jw products Several studies have found decreased
Several studies have found decreased astroglial and neuronal cell numbers and jw products damage after OP exposure. Neuronal loss and brain lesions increase proportionally to the severity and duration of OP-induced seizures (Albuquerque et al., 2006, Carpentier et al., 2000, Gullapalli et al., 2010, Myhrer et al., 2005). In the current study, severity of the toxicity induced by 1mg/kg of paraoxon was higher than animals exposed to 0.7mg/kg. Marked histological damage to the rat brain was found following sarin-induced seizure activity (Chapman et al., 2006). A significant decrease in dendritic spines in the hippocampal pyramidal neurons has also been observed in rats that were intoxicated with non-convulsive doses of paraoxon (Santos et al., 2004) and convulsive dose of soman (Carpentier et al., 1991). There might be several different mechanisms for OP-induced brain damage. OP compounds induce seizure-related brain damage through hyper-stimulation of ACh receptors and subsequent recruitment of glutamatergic system. Glutamate-induced excitotoxicity is thought to cause cytotoxic damage to neurons and glia (Shih et al., 1991). In addition to overstimulation of glutamate receptors, other mechanisms such as oxidative stress and mitochondrial dysfunction have also been proposed for brain damage implicated in OP-induced neurotoxicity (Qiao et al., 2005). Induction of oxidative stress was seen in paraoxon-treated rat brain and other tissues (Jafari et al., 2012). Apoptosis is another possible mechanism for OP-induced neuronal damage. Depletion of mitochondrial energy (ATP) and neuronal apoptotic cell death were observed after dichlorvos exposure in rat brain (Kaur et al., 2007). Furthermore, paraoxon-induced apoptosis has also been reported in EL4 cells via alterations in mitochondrial membrane permeability that leads to release of cytochrome c from the mitochondria into the cytosol and subsequent activation of caspase (Saleh et al., 2003). Apoptosis and necrosis have been suggested to be involved in glutamate-induced neuronal injury in cultured mice cortical neurons (Cheung et al., 1998). EAAC1-mediated glutamate uptake into GABAergic nerve terminals is important for GABA synthesis from glutamate and limiting excitotoxic brain cell damage or death (Sepkuty et al., 2002). Cystine/glutamate transporter (xCT) is expressed both within and outside the central nervous system (CNS) and mediates the exchange of extracellular L-cystine and intracellular L-glutamate across the cell membrane. By providing cells with cysteine, xCT regulates the synthesis of glutathione as an endogenous antioxidant and protects cells against oxidative stress and damage (Bridges et al., 2012, Shih et al., 2006). Extracellular accumulation of glutamate can induce oxidative stress through inhibition of the xCT and reducing glutathione production (Lewerenz et al., 2006). In the present study, expression of EAAC1 mRNA and protein was changed only in animals intoxicated with the highest dose of paraoxon (1mg/kg). Unlike the glial glutamate transporters, EAAC1 does not appear to play an important role in removing glutamate from the synaptic cleft (Rothstein et al., 1996). In addition to glutamate transporters located on glia and neurons, those exist on the luminal side of endothelial cells constituting the blood-brain barrier have also been shown to modulate brain extracellular glutamate levels by removing the excess brain glutamate into the blood (Cohen-Kashi-Malina et al., 2012). Treatment with blood glutamate scavenger provides neuroprotection in rat model of paraoxon intoxication by decreasing blood glutamate levels which leads to efflux of excess brain glutamate into the blood and subsequent reduction in the brain glutamate levels (Ruban et al., 2015, Ruban et al., 2014). Glutamate transporter dysfunction has been suggested to contribute in the pathophysiology of several neurological diseases. Therefore, drugs targeting glutamate transporters to enhance their expressions and functions have been considered as potential therapeutic strategies to decrease extracellular glutamate levels and prevent subsequently neuronal damage in these neurodegenerative disorders (Karki et al., 2014, Rothstein et al., 2005). The increased protein expression of EAAT2 and glutamate transport activity in brain after ceftriaxone treatment has got considerable attention (Rothstein et al., 2005).