Inhibiting α5 Subunit-Containing γ-Aminobutyric Acid Type A Receptors Attenuates Cognitive Deficits After Traumatic Brain Injury.

OBJECTIVES: Cognitive deficits after traumatic brain injury are a leading cause of disability worldwide, yet no effective pharmacologic treatments exist to improve cognition. Traumatic brain injury increases proinflammatory cytokines, which trigger excess function of α5 subunit-containing γ-aminobutyric acid type A receptors. In several models of brain injury, drugs that inhibit α5 subunit-containing γ-aminobutyric acid type A receptor function improve cognitive performance. Thus, we postulated that inhibiting α5 subunit-containing γ-aminobutyric acid type A receptors would improve cognitive performance after traumatic brain injury. In addition, because traumatic brain injury reduces long-term potentiation in the hippocampus, a cellular correlate of memory, we studied whether inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated deficits in long-term potentiation after traumatic brain injury. DESIGN: Experimental animal study. SETTING: Research laboratory. SUBJECTS: Adult male mice and hippocampal brain slices. INTERVENTIONS: Anesthetized mice were subjected to traumatic brain injury with a closed-head, free-weight drop method. One week later, the mice were treated with L-655,708 (0.5 mg/kg), an inhibitor that is selective for α5 subunit-containing γ-aminobutyric acid type A receptors, 30 minutes before undergoing behavioral testing. Problem-solving abilities were assessed using the puzzle box assay, and memory performance was studied with novel object recognition and object place recognition assays. In addition, hippocampal slices were prepared 1 week after traumatic brain injury, and long-term potentiation was studied using field recordings in the cornu Ammonis 1 region of slices that were perfused with L-655,708 (100 nM). MEASUREMENTS AND MAIN RESULTS: Traumatic brain injury increased the time required to solve difficult but not simple tasks in the puzzle box assay and impaired memory in the novel object recognition and object place recognition assays. L-655,708 improved both problem solving and memory in the traumatic brain injury mice. Traumatic brain injury reduced long-term potentiation in the hippocampal slices, and L-655,708 attenuated this reduction. CONCLUSIONS: Pharmacologic inhibition of α5 subunit-containing γ-aminobutyric acid type A receptors attenuated cognitive deficits after traumatic brain injury and enhanced synaptic plasticity in hippocampal slices. Collectively, these results suggest that α5 subunit-containing γ-aminobutyric acid type A receptors are novel targets for pharmacologic treatment of traumatic brain injury-induced persistent cognitive deficits.

Retraction Note: Effect of perioperative infusion of Dexmedetomidine combined with Sufentanil on quality of postoperative analgesia in patients undergoing laparoscopic nephrectomy: a CONSORT-prospective, randomized, controlled trial.

The authors have retracted this article.

The Properties of Cytokines in Multiple Sclerosis: Pros and Cons.

Multiple sclerosis (MS) is a chronic autoimmune disease that affects the central nervous system and is characterized by demyelination, axonal loss, gliosis and inflammation. The last plays a major role in the onset and propagation of the disease. MS presents with heterogeneous lesions containing a broad range of cells and soluble mediators of the immune system such as T cells, B cells, macrophages, microglia, cytokines, chemokines, antibodies, complement and other toxic substances. This review outlines, analyzes and discusses the different immune mechanisms of MS that are responsible for the initiation and propagation of active lesions, demyelination, axonal injury, remyelination and cell loss as well as the role of cytokines in the disease process. Proinflammatory cytokines such as interleukin-17 (IL-17), IL-22, tumor necrosis factor-α, IL-1, IL-12 and interferon-γ may cause MS through several signaling pathways. Conversely, anti-inflammatory circulating cytokines such as IL-4 and IL-10 are reduced and theoretically can exert a direct protective effect in this condition. Future studies are necessary to develop effective, safe and long-lasting strategies to reduce the abnormal cytokine cascades and to treat MS.

Effect of perioperative infusion of Dexmedetomidine combined with Sufentanil on quality of postoperative analgesia in patients undergoing laparoscopic nephrectomy: a CONSORT-prospective, randomized, controlled trial.

