Publications (7) View all
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Article: l-Ascorbate attenuates methamphetamine neurotoxicity through enhancing the induction of endogenous heme oxygenase-1.
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ABSTRACT: Methamphetamine (METH) is a drug of abuse which causes neurotoxicity and increased risk of developing neurodegenerative diseases. We previously found that METH induces heme oxygenase (HO)-1 expression in neurons and glial cells, and this offers partial protection against METH toxicity. In this study, we investigated the effects of l-ascorbate (vitamin C, Vit. C) on METH toxicity and HO-1 expression in neuronal/glial cocultures. Cell viability and damage were evaluated by 3-(4,5-dimethylthianol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) reduction and lactate dehydrogenase (LDH) release, respectively. Neuronal and glial localization of HO-1 were identified by double immunofluorescence staining. Reactive oxygen species (ROS) production was measured using the fluorochrome 2',7'-dichlorofluorescin diacetate. HO-1 mRNA and protein expression were examined by RT-qPCR and Western blotting, respectively. Results show that Vit. C induced HO-1 mRNA and protein expressions in time- and concentration-dependent manners. Inhibition of p38 mitogen-activated protein kinase (MAPK) but not extracellular signal-regulated kinase (ERK) significantly blocked induction of HO-1 by Vit. C. HO-1 mRNA and protein expressions were significantly elevated by a combination of Vit. C and METH, compared to either Vit. C or METH alone. Pretreatment with Vit. C enhanced METH-induced HO-1 expression and attenuated METH-induced ROS production and neurotoxicity. Pharmacological inhibition of HO activity abolished suppressive effects of Vit. C on METH-induced ROS production and attenuated neurotoxicity. We conclude that induction of HO-1 expression contributes to the attenuation of METH-induced ROS production and neurotoxicity by Vit. C. We suggest that HO-1 induction by Vit. C may serve as a strategy to alleviate METH neurotoxicity.Toxicology and Applied Pharmacology 09/2012; · 4.45 Impact Factor -
Article: Methamphetamine induces heme oxygenase-1 expression in cortical neurons and glia to prevent its toxicity.
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ABSTRACT: The impairment of cognitive and motor functions in humans and animals caused by methamphetamine (METH) administration underscores the importance of METH toxicity in cortical neurons. The heme oxygenase-1 (HO-1) exerts a cytoprotective effect against various neuronal injures; however, it remains unclear whether HO-1 is involved in METH-induced toxicity. We used primary cortical neuron/glia cocultures to explore the role of HO-1 in METH-induced toxicity. Exposure of cultured cells to various concentrations of METH (0.1, 0.5, 1, 3, 5, and 10 mM) led to cytotoxicity in a concentration-dependent manner. A METH concentration of 5 mM, which caused 50% of neuronal death and glial activation, was chosen for subsequent experiments. RT-PCR and Western blot analysis revealed that METH significantly induced HO-1 mRNA and protein expression, both preceded cell death. Double and triple immunofluorescence staining further identified HO-1-positive cells as activated astrocytes, microglia, and viable neurons, but not dying neurons. Inhibition of the p38 mitogen-activated protein kinase pathway significantly blocked HO-1 induction by METH and aggravated METH neurotoxicity. Inhibition of HO activity using tin protoporphyrine IX significantly reduced HO activity and exacerbated METH neurotoxicity. However, prior induction of HO-1 using cobalt protoporphyrine IX partially protected neurons from METH toxicity. Taken together, our results suggest that induction of HO-1 by METH via the p38 signaling pathway may be protective, albeit insufficient to completely protect cortical neurons from METH toxicity.Toxicology and Applied Pharmacology 08/2009; 240(3):315-26. · 4.45 Impact Factor -
Article: Neonatal status epilepticus alters prefrontal-striatal circuitry and enhances methamphetamine-induced behavioral sensitization in adolescence.
