Memantine improves integration of the newborn neurons in the irradiated juvenile brain
Ahmed Osman1, Elene Nicola1, and Klas Blomgren1 1Karolinska Institutet, Department of Women's and Children's Health, Stockholm, Sweden Cranial irradiation is essential treatment for primary brain tumors and metastases. Despite its effectiveness, it however causes several adverse effects, including long-term cognitive dysfunctions that are more severe in pediatric cancer survivors. Cognitive dysfunctions include impaired learning abilities, memory and attention problems, and low speed of processing information. That is often translated into a poor quality of life compared to their peers, and adding extra burden to their families and society. The pathophysiology of irradiation-induced cognitive impairments is not well understood yet, however accumulating evidence suggests that depletion of hippocampal neurogenesis, inflammation, impaired neural plasticity and synaptic transmission are critically involved. These features are common pathological hallmarks in numerous of neurocognitive disorders such as Alzheimer's disease and aging. This led us to seek whether the therapeutic agents for other neurocognitive diseases would be beneficial to treat or minimize the cognitive impairments caused after irradiation. Here, we chose to examine the effect memantine, N-methyl-D-aspartate (NMDA) receptor antagonist and approved drug in the clinical practice for treatment of Alzheimer's disease. Memantine acts at multiple physiological domains, as neuroprotectant, and as a modulator of synaptic transmission and hippocampal neurogenesis. In this study, we investigated the effects of memantine on hippocampal neurogenesis in the irradiated juvenile brain. Young mice were subjected to whole-brain irradiation. Irradiated animals (or their littermate controls) were then either treated with mematine (10mg/kg, in the drinking water) or supplemented with regular drinking water for 2 weeks. Our results showed that memantine substantially augmented the integration of the newborn neurons and the arborization of their dendritic tree, both in control and irradiated animals. These results suggest that memantine increases the neural plasticity in the irradiated brain, and therefore might be a promising treatment to prevent the cognitive impairment caused by radiotherapy.