Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice

doi:10.1016/j.neuint.2021.105215

Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice

2021-12-01

7

PRE

AI

N

Nauana Somensi *

S

Samantha Cristiane Lopes

J

Juciano Gasparotto

R

Rosângela Mayer Gonçalves

C

Camila Tiefensee Ribeiro

D

Daniel Oppermann Peixoto

José Cláudio Fonseca Moreira

DOI：10.1016/j.neuint.2021.105215

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Abstract

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Parkinson's disease (PD) is a neurodegenerative disease characterized by progressive loss of the nigrostriatal dopaminergic neurons that are associated with motor alterations and non-motor manifestations (such as depression). Neuroinflammation is a process with a critical role in the pathogenesis of PD. In this regard, toll-like receptor 4 (TLR4) is a central mediator of immune response in PD. Moreover, there are gender-related differences in the incidence, prevalence, and clinical features of PD. Therefore, we aimed to elucidate the role of TLR4 in the sex-dependent response to dopaminergic denervation induced by 6-hydroxydopamine (6-OHDA) in mice. Female and male adult wildtype (WT) and TLR4 knockout (TLR4-/-) mice were administered with unilateral injection of 6-OHDA in the dorsal striatum, and non-motor and motor impairments were evaluated for 30 days, followed by biochemistry analysis in the substantia nigra pars compacta (SNc), dorsal striatum, and dorsoventral cortex. Early non-motor impairments (i.e., depressive-like behavior and spatial learning deficits) induced by 6-OHDA were observed in the male WT mice but not in male TLR4-/- or female mice. Motor alterations were observed after administration of 6-OHDA in both strains, and the lack of TLR4 was also related to motor commitment. Moreover, ablation of TLR4 prevented 6-OHDA-induced dopaminergic denervation and microgliosis in the SNc, selectively in female mice. These results reinforced the existence of sex-biased alterations in PD and indicated TLR4 as a promising therapeutic target for the motor and non-motor symptoms of PD, which will help counteract the neuroinflammatory and neurodegenerative processes.

Keywords:

6-Hydroxydopamine

Motor function

Toll-like receptor 4

Microglia

Neuroinflammation

Role of toll-like receptor 4 and sex in 6-hydroxydopamine-induced behavioral impairments and neurodegeneration in mice

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