Role of Toll-like receptor 4 (TLR4) in neuroinflammation and L-DOPA induced dyskinesia in mice

• Grant number: 17/05361-2
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: August 01, 2017
• End date: December 01, 2018
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Elaine Aparecida Del Bel Belluz Guimarães
• Grantee: Gabriel Henrique Dias de Abreu
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 14/25029-4 - Contribution of the neuroinflamation to L-DOPA induced dyskinesia, AP.TEM
• Associated scholarship(s): 18/01251-0 - Evaluation of NMNAT2 expression: on hippocampus neurons: targeting on future therapeutical approaches, BE.EP.IC

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disease affecting the world's population, only behind Alzheimer's disease. It is characterized by the development of symptoms involving motor impairments, such as muscular rigidity, tremor, bradykinesia and postural instability, with progression to dementia and cognitive damage. The development of these symptoms is related to molecular neurophysiology, mainly associated with the degeneration of the dopaminergic neurons of the substantia nigra pars compacta. Chronic treatment with levodopa, the precursor of dopamine, initially results in a reduction in the manifestation of motor symptoms in the majority of patients. After 5-10 years of treatment, highly motor complications appear, like abnormal involuntary movements or dyskinesia. Plenty of studies suggest the involvement of inflammatory pathways that exacerbate cell death in pathophysiology of PD and in dyskinesia. The neuroinflammatory phenomenon can manifest itself acutely or can be characterized by the simultaneous activation of cells of the central nervous system, such as neurons, microglia, astrocytes and leukocytes. Some of the major proinflammatory factors that have been shown to be elevated in patients with PD were reproduced in animal models, such as the appearance of the enzyme cyclooxygenase-2 (COX-2), tumor necrosis factor (TNF-±), interleukin 1² (IL-1²) and interleukin-6 (IL-6), present in the striatum and substantia nigra pars compacta among other regions of the central nervous system. Data from our group demonstrate that the development and manifestation of dyskinesia may be followed by an inflammatory response. We showed that atypical neurotransmitter nitric oxide (NO) is involved in levodopa-induced dyskinesia. NO modulates the expression of COX-2, which in turn can modulate the release of proinflammatory cytokines. The present project is based on the hypothesis that there is an inflammatory process in the injured striatum of hemiparkinsonian mice that may be exacerbated by chronic treatment with levodopa. There are few studies that analyze the contribution of the toll-like receptor 4 (TLR-4) in the central nervous system in pathological conditions. The literature points out its participation in ±-synucleopathies and the increase in the expression of TLR receptors in other PD models developed by toxins. Aiming at the benefits derived from a better understanding of immunomodulatory mechanisms dependent of the signaling pathway of this receptor, our focus is to study the role of the TLR-4 signaling pathway in the chronic treatment with L-DOPA in the experimental model of parkinsonism induced by unilateral administration of 6-hydroxydopamine (6-OHDA) in mice.