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.

Developmental exposure to manganese induces lasting motor and cognitive impairment in rats

“…These results represent the first evidence that developmental exposure to Mn can lead to long-lasting effects toward striatal GSH levels, observed during adulthood. Furthermore, oxidative stress may be related to motor damage, since co-treatment with Mn and the antioxidant Trolox improved the performance exhibited in the rotarod (Cordova et al, 2012(Cordova et al, , 2013. However, additional studies using antioxidants would be necessary to demonstrate whether oxidative stress contributes to motor impairment in Mn exposed animals.…”

“…with saline (0.9% NaCl; controls) or MnCl 2 5, 10, 20 mg/kg for five consecutive days (PND8-12) as previously described (Rocha et al, 1995;Cordova et al, 2012). The dose regimen was chosen based on previous studies (Cordova et al, 2013) in an attempt to mimic Mn exposures derived from TPN, which have been associated with significant increase in brain Mn levels both in adults and in children (Ejima et al, 1992;Fell et al, 1996;Nagatomo et al, 1999).…”

“…It was shown that Mn induces microglial activation and dopaminergic neurodegeneration in the substantia nigra of rats (Zhao et al, 2009). Mn may cause oxidative stress in vivo and in vitro, which can lead to the activation of intracellular signaling pathways, including mitogen activated protein kinases, MAPKs (Hirata et al, 2004;Ito et al, 2006;Milatovic et al, 2009;Posser et al, 2009;Herná ndez et al, 2011;Cordova et al, 2012Cordova et al, , 2013. It has been shown that the metal causes mitochondrial damage and consequent decrease in ATP production leading to activation of apoptotic pathways and necrosis in PC12 cells (rat pheochromocytoma cell line) (Roth et al, 2002).…”

Melatonin Antagonizes Mn-Induced Oxidative Injury Through the Activation of Keap1–Nrf2–ARE Signaling Pathway in the Striatum of Mice

“…Magnification 9400 a previous study (Oszlánczi et al 2010), our findings demonstrated that Mn significantly reduced spontaneous activity. Excessive Mn accumulation in the striatum can result in a neurological syndrome, which can further lead to motor abnormalities (Cordova et al 2013). In addition, we evaluated the extent of injuries by HE staining.…”

Effect of Manganese on Signaling Pathways

“…22,65 Moreover, striatal activation of both ERK1/2 in response to Mn exposure at PN8-12 and p38 MAPK in response to more prolonged exposure (PND8-27), in a manner dependent of oxidative stress production, were reported. 22,65 Consistent with this temporal effect and other in vitro and in vivo studies, 38,47 it is plausible that in vivo Mn exposure may lead to Immature rats treated at PND8-12 or PND8-27 with 20 mg kg À1 Mn displayed an increment of striatal Akt phosphorylation by undefined mechanism but apparently independent of oxidative stress. Moreover, striatal activation of both ERK1/2 in response to Mn exposure at PN8-12 and p38 MAPK in response to more prolonged exposure (PND8-27) was dependent on reactive oxygen species (ROS) production, since the antioxidant Trolox abrogated this effect.…”