Effects of escitalopram and paroxetine on mTORC1 signaling in the rat hippocampus under chronic restraint stress.

BACKGROUND: Recent studies have suggested that the activation of mammalian target of rapamycin (mTOR) signaling may be related to antidepressant action. Therefore, the present study evaluated whether antidepressant drugs would exert differential effects on mTOR signaling in the rat hippocampus under conditions of chronic restraint stress. Male Sprague-Dawley rats were subjected to restraint stress for 6 h/days for 21 days with either escitalopram (10 mg/kg) or paroxetine (10 mg/kg) administered after the chronic stress procedure. Western blot analyses were used to assess changes in the levels of phospho-Ser2448-mTOR, phospho-Thr37/46-4E-BP-1, phospho-Thr389-p70S6 K, phospho-Ser422-eIF4B, phospho-Ser240/244-S6, phospho-Ser473-Akt, and phospho-Thr202/Tyr204-ERK in the hippocampus. RESULTS: Chronic restraint stress significantly decreased the levels of phospho-mTOR complex 1 (mTORC1), phospho-4E-BP-1, phospho-p70S6 K, phospho-eIF4B, phospho-S6, phospho-Akt, and phospho-ERK (p < 0.05); the administration of escitalopram and paroxetine increased the levels of all these proteins (p < 0.05 or 0.01). Additionally, chronic restraint stress reduced phospho-mTORC1 signaling activities in general, while escitalopram and paroxetine prevented these changes in phospho-mTORC1 signaling activities. CONCLUSION: These findings provide further data that contribute to understanding the possible relationships among mTOR activity, stress, and antidepressant drugs.

Effects of Repetitive Transcranial Magnetic Stimulation Over Trunk Motor Spot on Balance Function in Stroke Patients.

OBJECTIVE: To assess the efficacy of high-frequency repetitive transcranial magnetic stimulation (rTMS) on balance function in patients with chronic stroke. METHODS: Thirty participants with chronic stroke were enrolled in this study. High frequency (10 Hz) rTMS was delivered with butterfly-coil on trunk motor spot. Each patient received both real and sham rTMS in a random sequence. The rTMS cycles (real or sham) were composed of 10 sessions each, administered over two weeks, and separated by a 4-week washout period. Balance function was measured by Berg Balance Scale and computerized dynamic posturography to determine the effect of rTMS before and one day after the end of each treatment period, as well as at a 1-month follow-up. RESULTS: The balance function was significantly improved after high frequency rTMS as compared with that after sham rTMS (p<0.05). There was no serious adverse effect in patients during the treatment period. CONCLUSION: In the chronic stroke patients, high frequency rTMS to the trunk motor area seems to be a helpful way to improve balance function without any specific adverse effects. Further studies are needed to identify the underlying mechanism and generate a detailed protocol.

p11 mediates the BDNF-protective effects in dendritic outgrowth and spine formation in B27-deprived primary hippocampal cells.

BACKGROUND: p11 (S100A10) is a key regulator of depression-like behaviors and antidepressant drug response in rodent models. Recent studies suggest that p11 mediates the behavioral antidepressant action of brain-derived neurotrophic factor (BDNF) in rodents. BDNF improves neural plasticity, which is linked to the cellular actions of antidepressant drugs. In the present study, we investigated whether p11 regulated BDNF action on neural plasticity in vitro. METHODS: We generated primary hippocampal cultures. p11 expression, total dendritic length, and spine density were investigated under toxic conditions induced by B27 deprivation, which causes hippocampal cell death. RESULTS: B27 deprivation significantly decreased p11 expression. Treatment with BDNF significantly prevented the B27 deprivation-induced decrease in p11 levels in a concentration-dependent manner, whereas these concentrations had no effect on control cultures. B27 deprivation significantly reduced the total length of hippocampal dendrites and spine density. BDNF increased the total dendritic length and spine density in conditions with or without B27. Furthermore, p11 knockdown through small interfering RNA (siRNA) transfection blocked these effects. The overexpression of p11 in B27-deprived cells increased the total dendritic length and spine density, and treatment with BDNF potentiated these effects. LIMITATION: This study should be confirmed in animal models of depression. CONCLUSION: Taken together, our data suggest that BDNF-induced improvement in neural plasticity may depend on the regulation of p11 in hippocampal cells with B27 deprivation. These results provide evidence to strengthen the theoretical basis of a role for p11 in BDNF-induced antidepressant action.

