Comparison of Balloon Guide Catheters and Standard Guide Catheters for Acute Ischemic Stroke: An Updated Systematic Review and Meta-analysis.

OBJECTIVE: The objective of this study was to update our 2021 systematic review and meta-analysis which reported that balloon guide catheters (BGC) are associated with superior clinical and angiographic outcomes compared to standard guide catheters for treatment of acute ischemic stroke. METHODS: We conducted a systematic review of 7 electronic databases to identify literature published between January 2010 and September 2023 reporting BGC versus non-BGC approaches. Primary outcomes were final modified thrombolysis in cerebral infarction (mTICI) ≥2b, first-pass effect (mTICI ≥2c on first pass), and modified Rankin scale 0-2 at 90 days. The risk of bias was assessed using the Newcastle Ottawa Scale. A separate random effects model was fitted for each outcome. Subgroup analyses by first-line approach were conducted. RESULTS: Twenty-four studies comprising 8583 patients were included (4948 BGC; 3635 non-BGC; 1561 BGC + Stent-retriever; 1297 non-BGC + Stent-retriever). Nine studies had low risk of bias, 3 were moderate risk, and 12 were high risk. Patients treated with BGCs had higher odds of achieving mTICI 2b/3, first-pass effect mTICI 2c/3, and modified Rankin scale 0-2 at 90 days (P < 0.001). The number of patients needed to treat in order to achieve one additional successful recanalization is 17. BGC + Stent-retriever was associated with higher odds of mTICI≥2b, 90-day modified Rankin scale 0-2, and reduced odds of 90-day mortality compared to non-BGC + Stent-retrievers. The main limitation was the absence of randomized trials. CONCLUSIONS: These findings corroborate our previous results suggesting that MT using BGCs is associated with better safety and effectiveness outcomes for acute ischemic stroke, especially BGC + Stent-retrievers.

MASTRO I: Meta-Analysis and Systematic Review of thrombectomy stent retriever outcomes: comparing functional, safety and recanalization outcomes between EmboTrap, Solitaire and Trevo in acute ischemic stroke.

Aim: Stent-retriever (SR) thrombectomy has demonstrated superior outcomes in patients with acute ischemic stroke compared with medical management alone, but differences among SRs remain unexplored. We conducted a Systematic Review/Meta-Analysis to compare outcomes between three SRs: EmboTrap®, Solitaire™, and Trevo®. Methods: We conducted a PRISMA-compliant Systematic Review among English-language studies published after 2014 in PubMed/MEDLINE that reported SRs in ≥25 patients. Functional and safety outcomes included 90-day modified Rankin scale (mRS 0-2), mortality, symptomatic intracranial hemorrhage (sICH), and embolization to new territory (ENT). Recanalization outcomes included modified thrombolysis in cerebral infarction (mTICI) and first-pass recanalization (FPR). We used a random effects Meta-Analysis to compare outcomes; subgroup and outlier-influencer analysis were performed to explore heterogeneity. Results: Fifty-one articles comprising 9,804 patients were included. EmboTrap had statistically significantly higher rates of mRS 0-2 (57.4%) compared with Trevo (50.0%, p = 0.013) and Solitaire (45.3%, p < 0.001). Compared with Solitaire (20.4%), EmboTrap (11.2%, p < 0.001) and Trevo (14.5%, p = 0.018) had statistically significantly lower mortality. Compared with Solitaire (7.7%), EmboTrap (3.9%, p = 0.028) and Trevo (4.6%, p = 0.049) had statistically significantly lower rates of sICH. There were no significant differences in ENT rates across all three devices (6.0% for EmboTrap, 5.3% for Trevo, and 7.7% for Solitaire, p = 0.518). EmboTrap had numerically higher rates of recanalization; however, no statistically significant differences were found. Conclusion: The results of our Systematic Review/Meta-Analysis suggest that EmboTrap may be associated with significantly improved functional outcomes compared with Solitaire and Trevo. EmboTrap and Trevo may be associated with significantly lower rates of sICH and mortality compared with Solitaire. No significant differences in recanalization and ENT rates were found. These conclusions are tempered by limitations of the analysis including variations in thrombectomy techniques in the field, highlighting the need for multi-arm RCT studies comparing different SR devices to confirm our findings.

