Role of melatonin in Tlr4-mediated inflammatory pathway in the mptp-induced mouse model

Abstract Neuroinflammation has an essential role in various neurodegenerative diseases including Parkinson’s disease (PD). Microglial activation as a result of neuroinflammation exacerbates the pathological consequences of the disease. The toxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) causes alpha-synuclein (α-synuclein) accumulation, which leads to dopaminergic neuron death in the MPTP-induced mouse model. Toll-like receptor 4 (TLR4) stimulates release of cytokine through NF-kB by activating glial cells, thus resulting in the death of dopaminergic neurons. Melatonin has the ability to cross the blood-brain barrier and protect neurons through anti-inflammatory properties. We hypothesized that melatonin could suppress TLR4-mediated neuroinflammation, decrease cytokine release due to the inflammatory response, and reduce dopaminergic neuron loss in the MPTP-induced mouse model. In the MPTP-induced mouse model, we aimed to assess the neuroinflammatory responses caused by TLR4 activation as well as the effect of melatonin on these responses. Three-month-old male C57BL/6 mice were randomly divided into five groups; Control (Group-C), Sham (Group-S), Melatonin-treated (Group-M), MPTP-injected (Group-P), and MPTP + melatonin-injected (Group-P + M). MPTP toxin (20 mg/kg) was dissolved in saline and intraperitoneally (i.p.) injected to mice for two days with 12 h intervals. The total dose per mouse was 80 mg/kg. Melatonin was administered (20 mg/kg) intraperitoneally to Group-M and Group-P + M twice a day for five days. Eight days after starting the experiment, the motor activities of mice were evaluated by locomotor activity tests. The SNpc area of ​​the brain was determined immunohistochemical by the tyrosine hydroxylase (TH). TLR4, α-synuclein, and p65 expression was evaluated by immunostaining as well. In addition, TNF-α amount in the total brain was also evaluated by western blot analysis. In our results seen that locomotor activity was lower in the Group-P compared to the Group-C. However, melatonin administration was improved this impairment. MPTPcaused decrease in TH immuno-expression in dopaminergic neurons in Group-P. TLR4 (p  In conclusion, our study revealed that melatonin administration reduced α-synuclein aggregation and TLR4-mediated inflammatory response in the MPTP-induced mouse model.