Increased iNOS and Nitrosative Stress in Dopaminergic Neurons of MDMA-Exposed Rats

Abstract

Several mechanisms underlying 3,4-Methylenedioxy-N-methylamphetamine (MDMA) neurotoxicity have been proposed, including neurochemical alterations and excitotoxicity mediated by reactive oxygen species (ROS), nitric oxide (NO), and reactive nitrogen species (RNS). However, ROS, NO, and RNS sources in the brain are not fully known. We aimed to investigate possible alterations in the expression of the ROS producer NOX enzymes (NOX2, NOX1, and NOX4), NO generators (iNOS, eNOS, and nNOS), markers of oxidative (8-hydroxy-2′-deoxyguanosine, 8OHdG), and nitrosative (3-nitrotyrosine, NT) stress, as well as the colocalization between cells positive for the dopamine transporter (DT1) and cells expressing the neuronal nuclei (NeuN) marker, in the frontal cortex of rats receiving saline or MDMA, sacrificed 6 h, 16 h, or 24 h after its administration. MDMA did not affect NOX2, NOX1, and NOX4 immunoreactivity, whereas iNOS expression was enhanced. The number of NT-positive cells was increased in MDMA-exposed animals, whereas no differences were detected in 8OHdG expression among experimental groups. MDMA and NT markers colocalized with DT1 positive cells. DT1 immunostaining was found in NeuN-positive stained cells. Virtually no colocalization was observed with microglia and astrocytes. Moreover, MDMA immunostaining was not found in NOX2-positive cells. Our results suggest that iNOS-derived nitrosative stress, but not NOX enzymes, may have a crucial role in the pathogenesis of MDMA-induced neurotoxicity, highlighting the specificity of different enzymatic systems in the development of neuropathological alterations induced by the abuse of this psychoactive compound.

Phagocytosis‐related NADPH oxidase 2 subunit gp91phox contributes to neurodegeneration after repeated systemic challenge with lipopolysaccharides

“…The link between NOX‐2 and necroptosis or apoptosis of neurons is unclear, but LPS often induce Nos2 transcription, which increases NO• release (Arimoto & Bing, 2003; Fonseca et al, 2003; Medeiros et al, 2007). The produced NO• and ROS released from the NOX‐2 oxidase can form highly toxic RNS like peroxynitrite, which could directly lead to neurodegeneration (Dias, Junn, & Mouradian, 2013; Dingjan et al, 2016; Schiavone et al, 2019).…”

Worsening of the Toxic Effects of (±)Cis-4,4′-DMAR Following Its Co-Administration with (±)Trans-4,4′-DMAR: Neuro-Behavioural, Physiological, Immunohistochemical and Metabolic Studies in Mice

“…A range of physiological (e.g., sweating, salivation, hyperthermia) and neuro-behavioural (e.g., psychomotor agitation, aggressiveness, convulsion) parameters were here assessed. Moreover, to highlight possible neurotoxic mechanisms, and similar to what previously investigated in relation to MDMA [23] the effects of 4,4 -DMAR on the expression of key markers of oxidative/nitrosative stress (8-OHdG, iNOS, NT and NOX2) and apoptosis (Smac/DIABLO and NF-κB) were here analysed. Furthermore, in taking from some current preliminary data, which showed the emergence of a 4,4 -DMAR-related hyperthermia, the expression of heat shock proteins (HSP27, HSP70, HSP90), markers related to heat-induced response [24][25][26], was here assessed as well.…”

“…The results of in vivo studies suggested the occurrence of phenomena related to CNS alterations (e.g., hyperthermia; seizures). By analogy to other stimulant drugs (e.g., MDMA [23] and cocaine [93]) we hypothesised that the oxidative and/or nitrosative stress occurred in the brain following the intake of 4,4 -DMAR.…”

Brain metastases: Radiobiological, molecular and biochemical approach

“…[94] Nitric oxide-depleting myeloperoxidase (MPO) can maintain long-term NOS activity by preventing NO feedback inhibition. [95] On the other hand, myeloperoxidase has an important role in the host's defense against glioblastoma multiforme (GBM), as its inhibition worsens survival after radiation therapy in an animal model of glioblastoma. [96] Therefore, NO is involved in numerous processes that promote glioma growth.…”