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Abstract: Mitochondria produce ATP, regulate apoptosis, and maintain calcium homeostasis, and thus, mitochondrial dysfunction critically impairs nervous system development. Furthermore, the disruption of oxidative phosphorylation (OXPHOS) in mitochondria could lead to energy depletion and elevate oxidative stress. In the present study, the authors investigated how perturbation of the respiratory chain and bioenergetics affects neural progenitor cells (NPCs). Mitochondrial OXPHOS was impaired by inhibiting electron transfer using the antimycin A and ATP synthase inhibitor oligomycin. It was found that oligomycin impaired NPCs proliferation and was toxic at high concentrations, whereas antimycin A-treated cells showed no changes in NPCs proliferation. Although ROS production was elevated concentration-dependently by both inhibitors, oligomycin-treated C17.2 NPCs, but not antimycin A-treated NPCs, showed a significantly higher cell death rate and lower levels of intracellular ATP. These findings suggest that bioenergetic considerations are critically important for cell viability regulation in NPCs. Taken together, the present study shows that OXPHOS disruption can have a neurotoxic effect on NPCs, and thus, adversely influence the developing brain and the neurogenic capacity of the adult brain. [Copyright &y& Elsevier]

Abstract: Bisphenol A (BPA) is widely used in the manufacture of plastics and epoxy resins, and is known to affect reproductive organ growth and development. However, the effects of BPA on hippocampal neurogenesis are unclear in young adult mice. Therefore, the present study was conducted to examine the effects of BPA on hippocampal neurogenesis and learning as well as memory performance in young adult mice. BPA (1, 5, and 20mg/kg/day) was administered orally to mice for 2weeks. It was found that high-dose BPA (20mg/kg/day) decreased the number of newly generated cells in hippocampus, but that low-dose BPA (1mg/kg) increased the survival of newly generated cells in hippocampi of young mice. Furthermore, high-dose BPA (20mg/kg/day) was found to impair learning and memory performance significantly. However, no significant differences were observed between high- and low-dose treated mice in terms of levels of brain-derived neurotrophic factor (BDNF) or reactive oxygen species production in hippocampus. In addition, BPA treatment did not induce neuronal loss or damage or astrocyte activation. These data suggest that exposure to BPA causes fluctuations in hippocampal neurogenesis in young adult mice that result in spatial learning and memory impairment via a BDNF-independent pathway. [Copyright &y& Elsevier]

Abstract: 1,2-Diacetylbenzene (DAB) is a neurotoxic minor metabolite of 1,2-diethylbenzene or naphthalene reaction product with OH radical. DAB causes central and peripheral neuropathies that lead to motor neuronal deficits. However, the potent effects and molecular mechanisms of DAB on neural progenitor cells and hippocampus are unknown. In the current study, we report the DAB damage at lower doses (less than 50μM) to neural progenitor cell (NPC) in vitro and hippocampal neurogenesis in vivo. DAB significantly suppressed NPC proliferation with increased reactive oxygen species (ROS) production in a dose-dependent manner. The suppression of NPC proliferation was effectively blunted by the action of an antioxidant, N-acetyl cysteine. Six-week-old male C57BL/6 mice were treated with 1 or 5mg/kg DAB for 2weeks. DAB significantly suppressed NPC proliferation in the dentate gyrus of the hippocampus, indicating impaired hippocampal neurogenesis. Increased ROS production and the formation of oxidative stress-associated dinitrophenyl adducts were detected in the hippocampal homogenates of DAB-treated mice. DAB activated Mac-1-positive immune cells which are involved in inflammatory process in the hippocampus. Taken together, these results confirm that oxidative stress by DAB might be cause of adverse effects in NPC proliferation and hippocampal neurogenesis. [Copyright &y& Elsevier]

Abstract: Acrylamide (ACR) is a well-known neurotoxin in mammalian species that causes neuropathy characterized by ataxia and skeletal muscle weakness. Therefore, ACR-mediated axon damage in the central and peripheral nervous systems is considered to be central-peripheral axonopathy. However, the molecular mechanisms underlying ACR''s toxicity to neural progenitor cells are unknown. This study investigated the adverse effects of ACR on mouse multipotent neural progenitor cells and adult hippocampal neurogenesis. ACR significantly reduced the proliferation of neural progenitor cells, and high ACR concentrations induced apoptotic and necrotic cell death. We found that elevated intracellular levels of reactive oxygen species were involved in ACR-mediated cytotoxicity. Interestingly, the administration of ACR to young mice resulted in a significant decrease in the number of newly generated cells in the dentate gyrus of the hippocampus, suggesting an impairment of adult neurogenesis. These results suggest that ACR''s deleterious effects on the central nervous system are due to the death of neural progenitor cells and impaired adult neurogenesis. [Copyright &y& Elsevier]

Abstract: 2,5-Hexanedione (HD), a metabolite of n-hexane, causes central and peripheral neuropathy leading to motor neuron deficits. Although chronic exposure to n-hexane is known to cause gradual sensorimotor neuropathy, there are no reports on the effects of low doses of HD on neurogenesis in the central nervous system. In the current study, we explored HD toxicity in murine neural progenitor cells (NPC), primary neuronal culture and young adult mice. HD (500nM∼50μM) dose-dependently suppressed NPC proliferation and cell viability, and also increased the production of reactive oxygen species (ROS). HD (10 or 50mg/kg for 2 weeks) inhibited hippocampal neuronal and NPC proliferation in 6-week-old male ICR mice, as measured by BrdU incorporation in the dentate gyrus, indicating HD impaired hippocampal neurogenesis. In addition, elevated microglial activation was observed in the hippocampal CA3 region and lateral ventricles of HD-treated mice. Lastly, HD dose-dependently decreased the viability of primary cultured neurons. Based on biochemical and histochemical evidence from both cell culture and HD-treated animals, the neurotoxic mechanisms by which HD inhibits NPC proliferation and hippocampal neurogenesis may relate to its ability to elicit an increased generation of deleterious ROS. [Copyright &y& Elsevier]

Abstract: Vitamin C (VC) has a strong antioxidant function evident as its ability to scavenge superoxide radicals in vitro. We verified that this property actually exists in vivo by using a real-time imaging system in which Lucigenin is the chemiluminescent probe for detecting superoxide in senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice, which cannot synthesize VC in vivo. SMP30/GNL KO mice were given 1.5g/L VC [VC(+)] for 2, 4, or 8 weeks or denied VC [VC(−)]. At 4 and 8 weeks, VC levels in brains from VC(−) KO mice were <6% of that in VC(+) KO mice. Accordingly, superoxide-dependent chemiluminescence levels determined by ischemia-reperfusion at the 4- and 8 weeks test intervals were 3.0-fold and 2.1-fold higher, respectively, in VC(−) KO mice than in VC(+) KO mice. However, total superoxide dismutase activity and protein levels were not altered. Thus, VC depletion specifically increased superoxide generation in a model of the living brain. [Copyright &y& Elsevier]