GPER and IGF-1R mediate the anti-inflammatory effect of genistein against lipopolysaccharide (LPS)-induced nigrostriatal injury in rats

Abstract

Neuroinflammation plays an important role in the pathogenesis of Parkinson's disease (PD). Genistein is an estrogen-like phytoestrogen that can exert biological effects via the crosstalk of estrogen receptor and insulin-like growth factor 1 receptor (IGF-1R). The present study aimed to evaluate the involvement of G protein-coupled estrogen receptor (GPER) and IGF-1R in the anti-inflammatory effects of genistein against lipopolysaccharide (LPS)-induced nigrostriatal injury in ovariectomized rats. Our results showed that genistein treatment could ameliorate the apomorphine-induced rotational behavior in LPS-induced inflammatory PD rat model. Genistein attenuated LPS-induced decrease of the contents of dopamine (DA) and its metabolites in striatum as well as the loss of tyrosine hydroxylase-immunoreactive (TH-IR) neurons in the substantia nigra (SN) of the lesioned side, which could be blocked by GPER antagonist G15 or IGF-1R antagonist JB1. Meanwhile, G15 or JB1 could attenuate the anti-inflammatory effects of genistein in LPS-induced microglial activation and production of tumor necrosis factor-α (TNF-α), interleukin 1β (IL-1β), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, genistein could inhibit the LPS-induced phosphorylation of p38, JNK, ERK and IκB in the lesioned side of SN and these effects could also be blocked by G15 or JB1. Taken together, our data provide the first evidence that genistein can inhibit the increase of microglia and protect dopaminergic neurons at least in part via GPER and IGF-1R signaling pathways in ovariectomized PD rat model.

Keywords: G protein-coupled estrogen receptor; Genistein; Insulin-like growth factor 1 receptor; Neuroinflammation; Parkinson’s disease.