BACKGROUND: Postoperative pain is one of the most common symptoms after surgery, which brings physical discomfort to patients. In addition, it may cause a series of complications, and even affect the long-term quality of life. The purpose of this prospective, randomized, double-blinded, controlled trial is to investigate the efficacy and safety of dexmedetomidine combined with sufentanil to attenuate postoperative pain in patients after laparoscopic nephrectomy. METHODS: Ninety patients undergoing laparoscopic nephrectomy were randomized into three groups: the control (sufentanil 0.02 µg/kg/h, Group C), sufentanil plus low dose of dexmedetomidine (0.02 µg/kg/h each, Group D1), and sufentanil plus high dose of dexmedetomidine (0.04 µg/kg/h, Group D2). The patient-controlled analgesia was programmed to deliver a bolus dose of 0.5 ml, followed by an infusion of 2 ml/h and a lockout time of 10 min. The primary goal was to calculate the cumulative amount of self-administered sufentanil; the secondary goals were to estimate pain intensity using the numerical rating scale (NRS), level of sedation, the first bowel movement, concerning adverse effects as well as duration of postoperative hospital stay. RESULTS: The total consumption of sufentanil in group D1 and D2 were significantly lower than in group C during the first 8 h after surgery (P < 0.05), whereas there were no statistically significant differences (P > 0.05) between group D1 and D2. Compared with group C, the NRS scores at rest during first 8 h after surgery were significantly lower in group D1 (P < 0.05). The NRS scores, neither at rest nor with movement, show statistically significant differences between group D1 and D2 at each time point following surgery (P > 0.05). The time to first flatus was shorter in group D1 compared with the control group (P < 0.05). In addition, compared with group C, group D1 and D2 had a shorter time for first defecation (P < 0.05). CONCLUSIONS: Dexmedetomidine combined with sufentanil showed better postoperative analgesia without adverse effects, as well as facilitated bowel movements for patients undergoing laparoscopic nephrectomy. TRIAL REGISTRATION: We registered this study in a Chinese Clinical Trial Registry (ChiCTR) centre on Dec 23 2015 and received the registration number: ChiCTR-IPR-15007628 .

Tyrosol attenuates pro-inflammatory cytokines from cultured astrocytes and NF-κB activation in in vitro oxygen glucose deprivation.

Subsequent inflammation in stroke plays an important role in the damage of neurons in the perilesional area. Therapeutic intervention targeting inflammation may be a promising complementary strategy to current treatments of stroke. Here, we explored the possible beneficial effects of tyrosol, a derivative of phenethyl alcohol and natural antioxidant, playing an anti-inflammatory role in astrocyte culture and in vitro oxygen glucose deprivation (OGD) model. MTT, western blot, ELISA and EMSA assays were carried out to investigate cell viability, protein expression level, cytokine expression and NF-κB activity. We found tyrosol protected cultured astrocytes against OGD-induced cell viability loss in MTT test. Meanwhile, tyrosol attenuated the released TNF-α and IL-6 level from astrocyte via regulating Janus N-terminal kinase (JNK). The reduction of cytokines from astrocyte might be due to its inhibition of astrocyte activation and regulation of STAT3 signaling pathway since tyrosol attenuated the expression level of GFAP (glial fibrillary acidic protein) and the phosphorylation of STAT3. Additionally, we demonstrated that tyrosol prevented the degradation of IκBα and the increase of IκBα phosphorylation in astrocytes exposed to OGD, which led to the suppression of NF-κB function during ischemia. Collectively, our results showed that tyrosol may be a promising complementary treatment compound for stroke via modulating the inflammatory response in astrocytes during ischemia.

Dexmedetomidine Prevents Excessive γ-Aminobutyric Acid Type A Receptor Function after Anesthesia.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Postoperative delirium is associated with poor long-term outcomes and increased mortality. General anesthetic drugs may contribute to delirium because they increase cell-surface expression and function of α5 subunit-containing γ-aminobutyric acid type A receptors, an effect that persists long after the drugs have been eliminated. Dexmedetomidine, an α2 adrenergic receptor agonist, prevents delirium in patients and reduces cognitive deficits in animals. Thus, it was postulated that dexmedetomidine prevents excessive function of α5 γ-aminobutyric acid type A receptors. METHODS: Injectable (etomidate) and inhaled (sevoflurane) anesthetic drugs were studied using cultured murine hippocampal neurons, cultured murine and human cortical astrocytes, and ex vivo murine hippocampal slices. γ-Aminobutyric acid type A receptor function and cell-signaling pathways were studied using electrophysiologic and biochemical methods. Memory and problem-solving behaviors were also studied. RESULTS: The etomidate-induced sustained increase in α5 γ-aminobutyric acid type A receptor cell-surface expression was reduced by dexmedetomidine (mean ± SD, etomidate: 146.4 ± 51.6% vs. etomidate + dexmedetomidine: 118.4 ± 39.1% of control, n = 8 each). Dexmedetomidine also reduced the persistent increase in tonic inhibitory current in hippocampal neurons (etomidate: 1.44 ± 0.33 pA/pF, n = 10; etomidate + dexmedetomidine: 1.01 ± 0.45 pA/pF, n = 9). Similarly, dexmedetomidine prevented a sevoflurane-induced increase in the tonic current. Dexmedetomidine stimulated astrocytes to release brain-derived neurotrophic factor, which acted as a paracrine factor to reduce excessive α5 γ-aminobutyric acid type A receptor function in neurons. Finally, dexmedetomidine attenuated memory and problem-solving deficits after anesthesia. CONCLUSIONS: Dexmedetomidine prevented excessive α5 γ-aminobutyric acid type A receptor function after anesthesia. This novel α2 adrenergic receptor- and brain-derived neurotrophic factor-dependent pathway may be targeted to prevent delirium.

