Different types of percutaneous endovascular interventions for acute ischemic stroke.

BACKGROUND: Acute ischemic stroke (AIS) is the abrupt reduction of blood flow to a certain area of the brain which causes neurologic dysfunction. Different types of percutaneous arterial endovascular interventions have been developed, but as yet there is no consensus on the optimal therapy for people with AIS. OBJECTIVES: To compare the safety and efficacy of different types of percutaneous arterial endovascular interventions for treating people with AIS. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL; Issue 4 of 12, 2022), MEDLINE Ovid (1946 to 13 May 2022), Embase (1947 to 15 May 2022), Science Citation Index Web of Science (1900 to 15 May 2022), Scopus (1960 to 15 May 2022), and China Biological Medicine Database (CBM; 1978 to 16 May 2022). We also searched the ClinicalTrials.gov trials register and the World Health Organization (WHO) International Clinical Trials Registry Platform to 16 May 2022. SELECTION CRITERIA: Randomized controlled trials (RCTs) comparing one percutaneous arterial endovascular intervention with another in treating adult patients who have a clinical diagnosis of AIS due to large vessel occlusion and confirmed by imaging evidence, including thrombo-aspiration, stent-retrieval thrombectomy, aspiration-retriever combined technique, and thrombus mechanical fragmentation. DATA COLLECTION AND ANALYSIS: Two review authors independently performed the literature searches, identified eligible trials, and extracted data. A third review author participated in discussions to reach consensus decisions when any disputes occurred. We assessed risk of bias and applied the GRADE approach to evaluate the quality of the evidence. The primary outcome was rate of modified Rankin Scale (mRS) of 0 to 2 at three months. Secondary outcomes included the rate of modified Thrombolysis In Cerebral Infarction (mTICI) of 2b to 3 postprocedure, all-cause mortality within three months, rate of intracranial hemorrhage on imaging at 24 hours, rate of symptomatic intracranial hemorrhage at 24 hours, and rate of procedure-related adverse events within three months. MAIN RESULTS: Four RCTs were eligible. The current meta-analysis included two trials with 651 participants comparing thrombo-aspiration with stent-retrieval thrombectomy. We judged the quality of evidence to be high in both trials according to Cochrane's risk of bias tool RoB 2. There were no significant differences between thrombo-aspiration and stent-retrieval thrombectomy in rate of mRS of 0 to 2 at three months (risk ratio [RR] 0.97, 95% confidence interval [CI] 0.82 to 1.13; P = 0.68; 633 participants; 2 RCTs); rate of mTICI of 2b to 3 postprocedure (RR 1.01, 95% CI 0.95 to 1.07; P = 0.77; 650 participants; 2 RCTs); all-cause mortality within three months (RR 1.01, 95% CI 0.74 to 1.37; P = 0.95; 633 participants; 2 RCTs); rate of intracranial hemorrhage on imaging at 24 hours (RR 1.03, 95% CI 0.86 to 1.24; P = 0.73; 645 participants; 2 RCTs); rate of symptomatic intracranial hemorrhage at 24 hours (RR 0.90, 95% CI 0.49 to 1.68; P = 0.75; 645 participants; 2 RCTs); and rate of procedure-related adverse events within three months (RR 0.98, 95% CI 0.68 to 1.41; P = 0.90; 651 participants; 2 RCTs). Another two included studies reported no differences for the comparisons of combined therapy versus stent-retrieval thrombectomy or thrombo-aspiration. One RCT is ongoing. AUTHORS' CONCLUSIONS: This review did not establish any difference in safety and effectiveness between the thrombo-aspiration approach and stent-retrieval thrombectomy for treating people with AIS. Furthermore, the combined group did not show any obvious advantage over either intervention applied alone.

Endovascular therapy versus medical treatment for symptomatic intracranial artery stenosis.

