Effects of mood-stabilizing drugs on dendritic outgrowth and synaptic protein levels in primary hippocampal neurons.

OBJECTIVES: Mood-stabilizing drugs, such as lithium (Li) and valproate (VPA), are widely used for the treatment of bipolar disorder, a disease marked by recurrent episodes of mania and depression. Growing evidence suggests that Li exerts neurotrophic and neuroprotective effects, leading to an increase in neural plasticity. The present study investigated whether other mood-stabilizing drugs produce similar effects in primary hippocampal neurons. METHODS: The effects of the mood-stabilizing drugs Li, VPA, carbamazepine (CBZ), and lamotrigine (LTG) on hippocampal dendritic outgrowth were examined. Western blotting analysis was used to measure the expression of synaptic proteins - that is, brain-derived neurotrophic factor (BDNF), postsynaptic density protein-95 (PSD-95), neuroligin 1 (NLG1), ß-neurexin, and synaptophysin (SYP). To determine neuroprotective effects, we used a B27-deprivation cytotoxicity model which causes hippocampal cell death upon removal of B27 from the culture medium. RESULTS: Li (0.5-2.0 mM), VPA (0.5-2.0 mM), CBZ (0.01-0.10 mM), and LTG (0.01-0.10 mM) significantly increased dendritic outgrowth. The neurotrophic effect of Li and VPA was blocked by inhibition of phosphatidylinositol 3-kinase, extracellular signal-regulated kinase, and protein kinase A signaling; the effects of CBZ and LTG were not affected by inhibition of these signaling pathways. Li, VPA, and CBZ prevented B27 deprivation-induced decreases in BDNF, PSD-95, NLG1, ß-neurexin, and SYP levels, whereas LTG did not. CONCLUSIONS: These results suggest that Li, VPA, CBZ, and LTG exert neurotrophic effects by promoting dendritic outgrowth; however, the mechanism of action differs. Furthermore, certain mood-stabilizing drugs may exert neuroprotective effects by enhancing synaptic protein levels against cytotoxicity in hippocampal cultures.

Tianeptine induces mTORC1 activation in rat hippocampal neurons under toxic conditions.

RATIONALE: Recent studies have demonstrated that mTORC1 activation may be related to antidepressant action. However, the relationship between mTORC1 signaling activation and currently prescribed antidepressants remains unclear. OBJECTIVE: The aim of the present study was to determine whether alterations in mTORC1 signaling are observable following treatment with tianeptine under toxic conditions induced by B27 deprivation. Additionally, we investigated whether this drug affects synaptic proteins, neurite outgrowth, and spine density via mTORC1 signaling. METHODS: Using Western blotting, we measured the phosphorylation levels of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK in rat primary hippocampal neurons. Changes in BDNF, dendritic outgrowth, spine density, and synaptic proteins (PSD-95, synaptophysin, and GluR1) were measured. RESULTS: Tianeptine significantly increased the phosphorylation of mTORC1, 4E-BP-1, p70S6K, Akt, and ERK. The increase in mTOR phosphorylation was blocked by the PI3K, MEK, and mTORC1 inhibitors. Tianeptine increased BDNF, dendritic outgrowth, spine density, and synaptic proteins; all of these effects were blocked by the mTORC1 inhibitor. CONCLUSIONS: In this study, we demonstrated that tianeptine activates the mTORC1 signaling pathway and increases dendritic outgrowth, spine density, and synaptic proteins through mTORC1 signaling under toxic conditions in rat primary hippocampal neurons.

Brain-derived Neurotrophic Factor Is Associated with Cognitive Impairment in Elderly Korean Individuals.

