Insulin and toll-like receptor 4 interaction in the rat model of Parkinson’s disease induced by lipopolysaccharide

Toll-like receptor (TLR) 4 is involved in neuroinflammatory processes in peripheral tissues and central nervous system. Pro-inflammatory cytokines production, due to over activation of TLR4, interfere with insulin signaling elements lead to insulin resistance. Regarding the critical roles of TLR4 and insulin in the pathogenesis of Parkinson’s disease (PD), in the present study the TLR4/insulin receptor interaction was assessed in a neuroinflammation model of PD.

LPS was injected into the right striatum of male Wistar rats (20µg/rat). Insulin (2.5IU/ day), insulin receptor antagonist (S961; 6.5nM/kg), or TLR4 antibody (Resatorvid (TAK242); 0.01µg/rat) were administered intracerebroventricularly (ICV) for 14 days. Insulin and TAK242 were also simultaneously injected in a distinct group. Behavioral assessments were performed using rotarod, apomorphine-induced rotation, and cylinder tests. The levels of α-synuclein, TLR4, and elements of the insulin signaling pathway were measured in the striatum.

LPS impaired motor performance of the animals and increased the levels of α-synuclein and TLR4. Furthermore, it reduced mRNA levels of IRS1 and IRS2 and enhanced GSK3β mRNA and protein levels, indicating the development of insulin resistance. Treatment with insulin and TAK 242 improved motor deficits, restored insulin signaling pathway, and reduced α-synuclein and TLR4 levels.

The findings indicate that LPS impaired motor function, at least in part, via α-synuclein and TLR4 overexpression, leading to insulin resistance. Suppression of TLR4 and activation of insulin receptors attenuated motor deficits, suggesting that TLR4 and insulin receptors are promising therapeutic targets for PD modification.