G-protein-coupled receptor 30 mediates rapid neuroprotective effects of estrogen via depression of NR2B-containing NMDA receptors.

17-ß-estradiol (E2) is a steroid hormone involved in neuroprotection against excitotoxicity and other forms of brain injury. Through genomic and nongenomic mechanisms, E2 modulates neuronal excitability and signal transmission by regulating NMDA and non-NMDA receptors. However, the mechanisms and identity of the receptors involved remain unclear, even though studies have suggested that estrogen G-protein-coupled receptor 30 (GPR30) is linked to protection against ischemic injury. In the culture cortical neurons, treatment with E2 and the GPR30 agonist G1 for 45 min attenuated the excitotoxicity induced by NMDA exposure. The acute neuroprotection mediated by GPR30 is dependent on G-protein-coupled signals and ERK1/2 activation, but independent on transcription or translation. Knockdown of GPR30 using short hairpin RNAs (shRNAs) significantly reduced the E2-induced rapid neuroprotection. Patch-clamp recordings revealed that GPR30 activation depressed exogenous NMDA-elicited currents. Short-term GPR30 activation did not affect the expression of either NR2A- or NR2B-containing NMDARs; however, it depressed NR2B subunit phosphorylation at Ser-1303 by inhibiting the dephosphorylation of death-associated protein kinase 1 (DAPK1). DAPK1 knockdown using shRNAs significantly blocked NR2B subunit phosphorylation at Ser-1303 and abolished the GPR30-mediated depression of exogenous NMDA-elicited currents. Lateral ventricle injection of the GPR30 agonist G1 (0.2 µg) provided significant neuroprotection in the ovariectomized female mice subjected to middle cerebral artery occlusion. These findings provide direct evidence that fast neuroprotection by estradiol is partially mediated by GPR30 and the subsequent downregulation of NR2B-containing NMDARs. The modulation of DAPK1 activity by GPR30 may be an important mediator of estradiol-dependent neuroprotection.

Kainate receptor mediated presynaptic LTP in agranular insular cortex contributes to fear and anxiety in mice.

Anxiety disorders represent serious social problems worldwide. Recent neuroimaging studies have found that elevated activity and altered connectivity of the insular cortex might account for the negative emotional states in highly anxious individuals. However, the exact synaptic mechanisms of specific insular subregions have yet to be studied in detail. To assess the electrophysiological properties of agranular insular cortex (AIC) neurons, basic synaptic transmission was recorded and different protocols were used to induce presynaptic and postsynaptic long-term potentiation in mice with anxiety-related behaviors. The presynaptic membrane expression of kainate receptors (KARs) and pharmacologic manipulations were quantified to examine the role of Gluk1 subtype in anxiety-like behaviors. Fear conditioning occludes electrically induced postsynaptic-LTP in the AIC. Quantal analysis of LTP expression in this region revealed a significant presynaptic component reflected by an increase in the probability of transmitter release. A form of presynaptic-LTP that requires KARs has been characterized. Interestingly, a simple emotional anxiety stimulus resulted in selective occlusion of presynaptic-LTP, but not of postsynaptic-LTP. Finally, injecting GluK1-specific antagonists into the AIC reduced behavioral responses to fear or anxiety stimuli in the mouse. These findings suggest that activity-dependent synaptic plasticity takes place in the AIC due to exposure to fear or anxiety, and inhibiting the presynaptic KAR function may help to prevent or treat anxiety disorder.

Electroconvulsive therapy improves antipsychotic and somnographic responses in adolescents with first-episode psychosis--a case-control study.

OBJECTIVE: Previous studies have demonstrated the effectiveness of electroconvulsive therapy (ECT) in pharmacotherapy-resistant neuropsychiatric conditions. This study aimed to evaluate the efficacy and safety of ECT in adolescents with first-episode psychosis. METHOD: This case-control study was conducted in inpatients aged 13-20 years with first-episode psychosis. Every three similar age and same gender patients consecutively recruited were randomly allocated to control and ECT group at a ratio of 1:2, while they had antipsychotic treatment. ECT treatment was performed for 3 sessions per week with a maximum of 14 sessions. The endpoint was discharge from hospital. Clinical outcomes were measured using hospital stay days, the Positive and Negative Syndrome Scale (PANSS) and response rate. Polysomnography (PSG) was conducted at baseline and at week 2. Safety and tolerability were also evaluated. RESULTS: Between March 2004 and November 2009, 112 eligible patients were allocated to control (n=38) and ECT (n=74) group. Additional ECT treatment significantly reduced hospital stay compared to controls (23.2±8.2 days versus 27.3±9.3 days, mean±SD, P=0.018). Survival analysis revealed that the ECT-treated group had a significantly higher cumulative response rate than controls (74.3% versus 50%, relative risk (RR)=1.961, P=0.001). Additional ECT also produced significantly greater improvement in sleep efficiency, rapid eye movement (REM) latency and density than control condition. The PSG improvement significantly correlated with reduction in scores on overall PANSS, positive symptoms, and general psychopathology. No patients discontinued ECT treatment regimen during hospital stay. The incidence of most adverse events was not different in the two groups, but ECT-treated group had more complaints of transient headache and dizziness than controls. CONCLUSIONS: ECT is an effective and safe intervention used in adolescents with first-episode psychosis. Its antipsychotic effects are associated with improved PSG variables. ECT can be considered as an early psychosis intervention.

