Rotenone-induced nigrostriatal toxicity is reduced by methylene blue

Abstract

This study investigated the effect of subcutaneously injected methylene blue on oxidative stress and nigrostriatal damage induced in the rat brain by systemic rotenone injection. Rotenone 1.5 mg/kg (injected subcutaneously three times per week) was given alone or in combination with methylene blue (5, 10, or 20 mg/kg subcutaneously daily) for 2 weeks. Brain concentrations of malondialdehyde, reduced glutathione, nitric oxide (nitrite), and acetylcholinesterase, paraoxonase 1 activity, and the antiapoptotic marker Bcl-2 (B-cell lymphoma 2) were determined. Histopathology, tyrosine hydroxylase immunoreactivity, tumor necrosis factor-alpha (TNF-α), and caspase-3 immunohistochemistry were also performed. Injection of rotenone resulted in increased oxidative stress in different regions of the brain. Substantial increases in malondialdehyde (by 59.6%-77.3%) and nitric oxide (by 43.7%-58.7%) were observed in the cortex, striatum, hippocampus, and medulla of rotenone-treated rats. Meanwhile, glutathione decreased by 24.3%-59.8% in these brain regions. Rotenone administration was associated with a significant decrease in paraoxonase 1 activity in the cerebral cortex, striatum, hippocampus, medulla, midbrain, and cerebellum (by 66%-73.6%). Further, acetylcholinesterase activity decreased by 44.4% in the cortex and Bcl-2 decreased in the striatum by 33.9% after rotenone injection. Rotenone induced a marked decrease in tyrosine hydroxylase immunoreactivity and increased both TNF-α and caspase-3 immunoreactivity in the striatum. These effects of rotenone were substantially reduced by coadministration of methylene blue, which resulted in significantly decreased malondialdehyde and nitrite and increased glutathione in different regions of the brain. In addition, there was increased paraoxonase 1 and acetylcholinesterase activity in response to treatment with methylene blue. Bcl-2 levels in the striatum increased significantly after the highest dose of methylene blue. Methylene blue also significantly decreased striatal expression of TNF-α and caspase-3 (apoptosis), and the degree of neuronal degeneration and gliosis in the striatum, substantia nigra, cortex, and hippocampus. Treatment with methylene blue resulted in an increased number of tyrosine hydroxylase-positive cells in the striatum, substantia nigra, and cerebral cortex, compared with the rotenone control group. The present findings suggest that treatment with methylene blue could prevent neuronal degeneration induced by rotenone injection in the rat brain. This effect may be mediated by inhibition of oxidative stress and apoptotic markers, and by enhancement of apoptotic markers and acetylcholinesterase activity.

Therapeutic Effects of Curcuma longa against Rotenone-Induced Gross Motor Skill Deficits in Rats

“…The transmitted signal is terminated by AChE in cholinergic neurotransmission. Study showed that pesticides including rotenone act as an AChE inhibitor and reduced the level of AChE enzyme which is in agreement with our study (Abdel-Salam et al, 2014;. In movement control DA acts as inhibitory neurotransmitter in basal ganglia and ACh acts as excitatory neurotransmitter.…”

“…This decrease in AChE activity following rotenone administration was attenuated by curcumin treatment which may be linked to restoration of cholinergic activity resulting in observed normalized ACh levels. ACh plays an important role in motor control in the central nervous systems (Abdel-Salam et al, 2014). The transmitted signal is terminated by AChE in cholinergic neurotransmission.…”

Methylene blue elicits non-genotoxic H₂O₂ production and protects brain mitochondria from rotenone toxicity

“…Poteet et al (2012) showed that MB reduces the ROS production and provides neuroprotection in HT-22 cells against the rotenone toxicity. The subcutaneous infusion of MB reduced oxidative stress caused by repeated injections of the rotenone (Abdel-Salam et al, 2014). Some studies have found that the administration of MB significantly reduced mortality after cyanide poisons (Berling, 1970;Salaris et al, 1991;Sun et al, 2018, Wen et al, 2011, which inhibits IV complex of ETC.…”

Methylene Blue Protects against Acidified Sodium Taurocholate-Induced Gastric Mucosal Damage

“…The dye is also an effective remedy for encephalopathy caused by the alkylating agent ifosfamide [13,14]. Recent interest in MethyB focuses on its neuroprotective potential that has been demonstrated in various in vitro and in vivo models of Parkinson's disease [15][16][17], Huntington's disease ROS [18], and Alzheimer's disease [19], and in mitigating neurotoxicity caused by organophosphates [20]. It also protected against brain and liver damage during endotoxemia [21].…”