Memantine increases the dendritic complexity of hippocampal young neurons in the juvenile brain after cranial irradiation

IntroductionCranial irradiation (IR) negatively regulates hippocampal neurogenesis and causes cognitive dysfunctions in cancer survivors, especially in pediatric patients. IR decreases proliferation of neural stem/progenitor cells (NSPC) and consequently diminishes production of new hippocampal neurons. Memantine, an NMDA receptor antagonist, used clinically to improve cognition in patients suffering from Alzheimer’s disease and dementia. In animal models, memantine acts as a potent enhancer of hippocampal neurogenesis. Memantine was recently proposed as an intervention to improve cognitive impairments occurring after radiotherapy and is currently under investigation in a number of clinical trials, including pediatric patients. To date, preclinical studies investigating the mechanisms underpinning how memantine improves cognition after IR remain limited, especially in the young, developing brain. Here, we investigated whether memantine could restore proliferation in the subgranular zone (SGZ) or rescue the reduction in the number of hippocampal young neurons after IR in the juvenile mouse brain.MethodsMice were whole-brain irradiated with 6 Gy on postnatal day 20 (P20) and subjected to acute or long-term treatment with memantine. Proliferation in the SGZ and the number of young neurons were further evaluated after the treatment. We also measured the levels of neurotrophins associated with memantine improved neural plasticity, brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF).ResultsWe show that acute intraperitoneal treatment with a high, non-clinically used, dose of memantine (50 mg/kg) increased the number of proliferating cells in the intact brain by 72% and prevented 23% of IR-induced decrease in proliferation. Long-term treatment with 10 mg/kg/day of memantine, equivalent to the clinically used dose, did not impact proliferation, neither in the intact brain, nor after IR, but significantly increased the number of young neurons (doublecortin expressing cells) with radial dendrites (29% in sham controls and 156% after IR) and enhanced their dendritic arborization. Finally, we found that long-term treatment with 10 mg/kg/day memantine did not affect the levels of BDNF, but significantly reduced the levels of NGF by 40%.ConclusionThese data suggest that the enhanced dendritic complexity of the hippocampal young neurons after treatment with memantine may contribute to the observed improved cognition in patients treated with cranial radiotherapy

Grafting Neural Stem and Progenitor Cells Into the Hippocampus of Juvenile, Irradiated Mice Normalizes Behavior Deficits

The pool of neural stem and progenitor cells (NSPCs) in the dentate gyrus of the hippocampus is reduced by ionizing radiation. This explains, at least partly, the learning deficits observed in patients after radiotherapy, particularly in pediatric cases. An 8 Gy single irradiation dose was delivered to the whole brains of postnatal day 9 (P9) C57BL/6 mice, and BrdU-labeled, syngeneic NSPCs (1.0 × 105 cells/injection) were grafted into each hippocampus on P21. Three months later, behavior tests were performed. Irradiation impaired novelty-induced exploration, place learning, reversal learning, and sugar preference, and it altered the movement pattern. Grafting of NSPCs ameliorated or even normalized the observed deficits. Less than 4% of grafted cells survived and were found in the dentate gyrus 5 months later. The irradiation-induced loss of endogenous, undifferentiated NSPCs in the dentate gyrus was completely restored by grafted NSPCs in the dorsal, but not the ventral, blade. The grafted NSPCs did not exert appreciable effects on the endogenous NSPCs; however, more than half of the grafted NSPCs differentiated. These results point to novel strategies aimed at ameliorating the debilitating late effects of cranial radiotherapy, particularly in children

Radiobiological modeling of hyperthermia combined with Gamma-Knife radiosurgery in pediatric brain cancer

Assessment of the synergistic effect of radiotherapy (RT) and hyperthermia (HT) in clinical settings is crucial for further expansion of hyperthermia. The radiobiological modeling using an extended version of the LQ model with temperature-dependent radiosensitivity parameters has been suggested in combination with external beam radiotherapy in previous studies. This study investigates the radiobiological effect of intracranial hyperthermia combined with stereotactic radiosurgery (SRS) in pediatric brain cancers.\ua0The hyperthermia treatment plan was achieved with an elliptical applicator consisting of 16 ORWG antennas working at 400 MHz and a hybrid Specific Absorption Rate (SAR) optimization procedure based on Time-Reversal and PSO. The radiotherapy plan was created by the treatment planning software of Leksell Gamma Knife\uae Icon™

Mitochondrial Cell Death Control in Familial Parkinson Disease

Many sporadic cases of Parkinsons disease have mutations in the PINK protein kinase, whose substrate is now revealed to be a protein that protects mitochondria from oxidative stress

Lithium Treatment Is Safe in Children With Intellectual Disability

Lithium is a widely used and effective treatment for individuals with psycho-neurological disorders, and it exhibits protective and regenerative properties in multiple brain injury animal models, but the clinical experience in young children is limited due to potential toxicity. As an interim analysis, this paper reports the safety/tolerability profiles of low-dose lithium treatment in children with intellectual disability (ID) and its possible beneficial effects. In a randomized, single-center clinical trial, 124 children with ID were given either oral lithium carbonate 6 mg/kg twice per day or the same dose of calcium carbonate as a placebo (n = 62/group) for 3 months. The safety of low-dose lithium treatment in children, and all the adverse events were monitored. The effects of low-dose lithium on cognition was evaluated by intelligence quotient (IQ), adaptive capacity was assessed by the Infant-Junior Middle School Students Social-Life Abilities Scale (IJMSSSLAS), and overall performance was evaluated according to the Clinical Global Impression-Improvement (CGI-I) scale. After 3 months of lithium treatment, 13/61 children (21.3%) presented with mild side effects, including 4 (6.6%) with gastrointestinal symptoms, 4 (6.6%) with neurological symptoms, 2 (3.3%) with polyuria, and 3 (4.9%) with other symptoms—one with hyperhidrosis, one with alopecia, and one with drooling. Four children in the lithium group had elevated blood thyroid stimulating hormone, which normalized spontaneously after lithium discontinuation. Both IQ and IJMSSSAS scores increased following 3 months of lithium treatment (F = 11.03, p = 0.002 and F = 7.80, p = 0.007, respectively), but such increases were not seen in the placebo group. CGI-I scores in the lithium group were 1.25 points lower (better) than in the placebo group (F = 82.66, p < 0.001) after 3 months of treatment. In summary, lithium treatment for 3 months had only mild and reversible side effects and had positive effects on cognition and overall performance in children with ID.Clinical Trial Registration: Chinese Clinical Trial Registry, ChiCTR-IPR-15007518