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ABSTRACT: Neonatal seizures may alter the developing neurocircuitry and cause behavioral abnormalities in adulthood. We found that rats previously subjected to lithium-pilocarpine (LiPC)-induced neonatal status epilepticus (NeoSE) exhibited enhanced behavioral sensitization to methamphetamine (MA) in adolescence. Neurochemically, dopamine (DA) and metabolites were markedly decreased in prefrontal cortex (PFC) and insignificantly changed in striatum by NeoSE, but were increased in both PFC and striatum by NeoSE+MA. Glutamate levels were increased in both PFC and striatum in the NeoSE+MA group. DA turnover, an index of utilization and activity, was increased by NeoSE but reversed by MA in PFC. Gene expression of the regulator of G-protein signaling 4 (RGS4) was downregulated in PFC and striatum by NeoSE and further suppressed by MA. These findings suggest NeoSE affects both dopaminergic and glutamatergic systems in the prefrontal-striatal circuitry that manifests as enhanced behavioral sensitization to MA in adolescence.Epilepsy & Behavior 02/2009; 14(2):316-23. · 2.34 Impact Factor -
Article: Lovastatin improves histological and functional outcomes and reduces inflammation after experimental traumatic brain injury.
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ABSTRACT: Traumatic brain injury (TBI) triggers a complex sequence of inflammatory responses that contribute to secondary injury. Statins have demonstrated neuroprotective effects against brain injury, but the underlying mechanisms remain unclear. This study evaluated the effects of lovastatin on a rat model of controlled cortical impact (CCI) injury. Our two hypotheses were that pre-administration of lovastatin would reduce functional deficits and extent of anatomical brain damage and that lovastatin would attenuate levels of pro-inflammatory cytokines. Rats were injected with lovastatin (4 mg/kg) or vehicle for 5 days and subjected to CCI. Neurological status was evaluated using rotarod and adhesive removal tests. Contusion volume and neuronal degeneration were examined using cresyl violet and FluoroJade B (FJB) histochemistry. Levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) mRNA and protein were assessed by real-time quantitative reverse transcriptase polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. Lovastatin significantly improved performance on both the rotarod and adhesive removal tests before post-injury day 7. Lovastatin also significantly reduced contusion volume (20%) and number of FJB-positive degenerating neurons (35%) at 4 days. These changes were associated with a significant decrease in levels of TNF-alpha and IL-1beta mRNA and protein at the contusion site at 6 h and 4 days, respectively. Our results show that pre-administration of lovastatin improved functional outcomes and reduced extent of brain damage, with a concomitant decrease in tissue levels of TNF-alpha and IL-1beta mRNA and protein. These findings suggest that lovastatin's protective mechanisms may be partly attributed to a dampening of the inflammatory response.Life Sciences 08/2007; 81(4):288-98. · 2.53 Impact Factor -
Article: Rapid glia expression and release of proinflammatory cytokines in experimental Klebsiella pneumoniae meningoencephalitis.
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ABSTRACT: The host immune/inflammatory response following CNS infection by Klebsiella pneumoniae remains poorly understood. Using a rat model of K. pneumoniae meningoencephalitis, we investigated the temporal profiles of brain proinflammatory cytokines and their cellular sources. Leukocyte counts significantly increased in cerebrospinal fluid (CSF) at 2 h after K. pneumoniae inoculation into the rat brain but were still much lower than blood leukocyte counts. However, concentrations of tumor necrosis factor alpha (TNF-alpha), interleukin-1beta (IL-1beta), and IL-6 in CSF were much higher than the simultaneously collected serum levels. The rapid increase in brain expression of these cytokines at the messenger RNA (mRNA) and protein levels occurred earlier than the onset of leukocytosis. Double immunofluorescence staining revealed the presence of TNF-alpha, IL-1beta, and IL-6 in astrocytes and microglia. Exposure of primary culture of glial cells to K. pneumoniae also resulted in time-dependent increases in the concentration of these cytokines in the culture media. Taken together, our results suggest that glial cells are an important early source of proinflammatory cytokines during K. pneumonia infection of CNS.Experimental Neurology 05/2007; 205(1):270-8. · 4.70 Impact Factor