Efficacy of antiviral therapies for COVID-19: a systematic review of randomized controlled trials.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to pose a significant threat to public health worldwide. The purpose of this study was to review current evidence obtained from randomized clinical trials on the efficacy of antivirals for COVID-19 treatment. METHODS: A systematic literature search was performed using PubMed to identify randomized controlled trials published up to September 4, 2021 that examined the efficacy of antivirals for COVID-19 treatment. Studies that were not randomized controlled trials or that did not include treatment of COVID-19 with approved antivirals were excluded. Risk of bias was assessed using the Scottish Intercollegiate Guidelines Network (SIGN) method. Due to study heterogeneity, inferential statistics were not performed and data were expressed as descriptive statistics. RESULTS: Of the 2,284 articles retrieved, 31 (12,440 patients) articles were included. Overall, antivirals were more effective when administered early in the disease course. No antiviral treatment demonstrated efficacy at reducing COVID-19 mortality. Sofosbuvir/daclatasvir results suggested clinical improvement, although statistical power was low. Remdesivir exhibited efficacy in reducing time to recovery, but results were inconsistent across trials. CONCLUSIONS: Although select antivirals have exhibited efficacy to improve clinical outcomes in COVID-19 patients, none demonstrated efficacy in reducing mortality. Larger RCTs are needed to conclusively establish efficacy.

Characteristics, treatment, and outcomes of Myasthenia Gravis in COVID-19 patients: A systematic review.

OBJECTIVE: Recent studies suggest that the clinical course and outcomes of patients with coronavirus disease 2019 (COVID-19) and myasthenia gravis (MG) are highly variable. We performed a systematic review of the relevant literature with a key aim to assess the outcomes of invasive ventilation, mortality, and hospital length of stay (HLoS) for patients presenting with MG and COVID-19. METHODS: We searched the PubMed, Scopus, Web of Science, and MedRxiv databases for original articles that reported patients with MG and COVID-19. We included all clinical studies that reported MG in patients with confirmed COVID-19 cases via RT-PCR tests. We collected data on patient background characteristics, symptoms, time between MG and COVID-19 diagnosis, MG and COVID-19 treatments, HLoS, and mortality at last available follow-up. We reported summary statistics as counts and percentages or mean±SD. When necessary, inverse variance weighting was used to aggregate patient-level data and summary statistics. RESULTS: Nineteen studies with 152 patients (mean age 54.4 ± 12.7 years; 79/152 [52.0%] female) were included. Hypertension (62/141, 44.0%) and diabetes (30/141, 21.3%) were the most common comorbidities. The mean time between the diagnosis of MG and COVID-19 was7.0 ± 6.3 years. Diagnosis of COVID-19 was confirmed in all patients via RT-PCR tests. Fever (40/59, 67.8%) and ptosis (9/55, 16.4%) were the most frequent COVID-19 and MG symptoms, respectively. Azithromycin and ceftriaxone were the most common COVID-19 treatments, while prednisone and intravenous immunoglobulin were the most common MG treatments. Invasive ventilation treatment was required for 25/59 (42.4%) of patients. The mean HLoS was 18.2 ± 9.9 days. The mortality rate was 18/152 (11.8%). CONCLUSION: This report provides an overview of the characteristics, treatment, and outcomes of MG in COVID-19 patients. Although COVID-19 may exaggerate the neurological symptoms and worsens the outcome in MG patients, we did not find enough evidence to support this notion. Further studies with larger numbers of patients with MG and COVID-19 are needed to better assess the clinical outcomes in these patients.

Endoluminal flow diverters in the treatment of sidewall and bifurcation aneurysm: A systematic review and meta-analysis of complications and angiographic outcomes.