Long-lasting effects of chronic rTMS to treat chronic rodent model of depression.

Repetitive transcranial magnetic stimulation (rTMS) has been demonstrated in the pre-clinical and clinical settings to have an antidepressant effect. However, studies on the long-lasting effect of rTMS, especially when the effect is measured after treatment has ceased for a few weeks is lacking. We examined this question in a chronic unpredicted mild stress (CUMS) rat model of depression. We gave 3 weeks of high frequency (15 Hz) rTMS, venlafaxine, or these two treatments combined to a modified CUMS paradigm, and then investigated the prolonged effect of treatments. Behavioral testing (sucrose preference test, open field test, forced swimming test, novelty suppressed feeding test), plasma hormone level, hippocampal BrdU labeling, and amount of related neurotropic factors were used to assess the effects of stress and treatments. Long-term chronic rTMS significantly reversed andehonic-like behavior, increased hippocampus cell proliferation, BDNF protein level, phosphorylation of ERK1/2 compared with CUMS rats two weeks after the cessation of rTMS treatment. However, the changes in plasma hormone level were not sustained for that amount of time. Venlafaxine had no interaction with the physical stimulation. Our results suggest that high frequency rTMS has long-lasting effects, which may have some relationship with neuroplasticity.

Neuroprotective effects of Salidroside and its analogue tyrosol galactoside against focal cerebral ischemia in vivo and H2O2-induced neurotoxicity in vitro.

Salidroside (Sal) is a natural antioxidant extracted from the root of Rhodiola rosea L. that elicits neuroprotective effects in vivo and in vitro. Tyrosol galactoside (Tyr), an analog of Sal, was recently synthesized in our laboratory. The purpose of the current study was to investigate and compare the neuroprotective effects of Sal and Tyr against focal cerebral ischemia in vivo and H(2)O(2)-induced neurotoxicity in vitro. Sal and Tyr significantly prevented a cerebral ischemic injury induced by a 2 h middle cerebral artery occlusion and a 24 h reperfusion in rats in vivo. Furthermore, the oxidative insult was markedly attenuated by treatments of Sal and Tyr in the cultured rat cortical neurons after a 30 min exposure to 50 µM of H(2)O(2). Western blot analysis revealed that Sal and Tyr decreased the expression of Bax and restored the balance of pro- and anti-apoptotic proteins. The neuroprotective effects of these two analogues show that Tyr has a better antioxidative action compared with Sal both in vivo and in vitro, and suggest that the antioxidant activity of Sal and Tyr may be partly due to their different substituents in their glycosyl groups. This gives a new insight into the development of therapeutic natural antioxidants against oxidative stress.

Hyperbaric oxygen preconditioning ameliorates anxiety-like behavior and cognitive impairments via upregulation of thioredoxin reductases in stressed rats.

The present study examined the protective effect of hyperbaric oxygen preconditioning (HBO-PC) and the role of thioredoxin reductase (TrxR) in a post-traumatic stress disorder (PTSD)-induced rat model by using single prolonged stress (SPS). Rats were randomly divided into Sham, HBO, SPS and HBO+SPS groups. HBO-PC was conducted by exposing rats to 100% oxygen at 2.5atm absolute for 1h each day for 5 consecutive days. SPS was performed 24h after the last HBO-PC conditioning event. At 1h, 6h, 12h, 24h and 72h after SPS, TrxR mRNA expression was analyzed in the hippocampus; Nissl and TUNEL staining were performed at 72h after SPS. The results indicated that HBO-PC was able to significantly preserve viable neurons in the CA1 subfield of hippocampus following SPS exposure, as evidenced by reduced amounts of CA1 neuronal apoptosis. Furthermore, HBO-PC upregulate the expression of TrxR-1 and TrxR-2 mRNA in the hippocampus at 6h and 12h after SPS exposure and ameliorated anxiety-like behavior and cognitive impairments normally induced by SPS. Taken together, these findings suggest that HBO-PC is beneficial for the improvement of anxiety-like behavior and cognitive impairments induced by SPS exposure, and this effect might be associated with inhibition of neuronal apoptosis via upregulation of TrxR in stressed rats.