Assessment of cognitive and neural recovery in survivors of pediatric brain tumors in a pilot clinical trial using metformin.

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.

Cranial irradiation in juvenile mice leads to early and sustained defects in the stem and progenitor cell pools and late cognitive impairments.

Cranial irradiation is used in combination with other therapies as a treatment for brain tumours and is thought to contribute to long-term cognitive deficits. Several rodent models have demonstrated that these cognitive deficits may be correlated with damage to neural progenitor cells in the subventricular zone (SVZ) and dentate gyrus (DG), the two neurogenic niches of the brain. Studies in rodent models typically assess the proliferating progenitor population, but rarely investigate the effect of cranial irradiation on the neural stem cell pool. Further, few studies evaluate the effects in juveniles, an age when children typically receive this treatment. Herein, we examine the cellular and behavioural effects of juvenile cranial irradiation on stem and progenitor populations in the two neurogenic regions of the brain and assess cognitive outcomes. We found regionally distinct effects of cranial irradiation in the juvenile brain. In the SVZ, we observed a defect in the stem cell pool and a concomitant decrease in proliferating cells that were maintained for at least one week. In the DG, a similar defect in the stem cell pool and proliferating cells was observed and persisted in the stem cell population. Finally, we demonstrated that cranial irradiation resulted in late cognitive deficits. This study demonstrates that juvenile cranial irradiation leads to regionally distinct defects in the stem and progenitor populations, and late cognitive deficits, which may be important factors in determining therapeutic targets and timing of interventions following cranial irradiation.

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

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.

Home sweet home: the neural stem cell niche throughout development and after injury.

Neural stem cells and their progeny reside in two distinct neurogenic niches within the mammalian brain: the subventricular zone and the dentate gyrus. The interplay between the neural stem cells and the niche in which they reside can have significant effects on cell kinetics and neurogenesis. A comprehensive understanding of the changes to the niche that occur through postnatal development and aging, as well as following injury, is relevant for developing therapeutics and interventions to promote neural repair. We discuss changes that occur within the neural stem and progenitor cell populations, the vasculature, extracellular matrix, microglia, and secreted proteins through aging which impact cell behavior within the neurogenic niches. We examine neural precursor cell and niche responses to injury in neonatal hypoxia-ischemia, juvenile cranial irradiation, and adult stroke. This review examines the interplay between the niche and stem cell behavior through aging and following injury as a means to understand intrinsic and extrinsic factors that regulate neurogenesis in vivo.

Differential effects of NMDA receptor antagonism on spine density.

The authors demonstrate that different NMDAR antagonists (ketamine and MK-801) have varying effects on spine density depending on dose, drug regimen, and brain region. While acute ketamine treatment increases cortical spine density in mice, subchronic exposure to either drug reduces spine density in both the cortex and striatum.