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RhFGF21 Mitigated D-gal-triggered Learning and Memory Dysfunction in Mice by Inhibiting Oxidative Stress,
Junyi Wu1, Xianshi Wang2, Shiyi Zheng1
1School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China.
Abstract:
Brain aging is characterized by memory loss and cognitive impairment. With the growth of the population and advances in medical care, the size of the aging population is increasing. Therefore, the discovery of anti-aging drugs has become a popular topic in recent years. Fibroblast growth factor 21 (FGF21) has been reported to inhibit oxidative stress, reduce inflammation, and delay senescence. The present study was designed to investigate the effects of recombinant human FGF21 (rhFGF21) on senescence in the brain in a mouse model of D-galactose (D-gal)-induced aging. The behavioral tests revealed that rhFGF21 improved D-gal-induced learning and memory impairment in mice. RhFGF21 improved the morphology of cortical and hippocampal neurons and increased the expression of PSD95 in the model mice. RhFGF21 reduced the number of microglia and astrocytes in the cortex and hippocampus, increased the activities of the antioxidant enzymes (GSH-PX, CAT, and SOD), and inhibited the expression of p-NFκB and p53 proteins, as well as the mRNA expression of the inflammatory cytokines (IL-1β, IL-6, TNFα, and iNOS). SIRT1 regulates senescence and inflammation, and FGF21 participates in physiological and pathological processes by binding to the FGFR1. Therefore, we measured SIRT1 and activated FGFR1 (p-FGFR1) levels. RhFGF21 administration increased the expression of cortical and hippocampal SIRT1 and p-FGFR1 in D-gal-induced aging mice. These data suggested that rhFGF21 alleviated learning and memory impairment in a mouse model of D-gal-induced aging by increasing antioxidant enzyme activity, inhibiting inflammation, and senescence-related gene expression via modulating FGFR1 and SIRT1.
Insights
Recombinant human FGF21 (rhFGF21) improved learning and memory in aging mice by reducing brain inflammation and oxidative stress. This anti-aging compound modulated FGFR1 and SIRT1 pathways, offering potential for cognitive decline therapies.
Area of Science:
- Neuroscience
- Aging Research
- Pharmacology
Background:
- Brain aging manifests as cognitive decline and memory loss, increasing with the aging global population.
- Fibroblast growth factor 21 (FGF21) shows potential anti-aging properties, including antioxidant and anti-inflammatory effects.
- Developing effective anti-aging drugs is crucial for addressing age-related cognitive impairments.
Purpose of the Study:
- To investigate the efficacy of recombinant human FGF21 (rhFGF21) in mitigating brain aging.
- To explore the effects of rhFGF21 on cognitive function and neuronal health in a D-galactose-induced aging mouse model.
- To elucidate the molecular mechanisms underlying rhFGF21's anti-aging effects in the brain.
Main Methods:
- Administered rhFGF21 to mice with D-galactose-induced brain aging.
- Assessed cognitive function using behavioral tests (learning and memory).
- Analyzed neuronal morphology, glial cell activation, oxidative stress markers, inflammatory cytokines, and key signaling proteins (p53, p-NFκB, SIRT1, FGFR1).
Main Results:
- rhFGF21 significantly improved learning and memory deficits in aging mice.
- Treatment preserved neuronal morphology and increased PSD95 expression.
- rhFGF21 reduced neuroinflammation (microglia, astrocytes, inflammatory cytokines) and oxidative stress (increased antioxidant enzymes).
- rhFGF21 inhibited senescence markers (p53, p-NFκB) and upregulated SIRT1 and p-FGFR1 expression.
Conclusions:
- rhFGF21 effectively alleviates cognitive impairment in a mouse model of brain aging.
- The therapeutic effects are mediated by enhanced antioxidant capacity, reduced inflammation, and suppressed senescence.
- Modulation of FGFR1 and SIRT1 pathways is a key mechanism for rhFGF21's anti-aging brain effects.
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