Factors Associated with 90-Day Outcomes of Patients with Acute Posterior Circulation Stroke Treated By Mechanical Thrombectomy.

BACKGROUND AND OBJECTIVE: Early recanalization of acute posterior circulation stroke caused by large intracranial vessel occlusion by mechanical thrombectomy with stent retrievers may improve the outcome of patients. However, evidence of patient selection is still lacking. This study investigated the prognostic factors of acute posterior circulation stroke caused by large intracranial arterial occlusion when treated with stent-retriever thrombectomy. METHODS: A total of 69 patients from March 2012 to November 2016 were included in the study. These patients presented with acute posterior circulation stroke caused by large intracranial vessel occlusion and underwent mechanical thrombectomy with Solitaire AB or combined with additional balloon and/or stenting angioplasty. Baseline characteristics, clinical course, and imaging data of the patients were analyzed. Good clinical outcome (defined as a modified Rankin Scale score of 0-2 at 90 days) and safety outcome (defined as death within 90 days after thrombectomy) were considered as end points. The association between factors with good clinical outcome and safety outcome was evaluated with both logistic regression and receiver operating characteristic curve analyses. RESULTS: Of the 69 patients, mean age was 59 years (standard deviation, 8 years) and men comprised 82.6% (57/69). The median onset-to-treatment time was 360 minutes (interquartile range, 250-537 minutes). The median National Institutes of Health Stroke Scale (NIHSS) score was 25 (interquartile range, 17-30) on admission. Successful recanalization was achieved in 62 of the 69 cases (89.9%) and 36.2% (25/69) were independent at 90 days. Regression analysis showed that stroke subtype (intracranial atherosclerotic disease vs. embolism; odds ratio [OR], 0.101; 95% confidence interval [CI], 0.020-0.501; P = 0.005), baseline NIHSS score (≥22 vs. <22; OR, 0.157; 95% CI, 0.040-0.614; P = 0.008) and posterior circulation Acute Stroke Prognosis Early CT Score (pc-ASPECTS) on diffusion-weighted imaging [DWI] (weighted magnetic resonance imaging) before thrombectomy (≥6 vs. <6; OR, 7.335; 95% CI, 1.495-36.191; P = 0.014) were independent predictive factors of good clinical outcome, respectively at 90 days, whereas high NIHSS score (≥30 vs. <30; OR, 5.569; 95% CI, 1.573-19.716; P = 0.008) and collateral status (≥2 vs. <2; OR, 0.210; 95% CI, 0.059-0.752; P = 0.016) before treatment were associated with mortality at 90 days. Based on receiver operating characteristic curves, baseline NIHSS score (area under the curve [AUC] = 0.779; cutoff, ≥22; P < 0.001; sensitivity, 72%; specificity, 77.3%), pc-ASPECTS on DWI (AUC = 0.820; cutoff, ≥6; P < 0.001; sensitivity, 72%; specificity, 77.3%) before treatment were independent indicators predicting good clinical outcome at 90 days. Increased risk of death by 90 days was associated with baseline NIHSS score (AUC = 0.719; cutoff, ≥30; P = 0.007; sensitivity, 64.7%; specificity, 78.9%) and worse collateral status (AUC = 0.820; cutoff, ≥2; P < 0.001; sensitivity, 58.8%; specificity, 80.8%) before treatment. CONCLUSIONS: Stroke subtype, initial stroke severity, and pc-ASPECTS on DWI as well as collateral status before thrombectomy are independent factors affecting the clinical outcome in patients treated with Solitaire AB thrombectomy for acute posterior circulation stroke caused by large intracranial vessel occlusion.

Lamotrigine Reduces Inflammatory Response and Ameliorates Executive Function Deterioration in an Alzheimer's-Like Mouse Model.

Alzheimer's disease (AD) has been described in the literature, to be associated with impairment of executive function which develops early in the course of disease, and an effective treatment for this clinical feature remains elusive. Preclinical studies have implied that lamotrigine, an antiepileptic agent, could be a potential treatment for executive dysfunction in AD patients. Although there have been promising results in previous studies with lamotrigine, executive function has never been measured using animal models. The aim of the present study was to evaluate the effects of lamotrigine on executive function and determine whether lamotrigine can attenuate inflammatory response in an AD mouse model. Nontransgenic and transgenic mice were treated with lamotrigine (0 or 30 mg/kg/day) in a standard laboratory chow diet starting at 3 months of age. After 6 months of continuous lamotrigine administration, there was a marked improvement in executive function and a significant attenuation in the expression of proinflammatory cytokines. These results suggest that lamotrigine could ameliorate executive dysfunction and brain inflammatory response in the mouse model of AD and early lamotrigine intervention may be a promising therapeutic strategy for AD.