Abstract
Neuroinflammation and autoimmune mechanisms have a key part in the pathogenesis of Parkinson’s disease (PD). Therefore, we evaluated the role of Toll-like receptors (TLRs) as a link between inflammation and autoimmunity in PD. An in vivo model of PD was performed by administration of 1-metil 4-fenil 1,2,3,6-tetraidro-piridina (MPTP) at the dose of 20 mg/kg every 2 h for a total administration of 80/kg, both in single Knock Out (KO) mice for TLR7, TLR 8, and TLR9 and in double KO mice for TLR 7/8-/-. All animals were compared with WT animals used as a control group. All animals were sacrificed after 7 days form the first administration of MPTP. The genetic absence of TLR 7 and 8 modified the PD pathway, increasing the immunoreactivity for TH and DAT compared to PD groups and decreasing microglia and astrocytes activation. Moreover, the deletion of TLR7 and TLR8 significantly reduced T-cell infiltration in the substantia nigra and lymph nodes, suggesting a reduction of T-cell activation. Therefore, our result highlights a possibility that an immunotherapy approach, by using a dual antagonist of TLR 7 and 8, could be considered as a possible target to develop new therapies for Parkinson diseases.
Highlights
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a gradual damage of dopaminergic neurons in the substantia nigra pars compacta and presence of α-synuclein (α-syn)-rich cytoplasmic neuronal inclusion named Lewy bodies [1]
B cells have not been detected in the brains of patients with PD, deposits of Immunoglobulin G (IgG) are found on dopaminergic neurons in these patients, and Lewy bodies themselves are coated with IgG [6], which suggests that dopaminergic neurons might be targeted by these immunoglobulins
To validate our hypothesis of involvement of TLR7, TLR8, and TLR9, we looked at the motor and non-motor symptoms by pole test and Elevated Plus Maze (EPM)
Summary
Parkinson’s disease (PD) is a neurodegenerative disorder characterized by a gradual damage of dopaminergic neurons in the substantia nigra pars compacta and presence of α-synuclein (α-syn)-rich cytoplasmic neuronal inclusion named Lewy bodies [1]. The etiology of PD is still unknown, but recent evidence indicates that adaptive immunity in concern with inflammation are involved in the pathogenesis of PD [2]. It has observed that the levels of activated T cells are increased in the cerebrospinal fluid (CSF), as well as in the midbrains, of patients with PD [3,4]. A potential role for B cells in PD is recently emerging [5]. Despite increasing evidence of a potential role for B cells in PD, it is unclear whether the observed changes in adaptive immunity are causal or are secondary to the CNS injury associated with its pathogenesis. Clinical trials are under way to determine whether treatment with anti-α-synuclein monoclonal antibodies benefits patients with PD [7]
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