Exendin-4 protects the dopaminergic neurons by attenuating inflammatory responses of microglial cells via activation of AMPK

Parkinson's disease (PD) is a neurodegenerative disease characterized by preferential loss of the dopaminergic neurons in the substantia nigra and consequent occurrence of typical symptoms including resting tremor, rigidity and bradykinesia. PD remains a significant challenge due to the lack of disease-modifying drugs despite extensive research efforts. Glucagon-like peptide-1 and its analogues have shown neuroprotective properties. However, its specific molecular mechanisms for the neuroprotection remains to elucidate. In this study, we explored the anti-inflammatory and neuroprotective effects of exendin-4 by employing BV2 microglial cells and the MPTP-induced mouse model for PD. Our study showed that exendin-4 significantly suppressed the production of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6 in LPS-stimulated BV2 cells. Furthermore, exendin-4 increased AMPK phosphorylation and the activation of AMPK by exendin-4 played a crucial role in suppressing the production of proinflammatory cytokines, as addition of compound C, an inhibitor of AMPK diminished the effect. Additionally, exendin-4 demonstrated neuroprotective effects by attenuating SH-SY5Y cell death caused by conditioned media from BV2 cells exposed to LPS. Moreover, exendin-4 attenuated microglial and astroglial activation in the substantia nigra and striatum of MPTP-treated mice, which was accompanied by reduced proinflammatory cytokines. Exendin-4 also improved motor functions of MPTP-treated mice, as determined by beam test and rotarod test. In parallel with the anti-inflammatory effects, exendin-4 attenuated MPTP-mediated dopaminergic neurodegeneration as estimated by immunohistochemistry for tyrosine hydroxylase and HPLC analyses for the striatal dopamine and DOPAC. These results suggest that exendin-4 could be a promising therapeutic agent for PD, offering neuroprotection by modulating inflammatory pathways and preserving dopaminergic neurons.