reduced the Mn (20 mg/kg)-induced caspase activity and F2-isoprostane production. Trolox™ also reversed the Mn-induced motor coordination deficits. These findings are the first to show that long-term exposure to Mn during a critical period of neurodevelopment causes motor coordination dysfunction with parallel increment in oxidative stress markers, p38(MAPK) phosphorylation and caspase activity in the striatum. Moreover, we establish Trolox™ as a potential neuroprotective agent given its efficacy in reversing the Mn-induced neurodevelopmental effects.
authors: Departamento de Bioquímica, Centro de Ciências Biológicas, Universidade Federal de Santa Catarina, Florianópolis, SC 88040-900, Brazil.
authors: Fabiano M
authors: FM
authors: Cordova
authors: Aderbal S
authors: AS
authors: Aguiar
authors: Tanara V
authors: TV
authors: Peres
authors: Mark W
authors: MW
authors: Lopes
authors: Filipe M
authors: FM
authors: Gonçalves
authors: Daniela Z
authors: DZ
authors: Pedro
authors: Samantha C
authors: SC
authors: Lopes
authors: Célso
authors: C
authors: Pilati
authors: Rui D S
authors: RD
authors: Prediger
authors: Marcelo
authors: M
authors: Farina
authors: Keith M
authors: KM
authors: Erikson
authors: Michael
authors: M
authors: Aschner
authors: Rodrigo B
authors: RB
authors: Leal
mesh_terms: D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D000975:Antioxidants / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D020169:Caspases / Q000378:metabolism; D002839:Chromans / Q000494:pharmacology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D008297:Male; D020149:Manganese Poisoning / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D009043:Motor Activity / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test; D015398:Signal Transduction / Q000187:drug effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002839:Chromans; D018696:Neuroprotective Agents; D048051:p38 Mitogen-Activated Protein Kinases; D020169:Caspases; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid
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