Considerable effort has been devoted to discovery of glutamate antagonists (1, 2) in recent years, due to increasing evidence linking glutamate excitotoxicity to various neurological disorders (3). Unfortunately, while known antagonists can provide neuroprotection, excessive action of these classical blocking agents can obtain undesirable side effects (1, 2). To minimize these undesirable side effects, modification of the redox modulatory sulfhydryl groups of the glutamate receptor has been suggested as a possibly superior therapeutic strategy (4). Unlike classical antagonists, that can give complete inhibition by interaction at the glutamate receptor (e.g. CGS 19755) or directly at receptor-linked, calcium ion channels (e.g. phencyclidine or MK-801) (2), inhibition via the redox modulatory sites are expected to give only partial inhibition of function and thereby limit unwanted side effects associated with excessive antagonism (4). At present S-nitrosylation of glutamate receptors by an NO ϩ donor (e.g. nitroglycerin) is the only mechanism for partially blocking receptor response in vivo that would achieve this effect by interaction with the redox modulatory sites (5, 6).Disulfiram has been used in the treatment of alcoholism for almost 50 years (7,8). It has recently been demonstrated that disulfiram exerts its anti-alcohol effect in vivo only after bioactivation to the active metabolite S-methyl-N,N-diethylthiolcarbamate sulfoxide (DETC-MeSO) 1 (9) that is a potent and selective carbamoylating agent for sulfhydryl groups (10). We now report that DETC-MeSO also partially blocks glutamate binding to synaptic membrane preparations isolated from the brains of mice, and in addition, DETC-MeSO prevents seizures induced in mice by glutamate analogs or by exposure to hyperbaric oxygen. MATERIALS AND METHODS Animals-MaleSwiss Webster mice (20 -30 g) or male SpragueDawley rats (250 -300 g) were used in the study. All experiments that employed animals were conducted in strict compliance with the National Institutes of Health guidelines on animal use and institutional regulations concerning animal experimentation. Animals were exposed to hyperbaric oxygen in a specially designed pressure chamber as described previously (11, 12). The time to first clonic-tonic seizure after bringing animals to a final pressure of 5 atmospheres of 100% oxygen or after intraperitoneal injection of convulsants was noted by criteria outlined previously (11, 12). Unless otherwise specified, the ability of DETC-MeSO to prevent seizures was tested by intraperitoneal injection of 5.2 mg/kg DETC-MeSO 1-2 h prior to bringing the animal to a final pressure of 5 atmospheres of 100% oxygen or intraperitoneal injection of N-methyl-D-aspartate (NMDA) (125 mg/kg) or L-methionine sulfoximine (MetSOX) (250 mg/kg). Evaluation of the statistics for whole animal experiments or for changes in brain glutamate binding after administration of DETC-MeSO was conducted by use of the program GraphPAD InStat from GraphPAD Software (San Diego, CA).Binding Studies-Synap...
Background and objectives:COVID-19 related inflammation, endothelial dysfunction and coagulopathy may increase the bleeding risk and lower efficacy of revascularization treatments in patients with acute ischemic stroke. We aimed to evaluate the safety and outcomes of revascularization treatments in patients with acute ischemic stroke and COVID-19.Methods:Retrospective multicenter cohort study of consecutive patients with acute ischemic stroke receiving intravenous thrombolysis (IVT) and/or endovascular treatment (EVT) between March 2020 and June 2021, tested for SARS-CoV-2 infection. With a doubly-robust model combining propensity score weighting and multivariate regression, we studied the association of COVID-19 with intracranial bleeding complications and clinical outcomes. Subgroup analyses were performed according to treatment groups (IVT-only and EVT).Results:Of a total of 15128 included patients from 105 centers, 853 (5.6%) were diagnosed with COVID-19. 5848 (38.7%) patients received IVT-only, and 9280 (61.3%) EVT (with or without IVT). Patients with COVID-19 had a higher rate of symptomatic intracerebral hemorrhage (SICH) (adjusted odds ratio [OR] 1.53; 95% CI 1.16–2.01), symptomatic subarachnoid hemorrhage (SSAH) (OR 1.80; 95% CI 1.20–2.69), SICH and/or SSAH combined (OR 1.56; 95% CI 1.23–1.99), 24-hour (OR 2.47; 95% CI 1.58–3.86) and 3-month mortality (OR 1.88; 95% CI 1.52–2.33).COVID-19 patients also had an unfavorable shift in the distribution of the modified Rankin score at 3 months (OR 1.42; 95% CI 1.26–1.60).Discussion:Patients with acute ischemic stroke and COVID-19 showed higher rates of intracranial bleeding complications and worse clinical outcomes after revascularization treatments than contemporaneous non-COVID-19 treated patients. Current available data does not allow direct conclusions to be drawn on the effectiveness of revascularization treatments in COVID-19 patients, or to establish different treatment recommendations in this subgroup of patients with ischemic stroke. Our findings can be taken into consideration for treatment decisions, patient monitoring and establishing prognosis.
Background and Objectives:Declines in stroke admission, intravenous thrombolysis, and mechanical thrombectomy volumes were reported during the first wave of the COVID-19 pandemic. There is a paucity of data on the longer-term effect of the pandemic on stroke volumes over the course of a year and through the second wave of the pandemic. We sought to measure the impact of the COVID-19 pandemic on the volumes of stroke admissions, intracranial hemorrhage (ICH), intravenous thrombolysis (IVT), and mechanical thrombectomy over a one-year period at the onset of the pandemic (March 1, 2020, to February 28, 2021) compared with the immediately preceding year (March 1, 2019, to February 29, 2020).Methods:We conducted a longitudinal retrospective study across 6 continents, 56 countries, and 275 stroke centers. We collected volume data for COVID-19 admissions and 4 stroke metrics: ischemic stroke admissions, ICH admissions, intravenous thrombolysis treatments, and mechanical thrombectomy procedures. Diagnoses were identified by their ICD-10 codes or classifications in stroke databases.Results:There were 148,895 stroke admissions in the one-year immediately before compared to 138,453 admissions during the one-year pandemic, representing a 7% decline (95% confidence interval [95% CI 7.1, 6.9]; p<0.0001). ICH volumes declined from 29,585 to 28,156 (4.8%, [5.1, 4.6]; p<0.0001) and IVT volume from 24,584 to 23,077 (6.1%, [6.4, 5.8]; p<0.0001). Larger declines were observed at high volume compared to low volume centers (all p<0.0001). There was no significant change in mechanical thrombectomy volumes (0.7%, [0.6,0.9]; p=0.49). Stroke was diagnosed in 1.3% [1.31,1.38] of 406,792 COVID-19 hospitalizations. SARS-CoV-2 infection was present in 2.9% ([2.82,2.97], 5,656/195,539) of all stroke hospitalizations.Discussion:There was a global decline and shift to lower volume centers of stroke admission volumes, ICH volumes, and IVT volumes during the 1st year of the COVID-19 pandemic compared to the prior year. Mechanical thrombectomy volumes were preserved. These results suggest preservation in the stroke care of higher severity of disease through the first pandemic year.Trial Registration Information:This study is registered underNCT04934020.
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