BACKGROUND: Intracranial atherosclerotic stenosis (ICAS) is an arterial narrowing in the brain that can cause stroke. Endovascular therapy and medical management may be used to prevent recurrent ischaemic stroke caused by ICAS. However, there is no consensus on the best treatment for people with ICAS. OBJECTIVES: To compare the safety and efficacy of endovascular therapy (ET) plus conventional medical treatment (CMT) with CMT alone for the management of symptomatic ICAS. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (30 August 2019), Cochrane Central Register of Controlled Trials (CENTRAL: to 30 August 2019), MEDLINE Ovid (1946 to 30 August 2019), Embase Ovid (1974 to 30 August 2019), Scopus (1960 to 30 August 2019), Science Citation Index Web of Science (1900 to 30 July 2019), Academic Source Complete EBSCO (ASC: 1982 to 30 July 2019), and China Biological Medicine Database (CBM: 1978 to 30 July 2019). We also searched the following trial registers: ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, and Stroke Trials Registry. We also contacted trialists and researchers where additional information was required. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing ET plus CMT with CMT alone for the treatment of symptomatic ICAS. ET modalities included angioplasty alone, balloon-mounted stent, and angioplasty followed by placement of a self-expanding stent. CMT included antiplatelet therapy in addition to control of risk factors such as hypertension, hyperlipidaemia, and diabetes. DATA COLLECTION AND ANALYSIS: Two review authors independently screened trials to select potentially eligible RCTs and extracted data. Any disagreements were resolved by discussing and reaching consensus decisions with the full team. We assessed risk of bias and applied the GRADE approach to assess the quality of the evidence. The primary outcome was death of any cause or non-fatal stroke of any type within three months of randomisation. Secondary outcomes included any-cause death or non-fatal stroke of any type more than three months of randomisation, ipsilateral stroke, type of recurrent event, death, restenosis, dependency, and health-related quality of life. MAIN RESULTS: We included three RCTs with 632 participants who had symptomatic ICAS with an age range of 18 to 85 years. The included trials had high risks of performance bias and other potential sources of bias due to the impossibility of blinding of the endovascular intervention and early termination of the trials. Moreover, one trial had a high risk of attrition bias because of the high rate of loss of one-year follow-up and the high proportion of participants transferred from endovascular therapy to medical management. The quality of evidence ranged from low to moderate, downgraded for imprecision. Compared to CMT, ET probably results in a higher rate of 30-day death or stroke (risk ratio (RR) 3.07, 95% confidence interval (CI) 1.80 to 5.24; 3 RCTs, 632 participants, moderate-quality evidence), 30-day ipsilateral stroke (RR 3.54, 95% CI 1.98 to 6.33; 3 RCTs, 632 participants, moderate-quality evidence), 30-day ischaemic stroke (RR 2.52, 95% CI 1.37 to 4.62; 3 RCTs, 632 participants, moderate-quality evidence), and 30-day haemorrhagic stroke (RR 15.53, 95% CI 2.10 to 115.16; 3 RCTs, 632 participants, low-quality evidence). ET was also likely associated with a worse outcome in one-year death or stroke (RR 1.69, 95% CI 1.21 to 2.36; 3 RCTs, 632 participants, moderate-quality evidence), one-year ipsilateral stroke (RR 2.28, 95% CI 1.52 to 3.42; 3 RCTs, 632 participants, moderate-quality evidence), one-year ischaemic stroke (RR 2.07, 95% CI 1.37 to 3.13; 3 RCTs, 632 participants, moderate-quality evidence), and one-year haemorrhagic stroke (RR 10.13, 95% CI 1.31 to 78.51; 2 RCTs, 521 participants, low-quality evidence). There were no significant differences between ET and CMT in 30-day transient ischaemic attacks (TIA) (RR 0.52, 95% CI 0.11 to 2.35, P = 0.39; 2 RCTs, 181 participants, moderate-quality evidence), 30-day death (RR 5.53, 95% CI 0.98 to 31.17, P = 0.05; 3 RCTs, 632 participants, low-quality evidence), one-year TIA (RR 0.82, 95% CI 0.32 to 2.12; 2 RCTs, 181 participants, moderate-quality evidence), one-year death (RR 1.20, 95% CI 0.50 to 2.86, P = 0.68; 3 RCTs, 632 participants, moderate-quality evidence), and one-year dependency (RR 1.90, 95% CI 0.91 to 3.97, P = 0.09; 3 RCTs, 613 participants, moderate-quality evidence). No data on restenosis and health-related quality of life for meta-analysis were available from the included trials. Two RCTs are ongoing. AUTHORS' CONCLUSIONS: This systematic review provides moderate-quality evidence showing that ET, compared with CMT, in people with recent symptomatic severe intracranial atherosclerotic stenosis probably does not prevent recurrent stroke and appears to carry an increased hazard. The impact of delayed ET intervention (more than three weeks after a qualifying event) is unclear and may warrant further study.