BACKGROUND AND AIM: The use of endoluminal flow diversion in bifurcation aneurysms has been questioned due to the potential for complications and lower occlusion rates. In this study we assessed outcomes of endovascular treatment of intracranial sidewall and bifurcation aneurysms with flow diverters. METHODS: In July 2020, a literature search for all studies utilizing endoluminal flow diverter treatment for sidewall or bifurcation aneurysms was performed. Data were collected from studies that met our inclusion/exclusion criteria by two independent reviewers and confirmed by a third reviewer. Using random-effects meta-analysis the target outcomes including overall complications (hematoma, ischemic events, minor ischemic stroke, aneurysm rupture, side vessel occlusion, stenosis, thrombosis, transient ischemic stroke, and other complications), perioperative complications, and follow-up (long-term) aneurysm occlusion were intestigated. RESULTS: Overall, we included 35 studies with 1084 patients with 1208 aneurysms. Of these aneurysms, 654 (54.14%) and 554 (45.86%) were classified as sidewall and bifurcation aneurysm, respectively, based on aneurysm location. Sidewall aneurysms had a similar total complication rate (R) of 27.12% (95% CI, 16.56%-41.09%), compared with bifurcation aneurysms (R, 20.40%, 95% CI, 13.24%-30.08%) (p = 0.3527). Follow-up angiographic outcome showed comparable complete occlusion rates for sidewall aneurysms (R 69.49%; 95%CI, 62.41%-75.75%) and bifurcation aneurysms (R 73.99%; 95% CI, 65.05%-81.31%; p = 0.4328). CONCLUSIONS: This meta-analysis of sidewall and bifurcation aneurysms treated with endoluminal flow diverters demonstrated no significant differences in complications or occlusion rates. These data provide new information that can be used as a benchmark for comparison with emerging devices for the treatment of bifurcation aneurysms.

Procedural complications in patients undergoing microsurgical treatment of unruptured intracranial aneurysms: a single-center experience with 1923 aneurysms.

BACKGROUND: With the growing use of endovascular therapy (EVT) to manage unruptured intracranial aneurysms (IAs), detailed information regarding periprocedural complication rates of microsurgical clipping and EVT becomes increasingly important in determining the optimal treatment for individual cases. We report the complication rates associated with open microsurgery in a large series of unruptured IAs and highlight the importance of maintaining surgical skill in the EVT era. METHODS: We reviewed all cases of unruptured IAs treated with open microsurgery by a single neurosurgeon between July 1997 and June 2019. We analyzed surgical complications, deaths, and patient-reported outcomes. RESULTS: A total of 1923 unruptured IAs in 1750 patients (mean age 44 [range: 6-84], 62.0% [1085/1750] female) were treated surgically during the study period. Of the aneurysms treated, 84.9% (1632/1923) were small, 11.1% (213/1923) were large, and 4.1% (78/1923) were giant. Aneurysm locations included the middle cerebral artery (44.2% [850/1923]), internal carotid artery (29.1% [560/1923]), anterior cerebral artery (21.0% [404/1923]), and vertebrobasilar system (5.7% [109/1923]). The overall mortality rate was 0.3% (5/1750). Surgical complications occurred in 7.4% (129/1750) of patients, but only 0.4% (7/1750) experienced permanent disability. The majority of patients were able to return to their preoperative lifestyles with no modifications (95.9% [1678/1750]). CONCLUSIONS: At a high-volume, multidisciplinary center, open microsurgery in carefully selected patients with unruptured IAs yields favorable clinical outcomes with low complication rates. The improvement of EVT techniques and the ability to refer cases for EVT when a high complication rate with open microsurgery was expected have contributed to an overall decrease in surgical complication rates. These results may serve as a useful point of reference for physicians involved in treatment decision-making for patients with unruptured IAs.

Traumatic epidural hematoma treated with endovascular coil embolization.

BACKGROUND: Traumatic cerebrovascular injury may result in epidural hematoma (EDH) from laceration of the middle meningeal artery (MMA), which is a potentially life-threatening emergency. Treatment ranges from surgical evacuation to conservative management based on a variety of clinical and imaging factors. CASE DESCRIPTION: A 14-year-old male presented to our institution after falling from his bicycle with traumatic subarachnoid hemorrhage and a right frontotemporal EDH. The patient did not meet criteria for surgical evacuation and endovascular embolization of the right MMA was performed. Rapid resolution of the EDH was observed. CONCLUSION: This case corroborates the sparse existing literature for the potential role of endovascular embolization to treat acute EDH in carefully selected patients who do not meet or have borderline indications for surgical management.

Comparison of Balloon Guide Catheters and Standard Guide Catheters for Acute Ischemic Stroke: A Systematic Review and Meta-Analysis.

