Efficacy of agomelatine with cognitive behavioral therapy for delayed sleep-wake phase disorder in young adults: A randomized controlled study.

BACKGROUND: Delayed sleep-wake phase disorder (DSWPD) is common and easily misdiagnosed in young people, and to date, there is no evidence-based treatment. PURPOSE: A nonblinded randomized controlled study evaluated the effect of agomelatine therapy (AT) and cognitive behavior therapy (CBT) on DSWPD in young adults. METHODS: Sixty adolescents and young adults (range = 19-24 years, mean = 22 years, 52% female) diagnosed with DSWPD were randomized to receive 4 weeks of agomelatine therapy with or without cognitive behavior therapy. Sleep diaries, Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Insomnia Severity Index (ISI), and World Health Organization wellbeing questionnaire (WHO-5) were measured pre-treatment and post-treatment. RESULTS: Agomelatine therapy for 4 weeks shifted the sleep-wake rhythm (p < .001) forward in both groups at the week 4 assessment. There were no significant differences in sleep onset (p = .099) and sleep offset (p = .959) between the CBT group and the no treatment (NT) group at the follow-up visits. However, significant differences were found in sleep duration (p = .002), sleep quality (p=0.005), sleep difficulties (p < .001), daytime sleepiness (p = .001), and wellbeing (p = .007) between groups. CONCLUSIONS: The improvements were received largely through the sleep-promoting effects of agomelatine therapy, and combining with cognitive behavior therapy on maintenance of altered sleep rhythms might be feasible.

Long non-coding RNA RPL34-AS1 ameliorates oxygen-glucose deprivation-induced neuronal injury via modulating miR-223-3p/IGF1R axis.

Ribosomal protein L34-antisense RNA 1 (RPL34-AS1), one of the long non-coding RNAs (lncRNAs), plays an important function in regulating diverse human malignant tumors. Nevertheless, the functions of RPL34-AS1 in ischemic stroke remain unclear. The present work focused on determining the candidate targets of RPL34-AS1 and its related mechanism in ischemic injury. The oxygen-glucose deprivation (OGD/R) in vitro cell model and middle cerebral artery occlusion (MCAO) in vivo rat model were utilized to simulate the pathological process of ischemic stroke. Additionally, the CCK8, WB (detecting Bcl-2 and Bax protein levels), and caspase-3 activity assays were done to investigate the anti-apoptotic functions of RPL34-AS1. The relationship among RPL34-AS1, insulin-like growth factor 1 receptor (IGF1R), and microRNA-223-3p (miR-223-3p) was determined through luciferase reporter assay. In this study, RPL34-AS1 expression was reduced in patients suffering from ischemic stroke. The overexpression of RPL34-AS1 reduced ischemic brain damage. However, the cell viability and glucose uptake were increased, and the apoptosis rate was decreased in the OGD/R-induced neurons. Further, miR-223-3p resulted in the decreased cell viability and glucose uptake and the increased cell apoptosis to cause ischemic brain damage. Besides, the neuroprotective effects of RPL34-AS1 on OGD/R injury were partly reversed by miR-223-3p. Mechanistically, lncRNA RPL34-AS1 could function as the competing endogenous RNA (ceRNA) of miR-223-3p to regulate IGF1R. Collectively, our study demonstrated that lncRNA RPL34-AS1 attenuated OGD/R-induced neuronal injury by mediating miR-223-3p/IGF1R axis. This discovery might serve as the candidate therapeutic target for ischemic stroke.

The 15-LO-1/15-HETE system promotes angiogenesis by upregulating VEGF in ischemic brains.

