Metformin treatment ameliorates diabetes‐associated decline in hippocampal neurogenesis and memory via phosphorylation of insulin receptor substrate 1

Abstract

Age‐related reduction in adult hippocampal neurogenesis is correlated with cognitive impairment. Diabetes is a chronic systemic disease that negatively affects adult neural stem cells and memory functions in the hippocampus. Despite growing concern regarding the potential role of diabetic drugs in neural abnormalities, their effects on progressive deterioration of neurogenesis and cognitive functions remain unknown. Here, we show that the combination of aging and diabetes in mice causes a marked decrease in hippocampal neurogenesis along with memory impairment and elevated neuroinflammation. Prolonged treatment with metformin, a biguanide antidiabetic medication, promotes cell proliferation and neuronal differentiation and inhibits aging‐ and diabetes‐associated microglial activation, which is related to homeostatic neurogenesis, leading to enhanced hippocampal neurogenesis in middle‐aged diabetic mice. Although chronic therapy with metformin fails to achieve recovery from hyperglycemia, a key feature of diabetes in middle‐aged diabetic mice, it improves hippocampal‐dependent spatial memory functions accompanied by increased phosphorylation of adenosine monophosphate‐activated protein kinase ( AMPK ), atypical protein kinase C ζ ( aPKC ζ), and insulin receptor substrate 1 ( IRS 1) at selective serine residues in the hippocampus. Our findings suggest that signaling networks acting through long‐term metformin‐stimulated phosphorylation of AMPK , aPKC ζ/λ, and IRS 1 serine sites contribute to neuroprotective effects on hippocampal neurogenesis and cognitive function independent of a hypoglycemic effect.

Traumatic Brain Injury and Blood–Brain Barrier (BBB): Underlying Pathophysiological Mechanisms and the Influence of Cigarette Smoking as a Premorbid Condition

“…These studies highlight the additional MF therapeutic potential outside the treatment of diabetes [149,150]. These findings highlight the other MF therapeutic potential outside the treatment of diabetes for the treatment of cerebrovascular and neuroinflammatory disorders associated with oxidative stress and inflammation, primarily due to its dual effect as an NRF2 activator and NF-κB inhibitor [144,[151][152][153].…”

High-Fat Diet-Induced Obesity Causes Sex-Specific Deficits in Adult Hippocampal Neurogenesis in Mice

“…Interventions that improve metabolic outcomes, such as physical exercise and caloric restriction, promote neurogenesis and gliogenesis, increase growth factors and synaptic plasticity in the hippocampus, and improve cognitive performance (Lee et al, 2002;Bondolfi et al, 2004;Park and Lee, 2011;Kaptan et al, 2015;Chatterjee et al, 2016;Klein et al, 2016). Moreover, treatment with medications traditionally used to treat type 2 diabetes increases adult hippocampal neurogenesis in HF diet-fed rodents (Hamilton et al, 2011;Porter et al, 2013;Pathak et al, 2015;Tanokashira et al, 2018). If adult hippocampal neurogenesis serves to preserve cognitive function during aging and neuropathology (e.g., AD pathology), but metabolic disease impairs neurogenesis, those with metabolic disease would be at increased risk for cognitive decline, particularly in women.…”

“…High-fat (HF) diet and metabolic disease, such as obesity and type 2 diabetes, are associated with dysregulated neurogenesis (Park et al, 2010;Ho et al, 2013;Nam et al, 2016;Nam et al, 2017;Tanokashira et al, 2018;Tang et al, 2019). Poor diet and metabolic disease are also associated with cognitive impairment, increased risk/ severity of Alzheimer's disease, and anxiety and depression (Jacka et al, 2010;Xu et al, 2011;Boitard et al, 2012;Spauwen et al, 2013;Boitard et al, 2014;Knight et al, 2014;Chatterjee et al, 2016;Klein et al, 2016;Zuloaga et al, 2016;Shalev and Arbuckle, 2017).…”

Obesity-induced type 2 diabetes impairs neurological recovery after stroke in correlation with decreased neurogenesis and persistent atrophy of parvalbumin-positive interneurons

“…Therefore, it is important to determine whether reduced cognitive recovery in T2D after stroke is linked to decreased stroke-induced hippocampal neurogenesis. Few studies have in part addressed this question by showing that early stages of stroke-induced hippocampal neurogenesis are impaired by T2D [10,29,30]. However, it remains unknown if terminal neuronal differentiation is also affected by T2D.…”