The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson’s Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia

Sirtuin deacetylases regulate diverse cellular pathways and influence disease processes. Our previous studies identified the brain-enriched sirtuin-2 (SIRT2) deacetylase as a potential drug target to counteract neurodegeneration. In the present study, we characterize SIRT2 inhibition activity of the brain-permeable compound AK7 and examine the efficacy of this small molecule in models of Parkinson’s disease, amyotrophic lateral sclerosis and cerebral ischemia. Our results demonstrate that AK7 is neuroprotective in models of Parkinson’s disease; it ameliorates alpha-synuclein toxicity in vitro and prevents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion and dopaminergic neuron loss in vivo. The compound does not show beneficial effects in mouse models of amyotrophic lateral sclerosis and cerebral ischemia. These findings underscore the specificity of protective effects observed here in models of Parkinson’s disease, and previously in Huntington’s disease, and support the development of SIRT2 inhibitors as potential therapeutics for the two neurodegenerative diseases

Selective ROCK2 inhibition in focal cerebral ischemia

Objective: Rho-associated kinase (ROCK) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology. ROCK inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant ROCK isoform (ROCK1 or ROCK2) in acute stroke is not known. Methods: We characterized the pharmacodynamic and pharmacokinetic profile, and tested the efficacy and safety of a novel selective ROCK2 inhibitor KD025 (formerly SLx-2119) in focal cerebral ischemia models in mice. Results: KD025 dose-dependently reduced infarct volume after transient middle cerebral artery occlusion. The therapeutic window was at least 3 h from stroke onset, and the efficacy was sustained for at least 4 weeks. KD025 was at least as efficacious in aged, diabetic or female mice, as in normal adult males. Concurrent treatment with atorvastatin was safe, but not additive or synergistic. KD025 was also safe in a permanent ischemia model, albeit with diminished efficacy. As one mechanism of protection, KD025 improved cortical perfusion in a distal middle cerebral artery occlusion model, implicating enhanced collateral flow. Unlike isoform-nonselective ROCK inhibitors, KD025 did not cause significant hypotension, a dose-limiting side effect in acute ischemic stroke. Interpretation Altogether, these data show that KD025 is efficacious and safe in acute focal cerebral ischemia in mice, implicating ROCK2 as the relevant isoform in acute ischemic stroke. Data suggest that selective ROCK2 inhibition has a favorable safety profile to facilitate clinical translation

Étude comparative des lésions athéromateuses carotidiennes et fémorales

Les résultats du traitement endovasculaire diffèrent selon le territoire artériel. Notre hypothèse est qu'une nature différente de la plaque d'athérome en fonction du site lésionnel soit à même d expliquer ces résultats. Une biocollection de 92 plaques a été constituée à partir de pièces d endartériectomie (46 fémorales, 46 carotides). Sur le plan morphologique, les analyses histologiques ont montré une prépondérance des plaques de type fibrocalcique pour les artères fémorales et de type fibrolipidique pour les artères carotides (p<0,001). Concernant l'analyse des calcifications, le résultat principal est la nette prépondérance de la métaplasie ostéoïde au sein des plaques fémorales (66% versus 17%, p<0,001). Sur le plan quantitatif, les plaques fémorales sont plus riches en calcium et moins riches en cholestérol que les plaques carotides (p<0,05).NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Data from: Early sitting in ischemic stroke patients (SEVEL): a randomized controlled trial

Background: Extended immobility has been associated with medical complications during hospitalization. However no clear recommendations are available for mobilization of ischemic stroke patients. Objective: As early mobilization has been shown to be feasible and safe, we tested the hypothesis that early sitting could be beneficial to stroke patient outcome. Methods: This prospective multicenter study tested two sitting procedures at the acute phase of ischemic stroke, in a randomized controlled fashion (clinicaltrials.org registration number NCT01573299). Patients were eligible if they were above 18 years of age and showed no sign of massive infarction or any contra-indication for sitting. In the early-sitting group, patients were seated out of bed at the earliest possible time but no later than one calendar day after stroke onset, whereas the progressively-sitting group was first seated out of bed on the third calendar day after stroke onset. Primary outcome measure was the proportion of patients with a modified Rankin score [0–2] at 3 months post stroke. Secondary outcome measures were a.) prevalence of medical complications, b.) length of hospital stay, and c.) tolerance to the procedure. Results: One hundred sixty seven patients were included in the study, of which 29 were excluded after randomization. Data from 138 patients, 63 in the early-sitting group and 75 in the progressively-sitting group were analyzed. There was no difference regarding outcome of people with stroke, with a proportion of Rankin [0–2] score at 3 months of 76.2% and 77.3% of patients in the early- and progressive-sitting groups, respectively (p = 0.52). There was also no difference between groups for secondary outcome measures, and the procedure was well tolerated in both arms. Conclusion: Due to a slow enrollment, fewer patients than anticipated were available for analysis. As a result, we can only detect beneficial/detrimental effects of +/- 15% of the early sitting procedure on stroke outcome with a realized 37% power. However, enrollment was sufficient to rule out effect sizes greater than 25% with 80% power, indicating that early sitting is unlikely to have an extreme effect in either direction on stroke outcome. Additionally, we were not able to provide a blinded assessment of the primary outcome. Taking these limitations into account, our results may help guide the development of more effective acute stroke rehabilitation strategies, and the design of future acute stroke trials involving out of bed activities and other mobilization regimens