Dying transplanted neural stem cells mediate survival bystander effects in the injured brain

Neural stem and progenitor cell (NSPC) transplants provide neuroprotection in models of acute brain injury, but the underlying mechanisms are not fully understood. Here, we provide evidence that caspase-dependent apoptotic cell death of NSPCs is required for sending survival signals to the injured brain. The secretome of dying NSPCs contains heat-stable proteins, which protect neurons against glutamate-induced toxicity and trophic factor withdrawal in vitro, and from ischemic brain damage in vivo. Our findings support a new concept suggesting a bystander effect of apoptotic NSPCs, which actively promote neuronal survival through the release of a protective “farewell” secretome. Similar protective effects by the secretome of apoptotic NSPC were also confirmed in human neural progenitor cells and neural stem cells but not in mouse embryonic fibroblasts (MEF) or human dopaminergic neurons, suggesting that the observed effects are cell type specific and exist for neural progenitor/stem cells across species.</p

Selective Neural Deletion of the Atg7 Gene Reduces Irradiation-Induced Cerebellar White Matter Injury in the Juvenile Mouse Brain by Ameliorating Oligodendrocyte Progenitor Cell Loss

Radiotherapy is an effective tool for treating brain tumors, but irradiation-induced toxicity to the normal brain tissue remains a major problem. Here, we investigated if selective neural autophagy related gene 7 (Atg7) deletion has a persistent effect on irradiation-induced juvenile mouse brain injury. Ten-day-old Atg7 knockout under a nestin promoter (KO) mice and wild-type (WT) littermates were subjected to a single dose of 6 Gy whole-brain irradiation. Cerebellar volume, cell proliferation, microglia activation, inflammation, and myelination were evaluated in the cerebellum at 5 days after irradiation. We found that neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell (OPC) loss in the white matter of the cerebellum, and Atg7 deficiency partly prevented this. The mRNA expression of oligodendrocyte and myelination-related genes (Olig2, Cldn11, CNP, and MBP) was higher in the cerebellum in Atg7 KO mice compared with WT littermates. The total cerebellar volume was significantly reduced after irradiation in both Atg7 KO and WT mice. Atg7-deficient cerebellums were in a regenerative state before irradiation, as judged by the increased OPC-related and neurogenesis-related transcripts and the increased numbers of microglia; however, except for the OPC parameters these were the same in both genotypes after irradiation. Finally, there was no significant change in the number of astrocytes in the cerebellum after irradiation. These results suggest that selective neural Atg7 deficiency reduces irradiation-induced cerebellar white matter injury in the juvenile mouse brain, secondary to prevention of OPC loss

Correction: Dying transplanted neural stem cells mediate survival bystander effects in the injured brain

The original version of this article contained an error in the author affiliations. Klas Blomgren is not affiliated with the University of Gothenburg anymore. The original article has been corrected.</p

Aggravated brain injury after neonatal hypoxic ischemia in microglia-depleted mice.

BACKGROUND:Neuroinflammation plays an important role in neonatal hypoxic-ischemic encephalopathy (HIE). Although microglia are largely responsible for injury-induced inflammatory response, they play beneficial roles in both normal and disease states. However, the effects of microglial depletion on neonatal HIE remain unclear.METHODS:Tamoxifen was administered to Cx3cr1CreER/+Rosa26DTA/+ (microglia-depleted model) and Cx3cr1CreER/+Rosa26DTA/- (control) mice at P8 and P9 to assess the effect of microglial depletion. The density of microglia was quantified using Iba-1 staining. Moreover, the proportion of resident microglia after the HI insult was analyzed using flow cytometric analysis. At P10, the HI insult was conducted using the Rice-Vannucci procedure at P10. The infarct size and apoptotic cells were analyzed at P13. Cytokine analyses were performed using quantitative polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA) at P13.RESULTS:At P10, tamoxifen administration induced > 99% microglial depletion in DTA+ mice. Following HI insult, there was persisted microglial depletion over 97% at P13. Compared to male DTA- mice, male DTA+ mice exhibited significantly larger infarct volumes; however, there were no significant differences among females. Moreover, compared to male DTA- mice, male DTA+ mice had a significantly higher density of TUNEL+ cells in the caudoputamen, cerebral cortex, and thalamus. Moreover, compared to female DTA- mice, female DTA+ mice showed a significantly greater number of TUNEL+ cells in the hippocampus and thalamus. Compared to DTA- mice, ELISA revealed significantly lower IL-10 and TGF-β levels in both male and female DTA+ mice under both normal conditions and after HI (more pronounced).CONCLUSION:We established a microglial depletion model that aggravated neuronal damage and apoptosis after the HI insult, which was predominantly observed in males