2,5-Hexanedione induces dopaminergic neurodegeneration through integrin αMβ2/NADPH oxidase axis-mediated microglial activation

Abstract

Recent study demonstrated that chronic exposure to solvents increases the risk of Parkinson’s disease (PD), the second most common neurodegenerative disorder characterized by progressive dopaminergic neurodegeneration in the substantia nigra (SN). n-Hexane, a widely used organic solvent, displays central-peripheral neurotoxicity, which is mainly mediated by its active metabolite, 2,5-hexanedione (HD). However, whether HD exposure contributes to PD remains unclear. In this study, we found that rats exposed to HD displayed progressive dopaminergic neurodegeneration in the nigrostriatal system. Microglial activation was also detected in HD-treated rats, which occurred prior to degeneration of dopaminergic neurons. Moreover, depletion of microglia markedly reduced HD-induced dopaminergic neurotoxicity. Mechanistic study revealed an essential role of microglial integrin αMβ2-NADPH oxidase (NOX2) axis in HD-elicited neurotoxicity. HD activated NOX2 by inducing membrane translocation of NOX2 cytosolic subunit, p47phox. Integrin αMβ2 was critical for HD-induced NOX2 activation since inhibition or genetic deletion of αMβ2 attenuated NOX2-generated superoxide and p47phox membrane translocation in response to HD. Src and Erk, two downstream signals of αMβ2, were recognized to bridge HD/αMβ2-mediated NOX2 activation. Finally, pharmacological inhibition of αMβ2-NOX2 axis attenuated HD-induced microglial activation and dopaminergic neurodegeneration. Our findings revealed that HD exposure damaged nigrostriatal dopaminergic system through αMβ2-NOX2 axis-mediated microglial activation, providing, for the first time, experimental evidence for n-hexane exposure contributing to the etiology of PD.

Cold‐inducible protein RBM3 mediates hypothermic neuroprotection against neurotoxin rotenone via inhibition on MAPK signalling

“…PD is the second most common neurodegenerative disease and is characterized by a loss of dopaminergic neurons . Some environmental risk factors, such as ROT and MPP + , are used as neurotoxins for evaluating potential neuroprotective strategies against apoptotic diseases like PD .…”

“…Our finding that RBM3 rescues many of the deficits in the ROT‐based model of PD agrees with previous observations regarding the role of RBM3 in neuroprotection. In vitro, studies have demonstrated that RBM3 prevents apoptosis induced by excessive NO, UV irradiation, RA, staurosporine, hexanedione contact inhibition and serum deprivation, in cultured neurons or neuroblastoma cells. In vivo, it was recently found that RBM3 mediates the protective effects of hypothermia by reducing synaptic loss in a mouse model of Alzheimer's disease .…”

“…PD is the second most common neurodegenerative disease and is characterized by a loss of dopaminergic neurons. 24,25 Some environmental risk factors, such as ROT and MPP + , are used as neurotoxins for evaluating potential neuroprotective strategies against apoptotic diseases like PD. [26][27][28][29][30] For in vitro PD studies, the SH-SY5Y human neuroblastoma cell line is frequently used as a cell model, because it exhibits many characteristics of dopaminergic neurons.…”

Resveratrol targeting tau proteins, amyloid‐beta aggregations, and their adverse effects: An updated review

“…The enhanced levels of Aβ and microglial activation have been identified in patients with AD. The increasing evidence has demonstrated that NADPH oxidase partially mediates the neuroinflammation caused by Aβ plaques (Abubaker et al, 2019;Tarafdar & Pula, 2018;C. Zhang et al, 2018).…”

The imbalance between dynamic and stable microtubules underlies neurodegeneration induced by 2,5-hexanedione

“…In detail, Pezzoli and colleagues demonstrated that n-hexane induces a specific dopamine depletion in rat Corpus striatum and behavioural defects [18,19]. More recently, Zhang and colleagues found neurodegeneration of nigrostriatal pathway in 2,5-HD-intoxicated mice with the loss of both nigral dopaminergic neurons and striatal dopaminergic terminals, thus supporting the causal effect of toxic exposure in PD etiology [20].…”