Methylene Blue as a Novel Neuroprotectant in Acute Malathion Intoxication

Abstract

The effect of methylene blue on oxidative stress and neuronal injury in rats following acute malathion intoxication was examined. Rats were intraperitoneally injected with malathion at 150 mg/kg body weight along with methylene blue at 5 or 10 mg/kg body weight, and euthanized 4 hr later. The levels of lipid peroxidation [malondialdehyde (MDA)], nitric oxide, and reduced glutathione (GSH), and the activities of paraoxonase 1 (PON1), acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) were measured in the brain tissue. Histopathological examination and glial fibrillary acidic protein (GFAP) immunostaining were also carried out in this study. Malathion induced a significant elevation in brain lipid peroxidation (MDA) by 32.8% associated with an increased nitric oxide level by 51.4%. Following malathion exposure, brain GSH level fell by 67.7%, and brain AChE and BChE activities decreased by 25% and 60.4%, respectively. Malathion exposure also inhibited PON1 activity by 39.6% and decreased brain glucose level by 30%. Neuronal degeneration in the cortex and hippocampus and strong GFAP immunostaining in the hippocampus were observed in malathion-exposed animals. Methylene blue co-treatment at 10 mg/kg body weight decreased brain MDA by 17.8%, and at 5 and 10 mg/kg body weight, decreased nitric oxide level by 29.2% and 35.8%, respectively. There was no significant effect on the GSH level, but PON1 activity was increased by 22.9%-30.9% upon methylene blue co-treatment. BChE activity did not change but that of AChE increased after cotreatment with the lower dose of methylene blue. Rats receiving methylene blue co-treatment at 10 mg/kg body weight showed no degenerating neurons in the cortex, and occasional degenerating neurons and weak GFAP immunostaining in the hippocampus. Taken together, our results suggest that methylene blue is neuroprotective in acute malathion intoxication, and the neuroprotective effect is likely due to inhibition of oxidative stress and decreased glial cell activation.

Neuro- and Hepatoprotective Effects of Methylene Blue in Rats Treated with Lipopolysaccharide Endotoxin

“…In cerebral ischemia/reperfusion injury, MethyB was shown to decrease cerebral nitric oxide content and the number of iNOS and nNOS activated cortical cells [44]. MethyB co-treatment at 10 mg/kg was also shown to decrease brain nitric oxide and to afford neuroprotection following malathion intoxication in rats [10].…”

“…This action is likely to underlie the enhancement of memory processing by the dye [61,62]. MethyB also appears to compete with acetylcholine at the muscarinic binding sites [59] which could explain the neuroprotective effect of the dye in rats intoxicated with the organophosphate compound malathion [10].…”

“…Studies in experimental animals indicated the ability of the dye to prevent neurodegeneration under different circumstances. In this context, MethyB was shown to prevent neuronal death caused by ischemia/reperfusion injury [6], serum deprivation [7], rotenone [8], traumatic brain injury [9], malathion [10], and toluene [11]. It was also protective in a mouse model of Huntington's disease [12].…”

“…MethyB enhances mitochondrial function due to cycling between its oxidized (leucomethylene blue) and reduced form in the mitochondria, reducing the formation of reactive oxygen metabolites [15]. MethyB exerts: (i) antioxidant activities [10,11]; (2) antiinflammatory effects decreasing microglia activation and gene expression of interleukin-1beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) in macrophages and microglia [9], as well as activation of nuclear factor kappa-B [11]; and (iii) antiapoptotic effects inhibiting caspase-3 activation and increasing Bcl2 expression [8]. Lipopolysaccharide (LPS), a constituent of the outer wall of Gram-negative bacteria, is widely used to induce a systemic inflammatory illness [16].…”

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].…”