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Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke.

ABSTRACT: Resident neural stem and progenitor cells, collectively termed neural precursor cells (NPCs), reside in a well-defined neurogenic niche in the subventricular zone (SVZ) and contribute to ongoing postnatal neurogenesis. It is well established that the NPC niche can alter the behavior of NPCs. NPC activation is a promising therapeutic strategy for brain repair. The drug metformin has been shown to activate neural stem cells, promote differentiation, and lead to functional motor recovery in a neonatal stroke model. We demonstrate that metformin-induced NPC expansion and functional recovery is sex hormone dependent. Metformin increases the size of the NPC pool in adult females, but not males, and promotes cognitive recovery in a model of brain injury in females, but not males. Our data demonstrate that metformin has age- and sex-dependent effects on NPCs that correlate with functional recovery, which has important implications for neural repair.

SUBMITTER: Ruddy RM

PROVIDER: S-EPMC6739114 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke.

Ruddy Rebecca M RM Adams Kelsey V KV Morshead Cindi M CM

Science advances 20190911 9

Resident neural stem and progenitor cells, collectively termed neural precursor cells (NPCs), reside in a well-defined neurogenic niche in the subventricular zone (SVZ) and contribute to ongoing postnatal neurogenesis. It is well established that the NPC niche can alter the behavior of NPCs. NPC activation is a promising therapeutic strategy for brain repair. The drug metformin has been shown to activate neural stem cells, promote differentiation, and lead to functional motor recovery in a neona ...[more]

PMID: 31535024

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Project description:We asked whether pharmacological stimulation of endogenous neural precursor cells (NPCs) may promote cognitive recovery and brain repair, focusing on the drug metformin, in parallel rodent and human studies of radiation injury. In the rodent cranial radiation model, we found that metformin enhanced the recovery of NPCs in the dentate gyrus, with sex-dependent effects on neurogenesis and cognition. A pilot double-blind, placebo-controlled crossover trial was conducted (ClinicalTrials.gov, NCT02040376) in survivors of pediatric brain tumors who had been treated with cranial radiation. Safety, feasibility, cognitive tests and MRI measures of white matter and the hippocampus were evaluated as endpoints. Twenty-four participants consented and were randomly assigned to complete 12-week cycles of metformin (A) and placebo (B) in either an AB or BA sequence with a 10-week washout period at crossover. Blood draws were conducted to monitor safety. Feasibility was assessed as recruitment rate, medication adherence and procedural adherence. Linear mixed modeling was used to examine cognitive and MRI outcomes as a function of cycle, sequence and treatment. We found no clinically relevant safety concerns and no serious adverse events associated with metformin. Sequence effects were observed for all cognitive outcomes in our linear mixed models. For the subset of participants with complete data in cycle 1, metformin was associated with better performance than placebo on tests of declarative and working memory. We present evidence that a clinical trial examining the effects of metformin on cognition and brain structure is feasible in long-term survivors of pediatric brain tumors and that metformin is safe to use and tolerable in this population. This pilot trial was not intended to test the efficacy of metformin for cognitive recovery and brain growth, but the preliminary results are encouraging and warrant further investigation in a large multicenter phase 3 trial.

Project description:The expanded lifespan of people, while a positive advance, has also amplified the prevalence of age-related disorders, which include mild cognitive impairment, dementia, and Alzheimer's disease. Therefore, competent therapies that could improve the healthspan of people have great significance. Some of the dietary and pharmacological approaches that augment the lifespan could also preserve improved cognitive function in old age. Metformin, a drug widely used for treating diabetes, is one such candidate that could alleviate age-related cognitive dysfunction. However, the possible use of metformin to alleviate age-related cognitive dysfunction has met with conflicting results in human and animal studies. While most clinical studies have suggested the promise of metformin to maintain better cognitive function and reduce the risk for developing dementia and Alzheimer's disease in aged diabetic people, its efficacy in the nondiabetic population is still unclear. Moreover, a previous animal model study implied that metformin could adversely affect cognitive function in the aged. However, a recent animal study using multiple behavioral tests has reported that metformin treatment in late middle age improved cognitive function in old age. The study also revealed that cognition-enhancing effects of metformin in aged animals were associated with the activation of the energy regulator adenosine monophosphate-activated protein kinase, diminished neuroinflammation, inhibition of the mammalian target of rapamycin signaling, and augmented autophagy in the hippocampus. The proficiency of metformin to facilitate these favorable modifications in the aged hippocampus likely underlies its positive effect on cognitive function. Nonetheless, additional studies probing the outcomes of different doses and durations of metformin treatment at specific windows in the middle and old age across sex in nondiabetic and non-obese prototypes are required to substantiate the promise of metformin to maintain better cognitive function in old age.

Project description:Adjunctive restorative therapies administered during the first few months after stroke, the period with the greatest degree of spontaneous recovery, reduce the number of stroke patients with significant disability.To examine the effect of escitalopram on cognitive outcome. We hypothesized that patients who received escitalopram would show improved performance in neuropsychological tests assessing memory and executive functions than patients who received placebo or underwent Problem Solving Therapy.Randomized trial.Stroke center.One hundred twenty-nine patients were treated within 3 months following stroke. The 12-month trial included 3 arms: a double-blind placebo-controlled comparison of escitalopram (n = 43) with placebo (n = 45), and a nonblinded arm of Problem Solving Therapy (n = 41).Change in scores from baseline to the end of treatment for the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) and Trail-Making, Controlled Oral Word Association, Wechsler Adult Intelligence Scale-III Similarities, and Stroop tests.We found a difference among the 3 treatment groups in change in RBANS total score (P < .01) and RBANS delayed memory score (P < .01). After adjusting for possible confounders, there was a significant effect of escitalopram treatment on the change in RBANS total score (P < .01, adjusted mean change in score: escitalopram group, 10.0; nonescitalopram group, 3.1) and the change in RBANS delayed memory score (P < .01, adjusted mean change in score: escitalopram group, 11.3; nonescitalopram group, 2.5). We did not observe treatment effects in other neuropsychological measures.When compared with patients who received placebo or underwent Problem Solving Therapy, stroke patients who received escitalopram showed improvement in global cognitive functioning, specifically in verbal and visual memory functions. This beneficial effect of escitalopram was independent of its effect on depression. The utility of antidepressants in the process of poststroke recovery should be further investigated. Trial Registration clinicaltrials.gov Identifier: NCT00071643.

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Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke.

Publications

Age- and sex-dependent effects of metformin on neural precursor cells and cognitive recovery in a model of neonatal stroke.

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