BACKGROUND: Balloon guide catheters (BGCs) are designed to induce flow arrest during mechanical thrombectomy procedures for acute ischemic stroke due to large-vessel occlusion and have been associated with improved clinical and angiographic outcomes. We conducted a systematic review and meta-analysis evaluating the relative technical and clinical outcomes associated with BGC versus non-BGC approaches. METHODS: A systematic review of clinical literature using the PubMed database was undertaken to identify multiarm studies published between 2010 and 2021 reporting the use of BGC versus non-BGC approaches for stroke treatment. Data collected included complete recanalization (thrombolysis in cerebral infarction, TICI), first-pass effect TICI 3, puncture-to recanalization time, number of endovascular attempts, distal embolization, symptomatic intracerebral hemorrhage, 90-day modified Rankin Scale score 0-2, and 90-day mortality. Subgroup analyses assessed the impact of treatment device (stent-retrievers, contact aspiration, combination therapy, and not specified/other). A random effects model was fit for each outcome measure. RESULTS: Fifteen studies were included. Compared with non-BGC approaches, patients treated with BGCs had greater odds of TICI 3 (odds ratio [OR] 1.57; 95% confidence interval [95% CI] 1.08-2.29) and first-pass effect TICI 3 (OR 3.63; 95% CI 2.34-5.62), reduced puncture-to-revascularization time (mean difference -7.8; 95% CI -13.3 to -2.2), fewer endovascular attempts (mean difference -0.47; 95% CI -0.68 to -0.26), reduced odds of distal emboli (OR 0.34; 95% CI 0.17-0.71) and symptomatic intracerebral hemorrhage (OR 0.66; 95% CI 0.51-0.86), greater odds of 90-day modified Rankin Scale score 0-2 (OR 1.51; 95% CI 1.27-1.79), and reduced odds of mortality (OR 0.69; 95% CI 0.57-0.82). CONCLUSIONS: BGCs yield superior technical and clinical outcomes while reducing patient complications.

Transport of patients with giant disfiguring cranial tumors from Africa to the US for collaborative multidisciplinary treatment.

BACKGROUND: Giant disfiguring cranial tumors are exceptionally rare and develop over the course of many years, typically in patients who lack access to medical care. Here, we describe four patients who were flown to our center for treatment by a multidisciplinary surgical team, who had previously been turned down for treatment at multiple international centers in Africa, Europe, and the United States (US) due to complexity and financial concerns. The case series describes socioeconomic implications and the feasibility of offering such care to patients from outside the US. CASE DESCRIPTIONS: Four patients with giant skull disfiguring tumors were flown internationally and treated by a surgical team consisting of a complex cranial neurosurgeon, a craniofacial reconstructive plastic surgeon, and an oculoplastic surgeon. All patients underwent aggressive surgical therapy with the aim of complete tumor removal and simultaneous cranial reconstruction. A patient with osteogenic sarcoma underwent two additional resections in 3 years, with delayed reconstruction. They returned home but ultimately succumbed to the disease. A patient with ossifying fibroma required two follow-up procedures for cosmetic reconstruction and sought asylum in the US, where they remain today. Two additional patients, one with a giant plexiform neurofibroma and one with a cerebellopontine angle meningioma, achieved good results and returned to Africa 1 month and 3 weeks after surgery, respectively. CONCLUSION: Resection of giant disfiguring cranial tumors and reconstruction of the impacted region requires an experienced multidisciplinary team. These cases can be managed by transporting such patients from areas without access to medical care to specialized centers able to provide excellent care.

Outcomes of acute respiratory distress syndrome in COVID-19 patients compared to the general population: a systematic review and meta-analysis.

INTRODUCTION: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) often leads to mortality. Outcomes of patients with COVID-19-related ARDS compared to ARDS unrelated to COVID-19 is not well characterized. AREAS COVERED: We performed a systematic review of PubMed, Scopus, and MedRxiv 11/1/2019 to 3/1/2021, including studies comparing outcomes in COVID-19-related ARDS (COVID-19 group) and ARDS unrelated to COVID-19 (ARDS group). Outcomes investigated were duration of mechanical ventilation-free days, intensive care unit (ICU) length-of-stay (LOS), hospital LOS, and mortality. Random effects models were fit for each outcome measure. Effect sizes were reported as pooled median differences of medians (MDMs), mean differences (MDs), or odds ratios (ORs). EXPERT OPINION: Ten studies with 2,281 patients met inclusion criteria (COVID-19: 861 [37.7%], ARDS: 1420 [62.3%]). There were no significant differences between the COVID-19 and ARDS groups for median number of mechanical ventilator-free days (MDM: -7.0 [95% CI: -14.8; 0.7], p = 0.075), ICU LOS (MD: 3.1 [95% CI: -5.9; 12.1], p = 0.501), hospital LOS (MD: 2.5 [95% CI: -5.6; 10.7], p = 0.542), or all-cause mortality (OR: 1.25 [95% CI: 0.78; 1.99], p = 0.361). Compared to the general ARDS population, results did not suggest worse outcomes in COVID-19-related ARDS.

