Melatonin protects against methamphetamine-induced Alzheimer's disease-like pathological changes in rat hippocampus.

Methamphetamine (METH) is a psychostimulant drug of abuse. METH use is associated with cognitive impairments and neurochemical abnormalities comparable to pathological changes observed in Alzheimer's disease (AD). These observations have stimulated the idea that METH abusers might be prone to develop AD-like signs and symptoms. Melatonin, the pineal hormone, is considered as a potential therapeutic intervention against AD. We thus conducted the present study to explore potential protective roles of melatonin against METH-induced deficits in learning and memory as well as in the appearance of AD-like pathological changes in METH-treated male Wistar rats. We found that melatonin ameliorated METH-induced cognitive impairments in those rats. Melatonin prevented METH-induced decrease in dopamine transporter (DAT) expression in rat hippocampus. Melatonin reversed METH-induced activation of ß-arrestin2, reduction of phosphorylation of protein kinase B (Akt) and METH-induced excessive activity of glycogen synthase kinase-3ß (GSK3ß). Importantly, melatonin inhibited METH-induced changes in the expression of ß-site APP cleaving enzyme (BACE1), disintegrin and metalloproteinase 10 (ADAM10), and presenilin 1 (PS1), as well as the reduction of amyloid beta (Aß)42 production. Immunofluorescence double-labeling demonstrated that melatonin not only prevented the METH-induced loss of DAT but also prevented METH-induced Aß42 overexpression in the dentate gyrus, CA1, and CA3. Furthermore, melatonin also suppressed METH-induced increase in phosphorylated tau. Significantly, melatonin attenuated METH-induced increase in N-methyl-D-aspartate receptor subtype 2 B (NR2B) protein expression and restored METH-induced reduction of Ca2+/calmodulin-dependent protein kinase II (CaMKII). This suggested that melatonin attenuated the toxic effect of METH on the hippocampus involving the amyloidogenic pathway. Taken together, our data suggest that METH abuse may be a predisposing risk factor for AD and that melatonin could serve as a potential therapeutic agent to prevent METH-induced AD like pathology.

Protective Effects of Melatonin on Methamphetamine-Induced Blood-Brain Barrier Dysfunction in Rat Model.

The specialized brain endothelial cells interconnected by unique junctions and adhesion molecules are distinctive features of the blood-brain barrier (BBB), maintaining the homeostasis of the cerebral microenvironment. This study was designed to investigate the protective effects of melatonin on methamphetamine (METH)-induced alterations of BBB integrity. Wistar rats were randomly distributed into groups and underwent melatonin pretreatment and escalating-high doses of METH treatment. Immunohistochemistry was performed to demonstrate the BBB leakage. Protein and RNA samples were isolated from hippocampal and prefrontal cortical tissues and measured expression levels of molecular markers associated with BBB structural components and inflammatory processes. METH provoked the loss of zonula occludens (ZO)-1, occludin, and claudin-5 tight junction proteins. Furthermore, METH caused an excessive increase in matrix metalloproteinase-9 (MMP-9) enzyme, intercellular adhesion molecule 1 (ICAM-1), and vascular cell adhesion molecule 1 (VCAM-1) and the increase in NAD(P)H oxidase 2 (NOX2). Melatonin exerted the protective effects by recovering tight junction loss; attenuating excessive MMP-9, NOX2, and cell adhesion molecule expression; and reducing serum albumin in the brain. Our results also showed the protective effects of melatonin against METH neurotoxic profiles, characterized by reactive gliosis: microglia (integrin-αM) and astrocyte (GFAP); an excessive upregulation of primary pro-inflammatory cytokines: interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α); activation of neuroinflammatory signaling: nuclear factor-kappa B (NF-κB); and suppression of anti-oxidative signaling: nuclear factor erythroid 2-related factor (Nrf2), that may exacerbate BBB structural impairment. Our results provide insights into the beneficial effects of melatonin against METH-induced BBB disruption and mechanisms that play detrimental roles in BBB impairment by in vivo design.

Increased blood oxidative stress in amphetamine users.

Amphetamine derivatives have been shown to be a potential brain neurotoxin based on the production of free radicals that occurs after administration. The purpose of this study was to examine the lipid peroxidation and antioxidant enzymes in the blood of amphetamine users. The plasma lipid peroxidation was determined and reported as thiobarbituric acid reactive substance and was significantly increased (+21%), whereas the activities of the erythrocyte antioxidant enzymes glutathione peroxidase, catalase, and superoxide dismutase were significantly decreased (-32%, -14% and -31%, respectively) in amphetamine users. These results implicated the potential role of oxidative stress in amphetamine-induced neurotoxicity.