OBJECTIVES: Angiogenesis promotes neurobehavioral recovery after cerebral ischemic stroke. 15(S)-hydroxyeicosatetraenoic acid (15-HETE) is one of the major metabolites of arachidonic acid by 15-lipoxygenase (15-LO) and stimulates the production of vascular endothelial growth factor (VEGF), thus, inducing autocrine-mediated angiogenesis. The present study aimed to investigate the role of 15-LO/15-HETE system on VEGF expression and angiogenesis in brain ischemia. METHODS: Rat cerebral arterial vascular endothelial cells were used to set up a cell injury model of oxygen-glucose deprivation and reoxygenation (OGD/R), mimicking a condition of brain ischemia. A mouse model of middle cerebral artery occlusion (MCAO) was established. RESULTS: Oxygen-glucose deprivation increased cellular expression of 15-LO-1 and VEGF. Transfection of 15-LO-1 siRNA depleted cells of 15-LO-1, and sequentially induced downregulation of VEGF expression; while, incubation of 15-HETE increased the expression of VEGF. Incubation of 15-HETE attenuated the reduction in cell viability induced by oxygen-glucose deprivation, and promoted cell migration, while transfection of 15-LO-1 siRNA showed an opposite effect. In animal experiments, the density of microvessels in hypoxic regions of brains was significantly increased after MCAO, while intracerebroventricular delivery of 15-LO-1 siRNA significantly reduced the density of microvessels, and downregulates VEGF expression. DISCUSSION: The results indicate that the 15-LO-1/15-HETE system promotes angiogenesis in ischemic brains by upregulation of VEGF, representing a potential target for improving neurobehavioral recovery after cerebral ischemic stroke.

The protective effect of epoxyeicosatrienoic acids on cerebral ischemia/reperfusion injury is associated with PI3K/Akt pathway and ATP-sensitive potassium channels.

Epoxyeicosatrienoic acids (EETs), the cytochrome P450 epoxygenase metabolite of arachidonic acid, have been demonstrated to have neuroprotective effect. Phosphatidylinositol 3-kinase (PI3K)/Akt and ATP-sensitive potassium (KATP) channels are thought to be important factors that mediate neuroprotection. However, little is known about the role of PI3K/Akt and KATP channels in brain after EETs administration. In vitro experiment, oxygen-glucose deprivation (OGD) was performed in cultured rat cerebral microvascular smooth muscle cells (SMCs) for 4 h. The effect of 14,15-EET on OGD induced cell apoptosis was examined after reoxygenation. Western blot and real-time PCR were used to analyze the expression of Kir6.1, SUR2B (two subunits of KATP channels) and p-Akt on cerebral microvascular SMCs. In vivo experiments, we use 12-(3-adamantan-1-yl-ureido)-dodecanoic acid [AUDA, a specific soluble epoxide hydrolase (sEH) inhibitor] to confirm the effect of EETs indirectly. Rats were injected intraperitoneally with AUDA before being subjected to middle cerebral artery occlusion (MCAO). We detected the apoptosis and the expression of p-Akt, Kir6.1 and SUR2B in ischemic penumbra. The results showed that EETs protect against cerebral ischemia/reperfusion (I/R) injury and upregulated the expression of p-Akt and Kir6.1 in both of ischemic penumbra and OGD induced cerebral microvascular SMCs. The protective effect was inhibited by Wortmannin (a specific PI3K inhibitor) and Glib (a specific KATP inhibitor) respectively in vitro experiment. In conclusion, these results suggested that the protective effect of EETs on cerebral I/R injury is associated with PI3K/Akt pathway and KATP channels. Furthermore, the PI3K pathway may contribute to mediating KATP channels on cerebral microvascular SMCs.

Identification of a known mutation in Notch 3 in familiar CADASIL in China.

BACKGROUND: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited disease leading to recurrent ischemic stroke and vascular dementia. Numerous mutations in the 23 exons of the NOTCH3 gene have been reported to cause CADASIL in Caucasian populations, but the full spectrum of genetic changes leading to this disease is yet to be known and, especially, very few reports are available on CADASIL in Asian populations. METHODS AND RESULTS: We genotyped members of a 5-generational Han Chinese family with CADASIL patients and identified an R133C mutation in the NOTCH3 gene. Clinical analysis demonstrated that the penetrance of the mutation was not complete. Five of the mutation carriers, not exposed to the known vascular risk factors, did not show any clinical feature of CADASIL, suggesting the importance of environmental factors to the development of this disease. CONCLUSIONS: Members of a 5-generational Han Chinese family with CADASIL patients had an R133C mutation in the NOTCH3 gene but only individuals exposed to known vascular risk factors developed CADASIL.