Abstract
BackgroundActivation of NADPH oxidase (PHOX) plays a critical role in mediating dopaminergic neuroinflammation. In the present study, we investigated the role of PHOX in methamphetamine (MA)-induced neurotoxic and inflammatory changes in mice.MethodsWe examined changes in mitogen-activated protein kinases (MAPKs), mitochondrial function [i.e., mitochondrial membrane potential, intramitochondrial Ca2+ accumulation, mitochondrial oxidative burdens, mitochondrial superoxide dismutase expression, and mitochondrial translocation of the cleaved form of protein kinase C delta type (cleaved PKCδ)], microglial activity, and pro-apoptotic changes [i.e., cytosolic cytochrome c release, cleaved caspase 3, and terminal deoxynucleotidyl transferase dUDP nick-end labeling (TUNEL) positive populations] after a neurotoxic dose of MA in the striatum of mice to achieve a better understanding of the effects of apocynin, a non-specific PHOX inhibitor, or genetic inhibition of p47phox (by using p47phox knockout mice or p47phox antisense oligonucleotide) against MA-induced dopaminergic neurotoxicity.ResultsPhosphorylation of extracellular signal-regulated kinases (ERK1/2) was most pronounced out of MAPKs after MA. We observed MA-induced phosphorylation and membrane translocation of p47phox in the striatum of mice. The activation of p47phox promoted mitochondrial stresses followed by microglial activation into the M1 phenotype, and pro-apoptotic changes, and led to dopaminergic impairments. ERK activated these signaling pathways. Apocynin or genetic inhibition of p47phox significantly protected these signaling processes induced by MA. ERK inhibitor U0126 did not exhibit any additional positive effects against protective activity mediated by apocynin or p47phox genetic inhibition, suggesting that ERK regulates p47phox activation, and ERK constitutes the crucial target for apocynin-mediated inhibition of PHOX activation.ConclusionsOur results indicate that the neuroprotective mechanism of apocynin against MA insult is via preventing mitochondrial burdens, microglial activation, and pro-apoptotic signaling process by the ERK-dependent activation of p47phox.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0478-x) contains supplementary material, which is available to authorized users.
Highlights
Activation of NADPH oxidase (PHOX) plays a critical role in mediating dopaminergic neuroinflammation
We suggested here for the first time that inhibition of the extracellular signal-regulated kinase (ERK)-dependent phosphorylation and membrane translocation of p47phox are critical for apocynin-mediated protective potentials against oxidative stress, neuroinflammatory change, and pro-apoptotic pathway induced by MA and that these morbid events require pro-apoptotic scenarios induced by a toxic dose of MA
Methamphetamine treatment significantly promoted phosphorylation and membrane translocation of p47phox and phosphorylation of mitogen-activated protein kinase (MAPK) in the striatum of wild-type mice It is recognized that phosphorylation of p47phox constitutes one of the key intracellular events associated with PHOX activation, and Ser345 phosphorylation of p47phox by the mitogen-activated protein kinases (MAPKs) protein plays a critical role in the potentiation of PHOX activation by pro-inflammatory agents [36, 51, 52]
Summary
Activation of NADPH oxidase (PHOX) plays a critical role in mediating dopaminergic neuroinflammation. We investigated the role of PHOX in methamphetamine (MA)-induced neurotoxic and inflammatory changes in mice. It has been well-recognized that high doses of methamphetamine (MA) result in impaired nigrostriatal dopaminergic systems in both rodents [1,2,3,4] and primates [5]. NADPH oxidase (PHOX) activation was observed in response to mitochondrial ROS formation in human leukocytes [32]
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