FGF21 Exhibits Neuroprotective Effects by Promoting 5-HTR-FGFR1 Heteroreceptor Complexes and Triggering MEK-ERK Signaling Pathway.

Approaches of promoting a neural milieu permissive for plasticity and resilience against neuronal injury are important strategies for the treatment of a range of neurological disorders. Fibroblast growth factor 21 (FGF21) which is known for its role as a potent regulator of glucose and energy metabolism has also proved to be neuroprotective against various mental diseases. However, the underlying molecular mechanisms remain elusive. Here, we report a study of the neuroprotective effects of FGF21 by promoting 5-HTR-FGFR1 heteroreceptor formation and triggering MEK-ERK signaling pathway in normal or abnormal neurological conditions. First, the in vitro cellular experiments demonstrated that FGF21 exerted a protective effect against glutamate-induced cytotoxicity and promoted cell differentiation and growth. Then, in wild-type and FGF21 mice, exogenous FGF21 promoted FGFR1-5-HTR heteromers formation in the CA3 and dentate gyrus region of the hippocampus and activated MEK-ERK signaling. Coordinately, FGF21 exerted similar influences in the hippocampi of IBA-induced neurological injury mice or combined stress-exposed mice. Besides, FGF21 treatment activated the phosphorylation of FGFR1 and elevated the expression of synaptophysin in these mice with neurological injury or combined stress exposure. These results illustrated that FGF21 alleviated neurological impairment through FGFR1-5-HTR heteromer and ERK signal activation and suggested that the regulation of FGFR1-5-HTR heteromers and MEK/ERK pathway may play a key role in mediating the neuroprotective effects of FGF21 against various neurodegeneration conditions.