Incidence and outcome of vertebral artery dissection in trauma setting: analysis of national trauma data base.

BACKGROUND: The natural history and epidemiological aspects of traumatic vertebral artery dissection (VAD) are not fully understood. We determined the prevalence of VAD and impact on outcome of patients with head and neck trauma. METHODS: All the patients who were admitted with traumatic brain injury or head and neck trauma were identified by ICD-9-CM codes from the National Trauma Data Bank (NTDB), using data files from 2009 to 2010. NTDB represents one of the largest trauma databases and contains data from over 900 trauma centers across the United States. Presence of VAD was identified in these patients by using ICD-9-CM codes. Admission Glasgow Coma Scale (GCS) score, injury severity score (ISS), in-hospital complications, and treatment outcome were compared between patients with and without VAD. RESULTS: A total of 84 VAD patients were identified which comprised 0.01 % of all patients admitted with head and neck trauma. The mean age (in years) for patients with VAD was significantly higher than patients without dissection [46 (95 % CI 41-50) vs. 41.3 (95 % CI 41.2-41.4); p = 0.003]. The proportion of patients presenting with GCS score <9 was significantly higher in patients with VAD (31 vs. 12 %, p < 0.0001). The rate of cervical vertebral fracture was significantly higher in patients with VAD (71 vs. 11 %, p < 0.0001). Patients with VAD had higher rates of in-hospital stroke than patients without dissection (5 vs. 0.2 %, p < 0.0001). Numbers of ICU days, ventilator days, and hospital length of stays were all significantly higher in patients with VAD. These differences remained significant after adjusting for the demographics, admission GCS score, and ISS (p < 0.0001). A total of 7 % (N = 6) of the patients with VAD received endovascular treatment and there was no in-hospital stroke in these patients. Patients with VAD had a higher chance of discharge to nursing facilities in comparison to head trauma patients without VAD (OR: 2.1; 95 % CI 1.4-3.5; p < 0.0001). CONCLUSION: Although infrequent, VAD in head and neck trauma is associated with higher rates of in-hospital stroke and longer length of ICU stay and total hospital stay. Early diagnosis and endovascular treatment may be an alternative option to reduce the rate of in-hospital stroke in these patients.

Factors associated with favorable response to hyperbaric oxygen therapy among patients presenting with iatrogenic cerebral arterial gas embolism.

BACKGROUND: Iatrogenic cerebral arterial gas embolism (CAGE) is an uncommon but potentially a fatal condition. Hyperbaric oxygen (HBO2) therapy is the only definitive treatment for patients with CAGE presenting with acute neurologic deficits. METHODS: We reviewed medical records and neuroimaging of consecutive CAGE patients treated with HBO2 at a state referral hyperbaric facility over a 22-year period. We analyzed the effect of demographics, source of intra-arterial gas, signs and symptoms, results of imaging studies, time between event and HBO2 treatment, and response to HBO2 treatment in 36 consecutive patients. Favorable outcome was defined by complete resolution or improvement of CAGE signs and symptoms at 24 h after HBO2 treatment. Unfavorable outcome was defined by unchanged or worsened neurologic signs and symptoms or in hospital death. RESULTS: A total of 26 (72%) of the 36 patients had favorable outcome. Patients with favorable outcome were younger compared to those with unfavorable outcome (mean age [years, SD] 44.7 ± 17.8 vs. 58.1 ± 24.1, p = 0.08). Cardiopulmonary symptoms were significantly more common in CAGE related to venous source of gas compared to arterial source (p = 0.024) but did not influence the rate of favorable outcomes. Adjusted multivariate analysis demonstrated that time from event to HBO2 ≤ 6 h (positively) and the presence of infarct/edema on head computerized tomography (CT)/magnetic resonance imaging (MRI) before HBO2 (negatively) were independent predictors of favorable outcome at 24 h after HBO2 treatment [odds ratio (OR) 9.08 confidence interval (CI) (1.13-72.69), p = 0.0376, and (OR) 0.034 (CI) (0.002-0.58), p = 0.0200, respectively]. Two of the 36 patients were treated with thrombolytics because of acute focal deficits and suspected ischemia-one with intravenous and the second with intra-arterial thrombolysis. The latter patient developed fatal intracerebral hemorrhage. CONCLUSIONS: A high proportion of CAGE patients treated with HBO2 had favorable outcomes. Time-to-HBO2 ≤ 6 h increased the odds of favorable outcome, whereas the presence of infarct/edema on CT/MRI scan before HBO2 reduced the odds of a favorable outcome. Timely diagnosis and differentiation from thrombo-embolic ischemic events appears to be an important determinant of successful HBO2 treatment.