Enhancement of alcohol aversion by the nicotinic acetylcholine receptor drug sazetidine-A.

The prevalence of alcohol use disorders (AUDs) has steadily increased in the United States over the last 30 years. Alcohol acts on multiple receptor systems including the nicotinic acetylcholine receptors (nAChRs), which are known to mediate alcohol consumption and reward. We previously reported that the preclinical drug sazetidine-A, a nAChR agonist and desensitizer, reduces alcohol consumption without affecting nicotine consumption in C57BL/6J mice. Here, we found that sazetidine-A enhances the expression of alcohol aversion without affecting the expression or acquisition of conditioned alcohol reward in C57BL/6J mice. Microinjection of sazetidine-A into the ventral midbrain targeting the ventral tegmental area (VTA) reduced binge alcohol consumption, implicating this region in mediating the effects of sazetidine-A. Furthermore, the sazetidine-A-induced reduction in alcohol consumption was mediated by non-α4 containing nAChRs, as sazetidine-A reduced binge alcohol consumption in both α4 knock-out and wild-type mice. Finally, we found that in mice pretreated with sazetidine-A, alcohol induced Fos transcript in Th-, but not Gad2-expressing neurons in the VTA as measured by increased Fos transcript expression. In summary, we find that sazetidine-A enhances the expression of alcohol aversion, which may underlie the reduction in alcohol consumption induced by sazetidine-A. Elucidating the identity of non-α4 nAChRs in alcohol aversion mechanisms will provide a better understanding the complex role of nAChRs in alcohol addiction and potentially reveal novel drug targets to treat AUDs.

Safety and efficacy of (+)-epicatechin in subjects with Friedreich's ataxia: A phase II, open-label, prospective study.

BACKGROUND: (+)-Epicatechin (EPI) induces mitochondrial biogenesis and antioxidant metabolism in muscle fibers and neurons. We aimed to evaluate safety and efficacy of (+)-EPI in pediatric subjects with Friedreich's ataxia (FRDA). METHODS: This was a phase II, open-label, baseline-controlled single-center trial including 10 participants ages 10 to 22 with confirmed FA diagnosis. (+)-EPI was administered orally at 75 mg/d for 24 weeks, with escalation to 150 mg/d at 12 weeks for subjects not showing improvement of neuromuscular, neurological or cardiac endpoints. Neurological endpoints were change from baseline in Friedreich's Ataxia Rating Scale (FARS) and 8-m timed walk. Cardiac endpoints were changes from baseline in left ventricular (LV) structure and function by cardiac magnetic resonance imaging (MRI) and echocardiogram, changes in cardiac electrophysiology, and changes in biomarkers for heart failure and hypertrophy. RESULTS: Mean FARS/modified (m)FARS scores showed nonstatistically significant improvement by both group and individual analysis. FARS/mFARS scores improved in 5/9 subjects (56%), 8-m walk in 3/9 (33%), 9-peg hole test in 6/10 (60%). LV mass index by cardiac MRI was significantly reduced at 12 weeks (P = .045), and was improved in 7/10 (70%) subjects at 24 weeks. Mean LV ejection fraction was increased at 24 weeks (P = .008) compared to baseline. Mean maximal septal thickness by echocardiography was increased at 24 weeks (P = .031). There were no serious adverse events. CONCLUSION: (+)-EPI was well tolerated over 24 weeks at up to 150 mg/d. Improvement was observed in cardiac structure and function in subset of subjects with FRDA without statistically significant improvement in primary neurological outcomes. SYNOPSIS: A (+)-epicatechin showed improvement of cardiac function, nonsignificant reduction of FARS/mFARS scores, and sustained significant upregulation of muscle-regeneration biomarker follistatin.

Efficacy and safety of lopinavir/ritonavir in the treatment of COVID-19: A systematic review.

