Chronic Acarbose Or DNj Administration Alleviate The Age-related Behavioural Alteration In Samp8 Mice: An Experimental Study

BackgroundThe world population is rapidly aging. Brain aging and age-related cognitive decline severely reduce the life quality of older people. The risk of Alzheimer’s disease or Parkinson’s disease rises sharply with age, and these neurodegenerative diseases have no effective treatment available. Therefore, approaches that alleviate brain aging are urgently needed. Studies have shown that the brain aging is associated with disturbance in insulin system and glucose homeostasis, and decrease of insulin-like growth factor-1(IGF-1) and brain-derived neurotrophic factor(BDNF) in the brain. Interventions that maintain the homeostasis of insulin/IGF-1 signaling and/or glucose metabolism may alleviate the deficits associated with the brain aging. A caloric restriction mimetic or a treatment for type 2 diabetes has the potential in the anti-brain aging. Acarbose and 1-Deoxynojirimycin(DNJ) are both α-glucosidase inhibitors that can lead to a decrease of blood glucose level and increase of insulin sensitivity, and exert a protective role in the cardiovascular and cerebrovascular system, thus may have the potential against the brain aging. Exploring the effect of chronic acarbose and DNJ treatment on the brain aging would help us to understand the mechanisms of the brain aging and provides new insight on the anti-brain aging treatment.ObjectiveThe aim of this study is to explore the effect of chronic administration of acarbose and DNJ on the age-related behavioral and biochemical changes in the SAMP8 mice. Methods(1) The SAMP8 mice were randomly divided into old control group, acarbose group(20 mg/kg/d), higher-dose DNJ group(20 mg/kg/d) and lower-dose DNJ group(10 mg/kg/d). The body weight of each group was monitored monthly from 3- to 9-months of age. The mice in the acarbose or DNJ group were administered acarbose or DNJ orally by drinking water from 3 to 9 months of age respectively. A new group of 2-month-old mice was added as young controls, after a 4-week acclimation period, undertook the same tests with the other groups.(2) The behavioral tests included: sensorimotor tasks(beam walking and tightrope), anxiety-based tasks(open field), learning and memory(Morris water maze, novel object recognition, novel location recognition and episodic-like memory).(3) After accomplished behavioral assessment, the mice were sacrificed, and the samples of blood and hippocampi were collected. The serum concentrations of glucose, insulin, BDNF and IGF-1 were tested by ELISA. The levels of insulin receptor(InsR), IGF-1 receptor(IGF-1R), BDNF, the presynaptic proteins synaptotagmin(Syt) 1 and syntaxin(Stx) 1, and the astrocyte marker glial fibrillary acidic protein(GFAP) in the different layers of hippocampus were detected by immunohistochemical staining.(3) The acetylation levels of histone H4 at lysine 8(H4K8) and H3 at lysine 9(H3K9) were detected by immunohistochemistry in the cell layer of dentate gyrus(DG), Cornu Ammonis(CA) subfield 1(CA1) and CA subfield 3(CA3) of hippocampus CA3. Results(1) The old SAMP8 mice displayed an impairment of motor ability, open-field anxiety, spatial and non-spatial learning and memory abilities in the MWM, novel object recognition, novel location recognition and episodic-like memory tests. The age-related behavioral deficits were relieved by the acarbose or DNJ treatment.(2) The SAMP8 mice displayed age-related decreases in the serum insulin level and the levels of InsR, BDNF and Stx 1 in the hippocampus, and increases in the levels of IGF-1R, Syt 1 and astrocyte activation. The acarbose or DNJ treatment(especially at high dose) alleviated the biochemical indicators in the serum and hippocampus layers. Besides, the DNJ treatment elevated the BDNF and IGF-1 content in the serum. The changes of serological test and proteins content in the hippocampus layers were closely related to the age-related behavior deficits.(3) The acarbose or DNJ treatment(especially at high dose) alleviated the decreases of H4K8 and H3K9 acetylation levels in the old hippocampus. SummaryThe chronic acarbose or DNJ treatment alleviated the age-related changes of behavioral and biochemical indicators, indicating their potentials against brain aging. Epigenetic modification mechanisms maybe involved in these changes.