Diagnosis of stroke by emergency medical dispatchers and its impact on the prehospital care of patients.

BACKGROUND: Emergency medical dispatchers represent the first line of communication with a patient, and their decision plays an important role in the prehospital care of stroke. We evaluated the rate and accuracy of stroke diagnosis by dispatchers and its influence in the prehospital care of potential stroke patients. METHODS: We analyzed the 2009 National Emergency Medical Services Information System. Study population was based on the diagnosis of stroke made by emergency medical technicians (EMT). This was then divided in those coded as stroke/cerebrovascular accident versus others reported by dispatchers and compared with each other. RESULTS: In all, 67,844 cases were identified as stroke by EMT, but transportation time was available for 52,282 cases that represented the final cohort. Cases identified as stroke by dispatchers were 27,566 (52.7%). When this group compared with stroke cases not identified by dispatchers, we found that the mean age was significantly higher (71.2 versus 68.6 years, P<.0001); advanced life support was dispatched more frequently (84% versus 72.8%, P<.0001), dispatchers offered help and instructions to the caller more frequently, and they arrived at a facility at a shorter time (41.8 versus 49.8 minutes, P<0001). Sensitivity and specificity for the diagnosis of stroke by dispatchers were 34.61 and 99.46, respectively. CONCLUSIONS: Recognition of symptoms and diagnosis of a potential stroke by dispatchers positively affect the care of patients by decreasing the arrival time to a hospital and providing the highest level of prehospital care possible. Education is needed to increase dispatcher's detection of stroke cases.

Determinants of neurologic deterioration and stroke-free survival after spontaneous cervicocranial dissections: a multicenter study.

Patients with spontaneous cervicocranial dissection (SCCD) may experience new or recurrent ischemic events despite antiplatelet or anticoagulant therapy. Treatment with stent placement is an available option; however, the literature on patient selection is limited. Thus, identifying patients at high risk for neurologic deterioration after SCCD is of critical importance. The present study examined the rate of neurologic deterioration in medically treated patients with SCCD and evaluated demographic, clinical, and radiologic factors affecting this deterioration. We retrospectively identified consecutive patients with SCCD over a 7-year period from 3 medical institutions, and evaluated the relationships between demographic data, clinical characteristics, and angiographical findings and subsequent neurologic outcomes. Neurologic deterioration was defined as transient ischemic attack (TIA), ischemic stroke, or death occurring during hospitalization or within 1 year of diagnosis. Kaplan-Meier curves were used to determine neurologic event-free survival up to 12 months. A total of 69 patients (mean age, 47.8 ± 14 years; 45 males) with SCCD were included in the study. Eleven patients (16%) experienced in-hospital neurologic deterioration (TIA in 9, ischemic stroke in 1) or death (1 patient). An additional 8 patients developed neurologic deterioration within 1 year after discharge (TIA in 5, ischemic stroke in 2, and death in 1). The overall 1-year event-free survival rate was 72%. Women (P = .046), patients with involvement of both vertebral arteries (P = .02), and those with intracranial arterial involvement (P = .018) had significantly higher rates of neurologic deterioration. Our findings indicate that neurologic deterioration is relatively common after SCCD despite medical treatment in women, patients with bilateral vertebral artery involvement, and those with intracranial vessel involvement.

Polyol-mediated zinc oxide nanoparticles using the refluxing method as an efficient photocatalytic and antimicrobial agent.