Objectives: To systematically review the clinical literature reporting the use of Lopinavir/ritonavir (LPV/r) for the treatment of patients with Cornonavirus disease 19 (COVID-19) to assess the efficacy of LPV/r for the treatment of COVID-19.Methods: The authors systematically searched PubMed and MedRxiv databases for studies describing treatment of COVID-19 patients using LPV/r compared to other therapies. Articles were excluded if they were case reports, opinion editorials, preclinical studies, single-armed studies, not written in English, not relevant to the topic, or published before May 2020. The included outcomes were viral clearance as measured by reverse-transcription polymerase chain reaction (RT-PCR) negativity and/or improvement on chest computed tomography (CT), mortality, and adverse events.Results: Among 858 total studies, 16 studies met the inclusion criteria and were included in the qualitative review. These studies consisted of 3 randomized control trials, 3 open-label trials, and 10 observational studies. Most of these studies did not report positive clinical outcomes with LPV/r treatment.Conclusion: The systematic review revealed insufficient evidence of effectiveness and clinical benefit of LPV/r in the treatment of COVID-19 patients. Specifically, LPV/r does not appear to improve clinical outcome, mortality, time to RT-PCR negativity, or chest CT clearance in patients with COVID-19.

Microsurgical Treatment of Unruptured Anterior Communicating Artery Aneurysms: Approaches and Outcomes in a Large Contemporary Series and Review of the Literature.

BACKGROUND: With advances in endovascular techniques, the relative roles of microsurgery and endovascular therapy in the management of intracranial aneurysms have become less clear, and data regarding treatment-specific outcomes are increasingly important. OBJECTIVE: To describe our experience with microsurgery in a large series of unruptured anterior communicating artery aneurysms (ACOMMAAs) and detail our treatment decision-making process based on individual aneurysm morphology. METHODS: We retrospectively reviewed unruptured ACOMMAAs treated microsurgically at our center between 1997 and 2018, recording aneurysm size, surgical approach, occlusion rates, neurological outcomes, and complications. RESULTS: We treated 300 unruptured ACOMMAAs in 300 patients, mean age 49 yr, 180 (60.0%) female, including 245 (81.7%) small, 50 (16.7%) large, and 5 (1.7%) giant aneurysms. Most underwent a pterional approach (253, 84.3%), with orbitozygomatic or anterior interhemispheric approaches in 35 (11.7%) and 12 (4%), respectively. Greater than 95% occlusion was achieved in 284 (94.7%), 90% to 95% occlusion in 13 (4.3%), and 3 (1.0%) underwent wrapping. Serious complications occurred in 3 patients (1.0%) resulting in 2 deaths (0.7%), and minor complications in 12 (4.0%). At final follow-up, good neurological outcome was observed in 297 (99.0%) patients. CONCLUSION: Given clinical equipoise regarding optimal treatment of unruptured ACOMMAAs, this work provides a benchmark for achievable microsurgical outcomes. Future surgical/endovascular studies should separate results of ruptured and unruptured lesions and describe aneurysm morphology to allow for better comparison of outcomes between treatments. We suggest that open microsurgery represents an important option for select, morphologically complex ACOMMAAs, and that a multidisciplinary approach offers optimal patient outcomes.

The Neurotoxin DSP-4 Induces Hyperalgesia in Rats that is Accompanied by Spinal Oxidative Stress and Cytokine Production.

Central neuropathic pain (CNP) a significant problem for many people, is not well-understood and difficult to manage. Dysfunction of the central noradrenergic system originating in the locus coeruleus (LC) may be a causative factor in the development of CNP. The LC is the major noradrenergic nucleus of the brain and plays a significant role in central modulation of nociceptive neurotransmission. Here, we examined CNS pathophysiological changes induced by intraperitoneal administration of the neurotoxin DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride). Administration of DSP-4 decreased levels of norepinephrine in spinal tissue and cerebrospinal fluid (CSF) and led to the development of thermal and mechanical hyperalgesia over 21 days, that was reversible with morphine. Hyperalgesia was accompanied by significant increases in noradrenochrome (oxidized norepinephrine) and expression of 4-hydroxynonenal in CSF and spinal cord tissue respectively at day 21, indicative of oxidative stress. In addition, spinal levels of pro-inflammatory cytokines (interleukins 6 and 17A, tumor necrosis factor-α), as well as the anti-inflammatory cytokine interleukin10 were also significantly elevated at day 21, indicating that an inflammatory response occurred. The inflammatory effect of DSP-4 presented in this study that includes oxidative stress may be particularly useful in elucidating mechanisms of CNP in inflammatory disease states.