Early mobilisation post-stroke: a systematic review and meta-analysis of individual participant data

Purpose: To investigate the safety and efficacy of early mobilisation (EM) compared to usual care by meta-analysing individual participant data (IPD). Materials and methods: IPD were sought from randomised controlled trials comparing out-of-bed mobilisation starting within 48 h from stroke onset to usual care for acute stroke patients. Six trials were sourced from a recent Cochrane review. Favourable outcome (modified Rankin Scale 0–2) and death at 3 months post-stroke were compared between both groups using mixed-effect logistic regression modelling. Adjusted odds ratios (aORs) with respective 95% confidence intervals (95%CI) were reported. Results: Out of 2630 participants, 1437 (54.6%) were assigned to EM and 1193 (45.4%) to usual care. Intervention protocols varied considerably between trials. The median (interquartile range) delay to starting mobilisation post-stroke onset was 20 h (14.5–23.8) for EM and 23 h (16.7–34.3) for usual care group. Fewer EM participants had a favourable outcome at 3 months post-stroke compared to the usual care group (678 [48%] vs. 611 [52%]; aOR = 0.75, 95%CI: 0.62–0.92, p = 0.005). No difference in death at 3 months post-stroke between EM and usual care was observed (102 [7%] vs. 84 [7%]; aOR = 1.46, 95%CI: 0.92–2.31, p = 0.108). Conclusion: The commencement of mobilisation should only be considered after 24 h post-stroke. Further research is required to identify safe, optimal dose, and timing of EM post-stroke

Early Sitting in Ischemic Stroke Patients (SEVEL): A Randomized Controlled Trial

<div><p>Background</p><p>Extended immobility has been associated with medical complications during hospitalization. However no clear recommendations are available for mobilization of ischemic stroke patients.</p><p>Objective</p><p>As early mobilization has been shown to be feasible and safe, we tested the hypothesis that early sitting could be beneficial to stroke patient outcome.</p><p>Methods</p><p>This prospective multicenter study tested two sitting procedures at the acute phase of ischemic stroke, in a randomized controlled fashion (clinicaltrials.org registration number NCT01573299). Patients were eligible if they were above 18 years of age and showed no sign of massive infarction or any contra-indication for sitting. In the early-sitting group, patients were seated out of bed at the earliest possible time but no later than one calendar day after stroke onset, whereas the progressively-sitting group was first seated out of bed on the third calendar day after stroke onset. Primary outcome measure was the proportion of patients with a modified Rankin score [0–2] at 3 months post stroke. Secondary outcome measures were a.) prevalence of medical complications, b.) length of hospital stay, and c.) tolerance to the procedure.</p><p>Results</p><p>One hundred sixty seven patients were included in the study, of which 29 were excluded after randomization. Data from 138 patients, 63 in the early-sitting group and 75 in the progressively-sitting group were analyzed. There was no difference regarding outcome of people with stroke, with a proportion of Rankin [0–2] score at 3 months of 76.2% and 77.3% of patients in the early- and progressive-sitting groups, respectively (p = 0.52). There was also no difference between groups for secondary outcome measures, and the procedure was well tolerated in both arms.</p><p>Conclusion</p><p>Due to a slow enrollment, fewer patients than anticipated were available for analysis. As a result, we can only detect beneficial/detrimental effects of +/- 15% of the early sitting procedure on stroke outcome with a realized 37% power. However, enrollment was sufficient to rule out effect sizes greater than 25% with 80% power, indicating that early sitting is unlikely to have an extreme effect in either direction on stroke outcome. Additionally, we were not able to provide a blinded assessment of the primary outcome. Taking these limitations into account, our results may help guide the development of more effective acute stroke rehabilitation strategies, and the design of future acute stroke trials involving out of bed activities and other mobilization regimens.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT01573299?term=NCT01573299&rank=1" target="_blank">NCT01573299</a></p></div

Subsequently excluded patients

List and causes related to the exclusion of the 29 patient

TABLE_3_OUTCOME_database

Patients outcome according to the sitting procedur

TABLE_4_MEDICAL_COMPLICATIONS database

Medical complication occurrence and description according to group affiliatio

Flow chart of the study.

<p>Flow chart of the study.</p