Nanomaterials have attracted more curiosity recently because of their wide-ranging application in environmental remediation and electronic devices. The current study focuses on zinc oxide nanoparticles' (ZnO NPs) simple production, characterization, and applications in several fields, including medicinal and photocatalytic degradation of dyes. The non-aqueous-based reflux method is helpful for ZnO NP synthesis; the procedure involves refluxing zinc acetate dihydrate precursor in ethylene glycol for 3 hours in the absence of sodium acetate, in which the refluxing rate and the cooling rate are optimized to get the desired phase, and the unique morphology of polyol-mediated ZnO NPs; it has been achieved using the capping agent TBAB (tetra-butyl ammonium bromide) and precursor zinc acetate dihydrate. UV-Vis, FTIR, XRD, and FESEM structurally characterized polyol-mediated ZnO-NPs. The results show that the material is pure and broadly aggregated into spherical nanoparticles with an average particle size of 18.09 nm. According to XRD analysis, heat annealing made the crystallites more prominent and favored a monocrystalline state. These results and the low cost of making polyol-mediated ZnO NPs demonstrate photocatalytic and antimicrobial properties.

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays a role in metabolic and CNS disorders. The modeling-supported design, synthesis and multi-parameter optimization (biological activity, solubility, metabolic stability, hERG) of novel quinazoline derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified. Clusters of refined hMCHR1 homology models derived from the X-ray structure of the ß2-adrenergic receptor, including extracellular loops, were developed and used to guide the design.

Design and optimization of quinazoline derivatives as melanin concentrating hormone receptor 1 (MCHR1) antagonists: part 2.

Melanin concentrating hormone receptor 1 (MCHR1) antagonists have potential for the treatment of obesity and several CNS disorders. In the preceding article, we have described a novel series of quinazolines as MCHR1 antagonists and demonstrated in vivo proof of principle with an early lead. Herein we describe the detailed SAR and SPR studies to identify an optimized lead candidate having good efficacy in a sub-chronic DIO model with a good cardiovascular safety window.

Novel pyrazole-3-carboxamide derivatives as cannabinoid-1 (CB1) antagonists: journey from non-polar to polar amides.

The synthesis and biological evaluation of novel pyrazole-3-carboxamide derivatives as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced. In general, a range of modifications were well tolerated. Several molecules with high polar surface area were also identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is exemplified with a lead compound from this series.

Structure-activity relationship studies of novel pyrazole and imidazole carboxamides as cannabinoid-1 (CB1) antagonists.

The synthesis and biological evaluation of novel pyrazole and imidazole carboxamides as CB1 antagonists are described. As a part of eastern amide SAR, various chemically diverse motifs were introduced on rimonabant template. The central pyrazole core was also replaced with its conformationally constrained motif and imidazole moieties. In general, a range of modifications were well tolerated. Several molecules with low- and sub-nanomolar potencies were identified as potent CB1 receptor antagonists. The in vivo proof of principle for weight loss is demonstrated with a lead compound in DIO mice model.

Mechanisms of statin treatment in cerebral vasospasm.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors, commonly known as statins, are widely used clinically for their lipid lowering properties. Recent experimental evidence shows that statins are also effective in ameliorating cerebral vasospasm, which occurs as sequelae of subarachnoid hemorrhage. This literature review focuses on the literature-based putative mechanisms involved in statin mediated attenuation of cerebral vasospasm, such as eNOS, vascular inflammation, apoptosis, especially the phosphatidylinositol 3-kinase/Akt (PI3K/Akt) pathway from our experimental study.

Immunological response in early brain injury after SAH.

This study summarized the role of inflammation in the early brain injury after subarachnoid hemorrhage. Elevation of cytokines, activation of MMPs and phosphorylation of MAPK contributes to neuronal apoptosis and brain edema. Anti-inflammation may be potential strategy for the prevention and suppression of early brain injury after subarachnoid hemorrhage.

Capsaicin pre-treatment provides neurovascular protection against neonatal hypoxic-ischemic brain injury in rats.

