Sodium butyrate prevents radiation-induced cognitive impairment by restoring pCREB/BDNF expression

Sodium butyrate is a histone deacetylase inhibitor that affects various types of brain damages.To investigate the effects of sodium butyrate on hippocampal dysfunction that occurs after whole-brain irradiation in animal models and the effect of sodium butyrate on radiation exposure-induced cognitive impairments,adult C57BL/6 mice were intraperitoneally treated with 0.6 g/kg sodium butyrate before exposure to 10 Gy cranial irradiation.Cognitive impairment in adult C57BL/6 mice was evaluated via an object recognition test 30 days after irradiation.We also detected the expression levels of neurogenic cell markers(doublecortin)and phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor.Radiation-exposed mice had decreased cognitive function and hippocampal doublecortin and phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor expression.Sodium butyrate pretreatment reversed these changes.These findings suggest that sodium butyrate can improve radiation-induced cognitive dysfunction through inhibiting the decrease in hippocampal phosphorylated cAMP response element binding protein/brain-derived neurotrophic factor expression.The study procedures were approved by the Institutional Animal Care and Use Committee of Korea Institute of Radiological Medical Sciences(approval No.KIRAMS16-0002)on December 30,2016.

Brain-derived neurotropic factor and GABAergic transmission in neurodegeneration and neuroregeneration

Neurotoxicity induced by stress,radiation,chemicals,or metabolic diseases,is commonly associated with excitotoxicity,oxidative stress,and neuroinflammation.The pathological process of neurotoxicity induces neuronal death,interrupts synaptic plasticity in the brain,and is similar to that of diverse neurodegenerative diseases.Animal models of neurotoxicity have revealed that clinical symptoms and brain lesions can recover over time via neuroregenerative processes.Specifically,brain-derived neurotropic factor（BDNF） and gamma-aminobutyric acid（GABA）-ergic transmission are related to both neurodegeneration and neuroregeneration.This review summarizes the accumulating evidences that suggest a pathogenic role of BDNF and GABAergic transmission,their underlying mechanisms,and the relationship between BDNF and GABA in neurodegeneration and neuroregeneration.This review will provide a comprehensive overview of the underlying mechanisms of neuroregeneration that may help in developing potential strategies for pharmacotherapeutic approaches to treat neurotoxicity and neurodegenerative disease.

Temporal profiles of synaptic plasticity-related signals in adult mouse hippocampus with methotrexate treatment

Methotrexate, which is used to treat many malignancies and autoimmune diseases, affects brain functions including hippocampal-dependent memory function. However, the precise mechanisms underlying methotrexate-induced hippocampal dysfunction are poorly understood. To evaluate temporal changes in synaptic plasticity-related signals, the expression and activity of N-methyI-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, extracellular signal-regulated kinase 1/2, cAMP responsive element-binding protein, glutamate receptor 1, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor were examined in the hippocampi of adult C57BL/6 mice after methotrexate （40 mg/kg） intraperitoneal injection. Western blot analysis showed biphasic changes in synaptic plasticity-related signals in adult hippocampi following methotrexate treatment. N-methyI-D-aspartic acid receptor 1, calcium/calmodulin-dependent protein kinase II, and glutamate receptor 1 were acutely activated during the early phase （1 day post-injection）, while extracellular signal-regulated kinase 1/2 and cAMP responsive element-binding protein activation showed biphasic increases during the eady （1 day post-injection） and late phases （7-14 days post-injection）. Brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor expression increased significantly during the late phase （7-14 days post-injection）. Therefore, methotrexate treatment affects synaptic plasticity-related signals in the adult mouse hippocampus, suggesting that changes in synaptic plasticity-related signals may be associated with neuronal survival and plasticity-related cellular remodeling.

Neurotoxicity of cancer chemotherapy

There is accumulating clinical evidence that chemotherapeutic agents induce neurological side effects, including memory deficits and mood disorders, in cancer patients who have undergone chemotherapeutic treatments. This review focuses on chemotherapy-induced neurodegeneration and hippocampal dysfunctions and related mechanisms as measured by in vivo and in vitro approaches. These investigations are helpful in determining how best to further explore the causa mechanisms of chemotherapy-induced neurological side effects and in providing direction for the future development of novel optimized chemotherapeutic agents.

Effects of cancer therapy on hippocampus-related function

Cancer treatments such as chemotherapy and radiotherapy are widely used to treat primary and metastatic cancers.Epidemiological studies have demonstrated that these types of treatment can effectively and successfully extend the lifespan of cancer patients,but they are also associated with various neurological complications such as cognitive deficits, seizures, and emotional problems （Taphoorn and Klein, 2004; Yang and Moon, 2013; Son et al., 2015b）.