Malathion increases apoptotic cell death by inducing lysosomal membrane permeabilization in N2a neuroblastoma cells: a model for neurodegeneration in Alzheimer’s disease

Abstract

Malathion is an organophosphate with severe neurotoxic effects. Upon acute exposure, malathion initially enhances cholinergic activity by inhibition of acetylcholinesterase, which is its major pathological mechanism. Malathion also induces non-cholinergic neuronal cell death in neurodegenerative conditions; the associated molecular mechanism is not well-characterized. To investigate the molecular mechanism of malathion-induced cell death, N2a mouse neuroblastoma cells were exposed to malathion and cell death-related parameters were examined. Malathion reduced cell viability mainly by apoptosis through mitochondrial dysfunction in N2a cells, as judged by an increase in the level of the pro-apoptotic protein Bax and decrease in the levels of the anti-apoptotic proteins p-Akt and Bcl2, resulting in cytochrome c release and caspase-dependent DNA fragmentation and condensation. Malathion treatment also induced autophagy and lysosomal membrane permeabilization (LMP) in N2a cells. LMP caused a lessening of autophagic flux via inhibition of lysosomal fusion with the autophagosome. LMP-induced cathepsin B release and its proteolytic effect may intensify apoptotic insults. Moreover, malathion-exposed N2a cells showed a marked reduction in the levels of the neuronal marker proteins vascular endothelial growth factor and heart fatty acid binding protein 3, along with diminished neuritogenesis in N2a cells and nerve growth factor secretion in C6 glioma cells. Our data suggest that the non-cholinergic effect of malathion may be mediated by apoptotic cell death via LMP induction in N2a cells. Malathion-treated N2a cells can be utilized as an in vitro model system to screen natural and new chemical drug candidates for neurodegenerative diseases such as Alzheimer’s disease.

Cytotoxic effects of parathion, paraoxon, and their methylated derivatives on a mouse neuroblastoma cell line NB41A3

“…Also, in previous studies, genes related to cell cycle and apoptosis were targeted by organophosphate pesticide chlorpyrifos in rat PC12 cells (Slotkin and Seidler, 2012), by diazinon in human NT2 cells (Aluigia et al, 2010), and by malathion in N2a neuroblastoma cells (Venkatesan et al, 2017).…”

Organophosphate toxicity: updates of malathion potential toxic effects in mammals and potential treatments

“…It was also found that MAL affects brain AChE rats and mice pubs exposed during lactation (da Silva et al 2006;Selmi et al 2012). Although AChE inhibition certainly plays a key role in MAL-induced neurotoxicity, but when alone cannot explain the wide range of neurological signs and symptoms that have been reported (Venkatesan et al 2017). Therefore, different noncholinergic mechanisms have been proposed.…”

Protective Role of EGCG Against Malathion Induced Genotoxicity Using Human Lymphocytes

“…In Montassar lasram et al study, that designed for investigation the malathion hepatic toxicity and the preventive effect of N-acetylcysteine in rats showed that oxidative stress in NAC treated animals, percent of CD4 + and CD8 + T cells and expression of pro-inflammatory cytokine, have reduced [21]. Parola M et al studied on the molecular mechanism in N2a neuroblastoma cells treated by malathion and showed that malathion in- [22].Gupta J et al study investigating in tea effects on cardiovascular disease and shows that catechins by antioxidant activity can reduce ROS and NADPH and by inducing eNOS improves endothelia dysfunction and decrease in Ang-(2) and by protecting mitochondria from dam-age improved cardiac hypertrophy [23].Malathion stimulated lipid peroxidation on subacute, subchronic and chronic periods. Therefore, especially MDA levels in plasma and GSH-Px and Cu-Zn SOD activities in erythrocytes were significantly changed [24].Consistent with previous studies, treatment with EGCG in our experiment led to enhancement in MDA levels and reduction in GSH content.…”