Capsaicin, a transient receptor potential vanilloid 1 (TRPV1) agonist, has recently been shown to provide neuroprotection against brain injury in experimental adult models of cerebral ischemia. Accordingly, in this study, we investigated the way in which capsaicin-mediated TRPV1 modulation could attenuate damage in an experimental hypoxic-ischemic (HI) neonatal brain injury model. The Rice-Vannucci method was used in 10-day-old rat pups by performing unilateral carotid artery ligation followed by 2 h of hypoxia (8% O2 at 37°C). Capsaicin was administered intraperitoneally (0.2 mg/kg or 2.0 mg/kg) at 3 h pre-HI or 1 h post-HI. Post assessment included measurement of infarction volume at 24 and 72 h in addition to an assessment of the vascular dynamics of the middle cerebral artery (MCA) at 6 h post-HI. The results indicated that pre-treatment with capsaicin reduced infarction volume significantly with either low-dose or high-dose treatment. Pre-treatment also improved myogenic tone and decreased apoptotic changes in the distal MCA. We concluded that capsaicin pre-treatment may provide neurovascular protection against neonatal HI.

Granulocyte colony-stimulating factor treatment provides neuroprotection in surgically induced brain injured mice.

Surgically induced brain injury (SBI) is a common concern after a neurosurgical procedure. Current treatments aimed at reducing the postoperative sequela are limited. Granulocyte-colony stimulating factor (G-CSF), a hematopoietic growth factor involved in the inflammatory process, has been shown in various animal models to be neuroprotective. Consequently, in this study, we investigated the use of G-CSF as a treatment modality to reduce cell death and brain edema, while improving neurobehavioral deficits following an SBI in mice. Eleven-week-old C57 black mice (n=76) were randomly placed into four groups: sham (n=19), SBI (n=21), SBI with G-CSF pre-treatment (n=15) and SBI with G-CSF pre/post-treatment (n=21). Treated groups received a single dose of G-CSF intraperitoneally at 24, 12 and 1 h pre-surgery and/or 6 and 12 h post-surgery. Postoperative assessment occurred at 24 h and included neurobehavioral testing and measurement for both cell death and brain edema. Results indicated that pre-treatment with G-CSF reduced both cell death and brain edema, while post-treatment reduced neurobehavioral deficits. This study implies that the morphological changes in the brain are effected by pre-treatment; however, in order to activate and/or amplify targets involved in the recovery process, more dosing regimens may be needed.

Prostaglandin E2 EP1 receptor inhibition fails to provide neuroprotection in surgically induced brain-injured mice.

Recent trials have shown that the prostaglandin E2 EP1 receptor is responsible for NMDA excitotoxicity in the brain after injury. Consequently, in this study, we investigated the use of SC-51089, a selective prostaglandin E2 EP1 receptor antagonist, as a pre-treatment modality to decrease cell death, reduce brain edema, and improve neurobehavioral function after surgically induced brain injury (SBI) in mice. Eleven-week-old C57 black mice (n=82) were randomly assigned to four groups: sham (n=31), SBI (n=27), SBI treated with SC51089 at 10 µg/kg (n=7), and SBI treated with SC51089 at 100 µg/kg (n=17). Treated groups received a single dose of SC51089 intrapertioneally at 12 and 1 h pre-surgery. SBI was performed by resecting the right frontal lobe using a frontal craniotomy. Postoperative assessment occurred at 24 and 72 h, and included neurobehavioral testing and measurement of brain water content and cell death. Results indicated that neither low- nor high-dose EP1 receptor inhibition protected against the SBI-related effects on brain edema formation or cell death. There was however a significant improvement in neurobehavioral function 24 h post-SBI with both dosing regimens. Further studies will be needed to assess the potential therapeutic role of EP1 receptor targeting in SBI.

Cyclooxygenase-2 inhibition provides lasting protection against neonatal hypoxic-ischemic brain injury.

