The effect of melatonin on toll like receptor 4 related inflammatory pathway in the parkinson's disease model

Purposes: Parkinson's disease (PD) is a progressive disabling neurodegenerative disease. Neurodegeneration is characterized by loss of dopaminergic (DA) neurons in substantia nigra pars compacta (SNpc). Microglial activation due to neuroinflammation also increases the pathology of the disease. In the models of PD formed with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), it was shown that the accumulation of alpha synuclein (α-syn) caused by the toxic effect caused DA death in neurons. TLR4; it is thought that it stimulates cytokine release through NF-kB by activating glial cells in the resulting neuroinflammation and thus initiates the death mechanisms on DA neurons. Melatonin can easily cross the blood-brain barrier and providing anti-inflammatory and neuronal protection. Our study was created that α-syn proteins in PH intensify the inflammatory response by activating TLR4 located in the microglia membrane. The aim of this study was to demonstrate, how melatonin plays its important role in the suppression of pathogenesis of PD model by using MPTP. Material-Method: Three-month old male C57BL/6 mice were randomly divided into 5 groups as Control, Solvent (EtOH), Melatonin-treated (MEL), MPTP-injected (MPTP), MPTP injected + Melatonin-treated (MPTP+MEL). In our study, MPTP was intraperitoneally injected at a dose of 4x20 mg/kg in saline. Melatonin was administered (20 mg/kg) by intraperitoneally to MEL and MPTP+MEL groups for 5 days. Motor activities of mice were evaluated by pole and locomotor activity tests on the 7th day of the utilization of experimental Parkinson's model. Total brain tissues were used in immunohistochemical analysis of the tyrosine hydroxylase (TH), TLR4, α-syn and p65. Results: In the MPTP group, it was seen that motor activity was decreased and treated with melatonin (p<0,001). TH immunohistochemical staining was significantly reduced due to decreased number of DA neurons; in addition to the TLR4 and α-syn expression observed in the grafts in the SNpc of MPTP group. The increase in TLR4 (p<0,001) and α-syn (p<0,001) expressions induced the NF-kB pathway and increased expression of p65 (p<0,01). These expressions decreased in MPTP+MEL group (p<0,001). Conclusion: We confirmed that TLR4 influences the MPTP-induced nigral degeneration. Our results suggested that TLR4 and α-syn increases microglial activity in experimental PH model and activates NF-kB pathway and causes DA neuron loss. An inflammation was suppressed and DA neuron loss was reduced with melatonin. The results of the present study indicated that melatonin has protective effects on DA neurons in PD. Key words: Parkinson's disease, MPTP, dopaminergic neuron, TLR4, melatonin