Metformin improves cognition of aged mice by promoting cerebral angiogenesis and neurogenesis

Abstract

Metformin is a widely used drug for type 2 diabetes that is considered to have potential anti-aging effects. However, the beneficial effects of metformin in middle-aged normoglycemic mice are less explored. Here, we report that metformin treated by tail vein injection improved cognitive function of aged mice better than oral administration, which seem to show a dose-dependent manner. Correspondingly, long-term oral administration of metformin was associated with significant disability rates. Further, metformin restored cerebral blood flow and brain vascular density and promoted neurogenic potential of the subependymal zone/subventricular zone both in vivo and in vitro . RNA-Seq and q-PCR results indicated that metformin could enhance relative mRNA glycolysis expression in blood and hippocampal tissue, respectively. Mechanistically, glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a key enzyme in glycolysis pathway, may contribute to angiogenic and neurogenic potentials of NSCs. Interestingly, the relative GAPDH mRNA expression of peripheral blood mononuclear cell was gradually decreased with aging. Meanwhile its expression level positively correlated with cognitive levels. Our results indicated that metformin represents a candidate pharmacological approach for recruitment of NSCs in aged mouse brain by enhancing glycolysis and promoting neurovascular generation, a strategy that might be of therapeutic value for anti-aging in humans.

Genetic expression of 4E-BP1 in juvenile mice alleviates mTOR-induced neuronal dysfunction and epilepsy

“…With regards to therapies for epilepsy, adult treatment with metformin, a widely used antidiabetic drug also known to inhibit mTORC1-mediated translation via AMP-activated protein kinase (AMPK) activation (Dowling et al, 2007), has been shown to decrease seizures in a mouse model of FMCD mice (Kim et al, 2019). However, since metformin activates multiple targets (Viollet et al, 2012) and has various effects in the brain, including inhibiting ERK signaling (Gantois et al, 2017), enhancing cerebral angiogenesis and neurogenesis (Wang et al, 2012; Zhu et al, 2020), decreasing glial activation and suppressing inflammatory pathways (Zhu et al, 2015; Ismaiel et al, 2016), and altering gut microbiome (Wu et al, 2017), it was unclear whether the mechanism of action was through inhibiting translation. In this study, we provide direct genetic support for reducing overactive translation via 4E-BP1 to alleviate established epilepsy.…”

Licochalcone A improves the cognitive ability of mice by regulating T- and B-cell proliferation

“…In the second stage, the platform was removed from the pool on day 6, and the mice were left to swim for 1 min at the farthest point from the platform. The swimming track of each mouse was recorded by a computerized tracking/image analyzer system [ 87 ].…”

Metformin: The next angiogenesis panacea?

“…Its mechanism enhanced glycolysis by increasing mRNA expression of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and finally increased the angiogenesis and neurogenic potential of neural stem cells. 43 Besides, metformin the activation of AMPK–FOXO3 signaling and inhibition of VEGF also plays a neuroprotective role in other models of Parkinson’s disease (PD) and neurodegenerative diseases. 44 …”