OBJECTIVE: To investigate whether inhibition of cyclooxygenase-2, a critical component of the inflammatory pathway, is neuroprotective in a neonatal rat model of cerebral hypoxia-ischemia. The development of brain inflammation largely contributes to neonatal brain injury that may lead to a lifetime of neurologic deficits. DESIGN: Laboratory investigation. SETTING: University research laboratory. SUBJECTS: Postnatal day ten Sprague-Dawley rats. INTERVENTIONS: Neonatal hypoxia-ischemia was induced by ligation of the right common carotid artery followed by 2 hrs of hypoxia (8% oxygen). The pups in treatment groups were administered 10 mg/kg (low dose) or 30 mg/kg (high dose) of a known selective cyclooxygenase-2 inhibitor (NS398). Animals were euthanized at three time points: 72 hrs, 2 wks, or 6 wks. Inflammation outcomes were assessed at 72 hrs; brain damage was assessed at 2 wks and 6 wks along with other organs (heart, spleen). Detailed neurobehavioral examination was performed at 6 wks. MEASUREMENTS AND MAIN RESULTS: Pharmacologic inhibition of cyclooxygenase-2 markedly increased survivability within the first 72 hrs compared with untreated rats (100% vs. 72%). Low- and high-dose NS398 significantly attenuated the loss of brain and body weights observed after hypoxia-ischemia. Neurobehavioral outcomes were significantly improved in some parameters with low-dose treatment, whereas high-dose treatment consistently improved all neurologic deficits. Immunohistochemical results showed a marked decrease in macrophage, microglial, and neutrophil abundance in ipsilateral hemisphere of the NS398-treated group along with a reduction in interleukin-6 expression. CONCLUSIONS: Selective cyclooxygenase-2 inhibition protected neonatal rats against death, progression of brain injury, growth retardation, and neurobehavioral deficits after a hypoxic-ischemic insult.

Discovery of novel, orally available benzimidazoles as melanin concentrating hormone receptor 1 (MCHR1) antagonists.

Melanin concentrating hormone (MCH) is an important mediator of energy homeostasis and plays role in several disorders such as obesity, stress, depression and anxiety. The synthesis and biological evaluation of novel benzimidazole derivatives as MCHR1 antagonists are described. The in vivo proof of principle for weight loss with a lead compound from this series is exemplified.

Reduced matrix metalloproteinase-9 activity and cell death after global ischemia in the brain preconditioned with hyperbaric oxygen.

Matrix metalloproteinase-9 (MMP-9) plays a deleterious role in cell death after global cerebral ischemia. Preconditioning with hyperbaric oxygen (HBO-PC) reduces neuronal damage in the post-ischemic brain; however, its effect on ischemia-induced increase in MMP-9 activity and expression remains unexplored.We investigated effects of HBO-PC on alterations in MMP-9 activity/tissue expression accompanying neuronal death after transient global cerebral ischemia.Male SD rats (300-350 g), were allocated either to non-ischemic (naive control or sham-operated) or ischemic (four-vessel occlusion, 4VO; 10 min) groups that were HBO-preconditioned (2.5 ATA, 1 h daily for 5 days; the last session 24 h before ischemia) or not. Neurobehavioral deficits were assessed prior to collection of brain tissue for gel zymography (MMP-9) and histology (MMP-9 immunofluorescence, TUNEL) at 0 (without ischemia), 6, 24, 72 h and 7 days after 4VO.Both, MMP-9 levels and cell death increased in the hippocampus at 72 h after 4VO. HBO-PC suppressed postischemic MMP-9 activity and CA1 cell damage, and improved functional performance. The increase in MMP-9 immunoreactivity in the brain was also detected after HBO-PC alone. HBO-PC suppresses MMP-9 activity and expression in the postischemic hippocampus. The mechanism of HBO preconditioning may depend on the induction of MMP-9 in the preischemic phase and may be in part mediated by exhaustion of MMP-9 stores in cerebral tissues.

Hyperbaric oxygen preconditioning reduces postoperative brain edema and improves neurological outcomes after surgical brain injury.

The present study was designed to examine if hyperbaric oxygen preconditioning (HBO-PC) is neuroprotective in a mouse model of surgical brain injury (SBI). C57BL mice were administered 100% oxygen for 1 h at 2.5 ATA for 5 consecutive days and subjected to SBI on the following day. The HBO-PC + SBI animals were compared to sham and normoxia + SBI groups for brain water content in different brain regions at 24 and 72 h after surgery. Blood-brain barrier (BBB) permeability was evaluated using Evan's blue dye extravasation at 24 h. Neurological assessment of the animals was done by a blinded observer at 24 and 72 h. The results showed that brain water content was significantly increased in the right (ipsilateral) frontal lobe surrounding the site of resection. This was attenuated by HBO-PC at 24 and 72 h. However, HBO-PC did not have any effect on the increased BBB permeability observed after SBI. Significant neurological deficits were observed after SBI. HBO-PC improved neurological deficits at 72 h on the 21-point sensorimotor scale and at 24 and 72 h on the wire hang and beam balance scoring. In conclusion, HBO-PC attenuates post-operative brain edema and improves neurological outcomes following SBI.