Estrogen is protective in experimental cerebral ischemia, yet the mechanism remains unclear. Fasmediated apoptosis has been shown to be induced after cerebral ischemia and significantly contribute to ischemic brain damage. In this study, we tested if estrogen is protective against cerebral ischemia by suppressing Fas-mediated apoptosis. 17β-estradiol-treated and untreated ovariectomized (OVX) female mice were subjected to 2 h middle cerebral artery occlusion (MCAO). Expression of Fas and Fas-associated death domain (FADD) were measured at 3, 6 and 12 h of reperfusion by RT-PCR and Western blot, respectively. Post-ischemic activities of caspase-8 and -3 activities, the two downstream effectors of Fas-induced apoptosis, were also assayed at same time points by ELISA. Finally, Fas antibody-induced cell death in primary cortical neurons was assayed by fluorescence activated cell sorter (FACS) in the presence and absence of estradiol. Our data showed that estradioltreated OVX female mice sustained smaller infarct compared to untreated OVX mice. Ischemia upregulated Fas and FADD expression, and increased caspase-8 and -3 activities in OVX female mouse cortex, which were significantly attenuated by estradiol. Estradiol also significantly inhibited Fas antibody-induced neuronal cell apoptosis. Our data suggests that inhibition of ischemia-induced Fas-mediated apoptosis is an important mechanism of neuroprotection by estrogen in cerebral ischemia.
The peroxisome proliferator activated receptor coactivator 1 alpha (PGC-1alpha) is a nuclear transcriptional coactivator that is widely expressed in the brain areas. Over-expression of PGC-1alpha can protect neuronal cells from oxidant-induced injury. The purpose of the current study is to investigate the role of PGC-1alpha in the oxygen (anoxia) deprivation (OGD) neurons. The PGC-1alpha mRNA and protein level between control and OGD neurons were examined by real-time PCR and Western blot. More PGC-1alpha expression was found in the OGD neurons compared with the normal group. Over-expression of PGC-1alpha suppressed cell apoptosis while inhibition of the PGC-1alpha expression induced cell apoptosis in OGD neurons. Furthermore, increase of PGC-1alpha resulted in activation of N-methyl-D-aspartate (NMDA) receptor, p38, and ERK mitogen-activated protein kinase (MAPK) pathway. The blocking of the NMDA receptor by its antagonists MK-801 reduced PGC-1alpha mRNA expression in OGD neurons, while NMDA itself can directly induce the expression of PGC-1alpha in neuronal cells. At the same time, PD98059 (ERK MAPK inhibitor) and SB203580 (P38 MAPK inhibitor) also prevented the up-regulation of PGC-1alpha in OGD neurons and MK801 can inhibit the expression of P38 and ERK MAPK. These data suggested that the expression of PGC-1alpha was up-regulated in OGD mice cortical neurons, which protected the neurons against OGD injury. Moreover, this effect was correlated to the NMDA receptor and the ERK and P38 MAPK pathway. The protective effect of PGC-1alpha on OGD cortical neurons may be useful for stroke therapy.
BackgroundThe key pathophysiological mechanism of executive dysfunction in patients with bipolar disorder type I (BD-I) is still unclear. Previous studies have demonstrated that it may be related to the disbalance of the sensory motor network (SMN).ObjectiveThis study was designed to explore the aberrant functional connectivity (FC) of SMN in BD-I patients and its potential associations with executive dysfunction.MethodsEighteen BD-I patients and 20 healthy controls (HCs) underwent resting-state fMRI scans. The intranetwork and internetwork functional connectivities of SMN were extracted by independent component analysis (ICA). Clinical symptoms were assessed by the Bech–Rafaelsen Mania Rating Scale (BRMS) and Positive and Negative Syndrome Scale (PANSS). Executive function was measured by digit span tasks and a verbal fluency test. Finally, linear regression and correlation analyses were applied to measure the potential associations between clinical symptoms, intranetwork and internetwork functional connectivities, and executive function performance.Results(1) Patients with BD-I showed increased connectivity in the right paracentral lobule and the right postcentral gyrus within the SMN, and the increased connectivity value was positively correlated with the BRMS score (P < 0.05) but negatively correlated with digit span forward scores (P < 0.05). (2) Compared with HC, the connectivity value increased between the SMN and dorsal attention network (DAN) (P < 0.01) and between the default mode network (DMN) and DAN (P < 0.05) but decreased between the DAN and auditory network (AN) (P < 0.05) and between the SMN and DMN (P < 0.01) in patients with BD-I. (3) Digit span forward scores and education of all participants were negatively correlated with FC between SMN and DAN. Age of all subjects was positively correlated with FC between SMN and DMN.ConclusionOur findings suggest that the sensorimotor network of BD-I has abnormal functional connections within and between networks, and the abnormal FC value correlated with clinical symptoms and executive function, which provide new information for exploring the neural physiopathology of executive dysfunction in BD-I patients.
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