The nicotinic receptor drug sazetidine-A reduces alcohol consumption in mice without affecting concurrent nicotine consumption.

Alcohol and nicotine addiction are frequently co-morbid. The nicotinic acetylcholine receptors (nAChRs) are critical for both alcohol and nicotine addiction mechanisms, since nAChR drugs that reduce nicotine consumption have been shown to also reduce alcohol consumption. Sazetidine-A, a pre-clinical nAChR drug with agonist and desensitizing effects at α4ß2 and α7 nAChRs, has been reported to reduce alcohol consumption and nicotine self-administration in rats when administered at high doses. However, this effect has not been replicated in mice. In this study, we examined the effect of sazetidine-A on alcohol and nicotine consumption in male and female mice utilizing voluntary oral consumption procedures previously developed in our lab. We found that sazetidine-A (1 mg/kg, i.p) reduced overnight alcohol consumption, but did not affect nicotine consumption when presented either alone or concurrently with alcohol. Sazetidine-A did not reduce water or saccharin consumption at any dose tested. In a chronic co-consumption experiment in which either alcohol or nicotine was re-introduced after one week of forced abstinence, sazetidine-A attenuated post-abstinence consumption of alcohol but not nicotine. Sazetidine-A also significantly reduced alcohol consumption in an acute, binge drinking-in-the-dark procedure. Finally, we tested the effect of sazetidine-A on alcohol withdrawal, and found that sazetidine-A significantly reduced handling-induced convulsions during alcohol withdrawal. Collectively, these data suggest a novel role for the nAChR targets of sazetidine-A in specifically mediating alcohol consumption, separate from the involvement of nAChRs in mediating nicotine consumption. Delineation of this pathway may provide insight into novel therapies for the treatment of alcohol use disorders.

Voluntary co-consumption of alcohol and nicotine: Effects of abstinence, intermittency, and withdrawal in mice.

Alcohol and nicotine are often used together, and there is a high rate of co-occurrence between alcohol and nicotine addiction. Most animal models studying alcohol and nicotine interactions have utilized passive drug administration, which may not be relevant to human co-addiction. In addition, the interactions between alcohol and nicotine in female animals have been understudied, as most studies have used male animals. To address these issues, we developed models of alcohol and nicotine co-consumption in male and female mice that utilized voluntary, oral consumption of unsweetened alcohol, nicotine and water. We first examined drug consumption and preference in single-drug, sequential alcohol and nicotine consumption tests in male and female C57BL/6 and DBA/2J mice. We then tested chronic continuous and intermittent access alcohol and nicotine co-consumption procedures. We found that male and female C57BL/6 mice readily co-consumed unsweetened alcohol and nicotine. In our continuous co-consumption procedures, we found that varying the available nicotine concentration during an alcohol abstinence period affected compensatory nicotine consumption during alcohol abstinence, and affected rebound alcohol consumption when alcohol was re-introduced. Consumption of alcohol and nicotine in an intermittent co-consumption procedure produced higher alcohol consumption levels, but not nicotine consumption levels, compared with the continuous co-consumption procedures. Finally, we found that intermittent alcohol and nicotine co-consumption resulted in physical dependence. Our data show that these voluntary co-consumption procedures can be easily performed in mice and can be used to study behavioral interactions between alcohol and nicotine consumption, which may better model human alcohol and nicotine co-addiction.

Direct intranigral injection of dopaminochrome causes degeneration of dopamine neurons.

Parkinson's disease (PD) is characterized by progressive neurodegeneration of nigrastriatal dopaminergic neurons leading to clinical motor dysfunctions. Many animal models of PD have been developed using exogenous neurotoxins and pesticides. Evidence strongly indicates that the dopaminergic neurons of the substantia nigra pars compacta (SNpc) are highly susceptible to neurodegeneration due to a number of factors including oxidative stress and mitochondrial dysfunction. Oxidation of DA to a potential endogenous neurotoxin, dopaminochrome (DAC), may be a potential contributor to the vulnerability of the nigrostriatal tract to oxidative insult. In this study, we show that DAC causes slow and progressive degeneration of dopaminergic neurons in contrast to 1-methyl-4-phenylpyridinium (MPP(+)), which induces rapid lesions of the region. The DAC model may be more reflective of early stresses that initiate the progressive neurodegenerative process of PD, and may prove a useful model for future neurodegenerative studies.