Protection of DFP-induced oxidative damage and neurodegeneration by antioxidants and NMDA receptor antagonist

Abstract

Prophylactic agents acutely administered in response to anticholinesterases intoxication can prevent toxic symptoms, including fasciculations, seizures, convulsions and death. However, anticholinesterases also have long-term unknown pathophysiological effects, making rational prophylaxis/treatment problematic. Increasing evidence suggests that in addition to excessive cholinergic stimulation, organophosphate compounds such as diisopropylphosphorofluoridate (DFP) induce activation of glutamatergic neurons, generation of reactive oxygen (ROS) and nitrogen species (RNS), leading to neurodegeneration. The present study investigated multiple affectors of DFP exposure critical to cerebral oxidative damage and whether antioxidants and NMDA receptor antagonist memantine provide neuroprotection by preventing DFP-induced biochemical and morphometric changes in rat brain. Rats treated acutely with DFP (1.25 mg/kg, s.c.) developed onset of toxicity signs within 7-15 min that progressed to maximal severity of seizures and fasciculations within 60 min. At this time point, DFP caused significant (p<0.01) increases in biomarkers of ROS (F 2 -isoprostanes, F 2 -IsoPs; and F 4 -neuroprostanes, F 4 -NeuroPs), RNS (citrulline), and declines in high-energy phosphates (HEP) in rat cerebrum. At the same time, quantitative morphometric analysis of pyramidal neurons of the hippocampal CA1 region revealed significant (p<0.01) reductions in dendritic lengths and spine density. When rats were pretreated with the antioxidants N-tert-butyl-α-phenylnitrone (PBN, 200 mg/kg, i.p.), or vitamin E (100 mg/kg, i.p./day for 3 days), or memantine (18 mg/kg, i.p.), significant attenuations in DFP-induced increases in F 2 -IsoPs, F 4 -NeuroPs, citrulline, and depletion of HEP were noted. Furthermore, attenuation in oxidative damage following antioxidants or memantine pretreatment was accompanied by rescue from dendritic degeneration of pyramidal neurons in the CA1 hippocampal area. These findings closely associated DFP-induced lipid peroxidation with dendritic degeneration of pyramidal neurons in the CA1 hippocampal area and point to possible interventions to limit oxidative injury and dendritic degeneration induced by anticholinesterase neurotoxicity.

The roles of AIF and Endo G in the apoptotic effects of benzyl isothiocyanate on DU 145 human prostate cancer cells via the mitochondrial signaling pathway

“…5A). It is known that AIF and Endo G were released from the mitochondria and this led to apoptosis which means that the agent induced apoptosis through the mitochondria (36). The present data show that BITC induces AIF and Endo G release from the mitochondria to the cytosol (Fig.…”

“…This finding suggests that the effect of the AIF and Endo G products via the mitochondria could be responsible for the modulation of BITC-induced apoptosis in the DU 145 cells. It has been reported that aberrant mitochondria can generate intracellular ROS and that excessive ROS can induce oxidative stress which can cause DNA injury, resulting in growth arrest and apoptosis (36). Furthermore, it has been reported that the enhancement of ROS production involved with the apoptotic response is induced by anti-cancer agents (37).…”

Administration of memantine and imipramine alters mitochondrial respiratory chain and creatine kinase activities in rat brain

“…In fact, memantine reduced the oxidative damage to proteins in cortex and hippocampus in aged rats (Pietá Dias et al 2007). Moreover, memantine was neuroprotective against rotenone, which an inhibitor of mitochondrial complex I (Rojas et al 2008) and reduced ROS and lipid peroxidation induced by organophosphate in rat brain (Zaja-Milatovic et al 2009). Memantine also prevent the deleterious effects of mitochondrial dysfunction induced by complex II inhibitors, malonate and 3-nitropropionic acid (Schulz et al 1996;Karanian et al 2006;Volbracht et al 2006).…”

Dose-dependent regional brain acetylcholinesterase and acylpeptide hydrolase inhibition without cell death after chlorpyrifos administration

“…In fact, recent approaches in the field of biomarkers of human exposure to OPs apart from considering the inhibition of cholinesteraseas (ChE), the standard biomarker, also include the level of APH activity, among others (Kim et al, 2010;Marsillach et al, 2011). Moreover, recent research have indicated the involvement of mechanisms such as oxidative stress (López-Granero et al, 2013;Qiao et al, 2005;Zaja-Milatovic et al, 2009), cytokine system (Carvajal et al, 2005;López-Grancha et al, 2006), or AChE expression as read-through splice variant (AChE-R) (López-Granero et al, 2013;Meshorer et al, 2002;Meshorer and Soreq, 2006) among the neurotoxic effects of OPs. Our group works on an animal model assessing the persistent consequences following OPs exposure after acute subcutaneous administration of Chlorpyrifos (CPF) in adult Wistar rats.…”