Early life stress increases stress vulnerability through BDNF gene epigenetic changes in the rat hippocampus.

Early life stress (ELS) exerts long-lasting epigenetic influences on the brain and makes an individual susceptible to later depression. It is poorly understood whether ELS and subsequent adult chronic stress modulate epigenetic mechanisms. We examined the epigenetic mechanisms of the BDNF gene in the hippocampus, which may underlie stress vulnerability to postnatal maternal separation (MS) and adult restraint stress (RS). Rat pups were separated from their dams (3 h/day from P1-P21). When the pups reached adulthood (8 weeks old), we introduced RS (2 h/day for 3 weeks) followed by escitalopram treatment. We showed that both the MS and RS groups expressed reduced levels of total and exon IV BDNF mRNA. Furthermore, RS potentiated MS-induced decreases in these expression levels. Similarly, both the MS and RS groups showed decreased levels of acetylated histone H3 and H4 at BDNF promoter IV, and RS exacerbated MS-induced decreases of H3 and H4 acetylation. Both the MS and RS groups had increased MeCP2 levels at BDNF promoter IV, as well as increased HDAC5 mRNA, and the combination of MS and RS exerted a greater effect on these parameters than did RS alone. In the forced swimming test, the immobility time of the MS + RS group was significantly higher than that of the RS group. Additionally, chronic escitalopram treatment recovered these alterations. Our results suggest that postnatal MS and subsequent adult RS modulate epigenetic changes in the BDNF gene, and that these changes may be related to behavioral phenotype. These epigenetic mechanisms are involved in escitalopram action.

The Dose-Related Effects of Extracorporeal Shock Wave Therapy for Knee Osteoarthritis.

OBJECTIVE: To investigate the dose-related effects of extracorporeal shock wave therapy (ESWT) for knee osteoarthritis. METHODS: Seventy-five subjects were recruited, 60 of which met the inclusion criteria. The patients were randomly classified into two groups: group L, which was a low-energy group (n=30; 1,000 shocks/session; energy flux density [EFD], 0.040 mJ/mm(2)) and group M, which was a medium-energy group (n=30; 1,000 shocks/session; EFD, 0.093 mJ/mm(2)). For each group, 1,000 shock waves were delivered to the medial tibial plateau area, once a week, for 3 weeks. The main outcome measures were the visual analogue scale (VAS), the Roles and Maudsley (RM) score, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, and the Lequesne index. Each assessment was performed at the baseline and at 1, 4, and 12 weeks after ESWT. RESULTS: In both groups, the VAS, the RM and WOMAC scores, and the Lequesne index were significantly improved over time (p<0.001), and group M showed greater improvement over group L at the 1, 4 and 12 weeks assessments. CONCLUSION: In this study, medium-energy group (group M) showed greater improvement in regard to relieving pain and restoring functional outcome than the low-energy group (group L). Therefore, EFD can be considered to have significant influence when treating with ESWT for knee osteoarthritis.

Effects of atrial fibrillation on the outcome of the rehabilitation in patients with cerebral infarction.

OBJECTIVE: To evaluate the influence of atrial fibrillation (Af) on the clinical characteristics and rehabilitation outcomes of patients with cerebral infarction. METHODS: We evaluated 87 of 101 consecutive patients with cerebral infarction admitted to the department of physical medicine and rehabilitation during their rehabilitation period. The patients were divided into two groups, Af and non-Af groups. We estimated characteristics of patient demographic features, disease duration, length of hospital stay, other comorbidities and risk factors for stroke, and functional status at admission and at discharge and compared those in patients with and without Af. Functional Independence Measure (FIM), the Modified Barthel Index (MBI), and the PULSES profile (PULSES) were used to evaluate functional status. RESULTS: The number in the Af group was 20 (22.9%) and that of the non-Af group was 67 (77.1%). Demographic features, other comorbidities, motor function, cognitive function, neurological scales, and brain lesions did not differ significantly between the groups. The incidence of coronary artery disease and valvular heart disease were significantly correlated with the incidence of Af in multivariate analysis. Based on FIM, MBI, and PULSES scores, functional improvement in the Af group after rehabilitation was significantly less than that of the non-Af group. CONCLUSION: Af was shown to be associated with a markedly negative result in rehabilitation in patients with cerebral infarction. Thus, early recognition and proper treatment of Af may help patients achieve more effective rehabilitation.