OBJECTIVE: Brain-derived neurotrophic factor (BDNF) is a neurotrophin that is widely expressed in the mammalian brain and acts to regulate neuronal survival and influence cognitive processes. The present study measured serum BDNF levels to investigate the associations of the BDNF Val66Met and 5-hydroxytryptamine transporter linked promoter region (5-HTTLPR) polymorphisms with cognitive function in elderly Korean individuals. METHODS: Over 60 years, a total of 834 subjects were recruited for the present study. The subjects were classified into groups based on the degree of cognitive impairment (age-associated cognitive decline, mild cognitive impairment, and Alzheimer's disease) and compared with normal controls in terms of a neuropsychological assessment and a clinical evaluation. RESULTS: Of the initial 834 study participants, 165 (59 controls and 106 subjects with cognitive impairments) completed the study. There was a significant increase in serum BDNF levels in subjects with cognitive impairments relative to the control group and the BDNF Val66Met polymorphism was significantly associated with cognitive function but not serum BDNF levels. The 5-HTTLPR polymorphism did not have any associations with cognitive impairment or serum BDNF levels. CONCLUSION: The present findings suggest that BDNF may play a role in the pathophysiology of cognitive impairment and the BDNF Val66Met polymorphism may be an important factor in the susceptibility to these age-related deficits.

Decreased serum brain-derived neurotrophic factor levels in elderly korean with dementia.

OBJECTIVE: The primary purpose of this study was to investigate the differences in the serum brain-derived neurotrophic factor (BDNF) level between elderly Korean people over 65 years with and without dementia. METHODS: 171 individuals over 65 years were enrolled in this study. Screening for cognitive impairments was carried out using the Mini-Mental Status Examination-Korean version (MMSE-KC). One hundred thirty-two subjects scored below 1.5 standard deviations (SD) of the mean MMSE-KC score, and these were evaluated using the Consortium to Establish a Registry for Alzheimer's Disease, Korean version (CERAD-K) and the Geriatric Depression Scale (GDS). The Clinical Dementia Rating Scale (CDRS) and the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria were used for further evaluation. Subjects with a CDRS score of 1 or higher were classified as having Alzheimer's disease (AD), and subjects with a CDRS score of 0.5 were classified as having a mild cognitive impairment (MCI). Subjects with a CDRS score of 0 were classified as having aging-associated cognitive decline (AACD). Serum BDNF levels were analyzed using the enzyme-linked immunosorbent assay (ELISA) method. RESULTS: The serum BDNF levels were significantly lower in the subjects with MCI and AD compared with the healthy controls (p<0.01). A significant correlation was found between the total MMSE-KC score and serum BDNF level (r=0.295; p<0.01). However, no significant correlation was observed between the severity of MMSE-KC and the total GDS score. A significant difference was found in the total score of GDS between the AACD group and subjects with AD (p<0.05). CONCLUSION: This study suggested that BDNF might be involved in the pathophysiology of cognitive decline in elderly people.

Prevalence of Alzheimer's dementia and its risk factors in community-dwelling elderly koreans.

OBJECTIVE: We estimated the prevalence of Alzheimer's dementia (AD) and mild cognitive impairment (MCI) and their risk factors in an urban community setting, focusing especially on metabolic syndrome. METHODS: A two-phase investigation based on a door-to-door survey was performed. In Phase I, we administered the Korean version of the Mini-Mental State Examination (MMSE-KC) of the Consortium to Establish a Registry for Alzheimer's disease (CERAD-K). Assessment Packet and the Korean version of the Geriatric Depression Scales (GDS-K) to all 706 participants aged 65 years or older. In Phase II of the study, 175 persons underwent physical and neurological examinations according to the protocol of the CERAD-K clinical assessment battery [CERAD-K (C)] and the neuropsychological assessment battery [CERAD-K (N)]. We also examined the association between cognitive decline and metabolic syndrome. AD and MCI were defined using the DSM-IV-TR criteria and the Clinical Dementia Rating (CDR) scales. RESULTS: The mean age (+/-SD) of the subjects was 74.3+/-16.7 years and the ratio of males to females was 53.2 to 46.8. The prevalence of Alzheimer's dementia was 9.0%, while that of MCI was 32.9%. Old age and lower educational level had significant associations with cognitive decline in the elderly, but gender, years of alcohol intake or smoking, and metabolic syndrome were not associated with AD or MCI. CONCLUSION: In this study, metabolic syndrome was not associated with Alzheimer's AD or MCI. Information regarding an association between Alzheimer's dementia and metabolic syndrome in this study will be helpful in formulating future public health policy and prevention strategies in Korea.