Person: Ayata, Cenk
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Ayata
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Cenk
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Ayata, Cenk
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Publication Rho‐kinase inhibitors do not expand hematoma volume in acute experimental intracerebral hemorrhage(John Wiley and Sons Inc., 2018) Akhter, Murtaza; Qin, Tom; Fischer, Paul; Sadeghian, Homa; Kim, Hyung Hwan; Whalen, Michael; Goldstein, Joshua; Ayata, CenkAbstract Rho‐associated kinase (ROCK) is an emerging target in acute ischemic stroke. Early pre‐hospital treatment with ROCK inhibitors may improve their efficacy, but their antithrombotic effects raise safety concerns in hemorrhagic stroke, precluding use prior to neuroimaging. Therefore, we tested whether ROCK inhibition affects the bleeding times, and worsens hematoma volume in a model of intracerebral hemorrhage (ICH) induced by intrastriatal collagenase injection in mice. Tail bleeding time was measured 1 h after treatment with isoform‐nonselective inhibitor fasudil, or ROCK2‐selective inhibitor KD025, or their vehicles. In the ICH model, treatments were administered 1 h after collagenase injection. Although KD025 but not fasudil prolonged the tail bleeding times, neither drug expanded the volume of ICH or worsened neurological deficits at 48 h compared with vehicle. Although more testing is needed in aged animals and comorbid models such as diabetes, these results suggest ROCK inhibitors may be safe for pre‐hospital administration in acute stroke.Publication Uncovering the Rosetta Stone: Report from the First Annual Conference on Key Elements in Translating Stroke Therapeutics from Pre-Clinical to Clinical(Springer US, 2018) Bix, Gregory J.; Fraser, Justin F.; Mack, William J.; Carmichael, S. Thomas; Perez-Pinzon, Miguel; Offner, Halina; Sansing, Lauren; Bosetti, Francesca; Ayata, Cenk; Pennypacker, Keith R.The first annual Stroke Translational Research Advancement Workshop (STRAW), entitled “Uncovering the Rosetta Stone: Key Elements in Translating Stroke Therapeutics from Pre-Clinical to Clinical” was held at the University of Kentucky on October 4–5, 2017. This workshop was organized by the Center for Advanced Translational Stroke Science. The workshop consisted of 2 days of activities. These included three presentations establishing the areas of research in stroke therapeutics, discussing the routes for translation from bench to bedside, and identifying successes and failures in the field. On day 2, grant funding opportunities and goals for the National Institute for Neurological Diseases and Stroke were presented. In addition, the meeting also included break-out sessions designed to connect researchers in areas of stroke, and to foster potential collaborations. Finally, the meeting concluded with an open discussion among attendees led by a panel of experts.Publication Multiparametric, Longitudinal Optical Coherence Tomography Imaging Reveals Acute Injury and Chronic Recovery in Experimental Ischemic Stroke(Public Library of Science, 2013) Srinivasan, Vivek J.; Mandeville, Emiri; Can, Anil; Blasi, Francesco; Climov, Mihail; Daneshmand, Ali; Lee, Jeong Hyun; Yu, Esther; Radhakrishnan, Harsha; Lo, Eng; Sakadzic, Sava; Eikermann-Haerter, Katharina; Ayata, CenkProgress in experimental stroke and translational medicine could be accelerated by high-resolution in vivo imaging of disease progression in the mouse cortex. Here, we introduce optical microscopic methods that monitor brain injury progression using intrinsic optical scattering properties of cortical tissue. A multi-parametric Optical Coherence Tomography (OCT) platform for longitudinal imaging of ischemic stroke in mice, through thinned-skull, reinforced cranial window surgical preparations, is described. In the acute stages, the spatiotemporal interplay between hemodynamics and cell viability, a key determinant of pathogenesis, was imaged. In acute stroke, microscopic biomarkers for eventual infarction, including capillary non-perfusion, cerebral blood flow deficiency, altered cellular scattering, and impaired autoregulation of cerebral blood flow, were quantified and correlated with histology. Additionally, longitudinal microscopy revealed remodeling and flow recovery after one week of chronic stroke. Intrinsic scattering properties serve as reporters of acute cellular and vascular injury and recovery in experimental stroke. Multi-parametric OCT represents a robust in vivo imaging platform to comprehensively investigate these properties.Publication Cortical spreading depression as a target for anti-migraine agents(Springer, 2013) Costa, Cinzia; Tozzi, Alessandro; Rainero, Innocenzo; Cupini, Letizia Maria; Calabresi, Paolo; Ayata, Cenk; Sarchielli, PaolaSpreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes, that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by massive increases in both extracellular K+ and glutamate, as well as rises in intracellular Na+ and Ca2+. These ionic shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is associated with changes in cortical parenchymal blood flow. CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet, no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD. Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the effectiveness of these drugs as anti-migraine agents. CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms of action relevant for migraine.Publication Phase III Preclinical Trials in Translational Stroke Research: Community Response on Framework and Guidelines(Springer US, 2016) Boltze, Johannes; Wagner, Daniel-Christoph; Henninger, Nils; Plesnila, Nikolaus; Ayata, CenkThe multicenter phase III preclinical trial concept is currently discussed to enhance the predictive value of preclinical stroke research. After public announcement, we collected a community feedback on the concept with emphasis on potential design features and guidelines by an anonymous survey. Response analysis was conducted after plausibility checks by applying qualitative and quantitative measures. Most respondents supported the concept, including the implementation of a centralized steering committee. Based on received feedback, we suggest careful, stepwise implementation and to leave selected competencies and endpoint analysis at the discretion of participating centers. Strict application of quality assurance methods is accepted, but should be harmonized. However, received responses also indicate that the application of particular quality assurance models may require more attention throughout the community. Interestingly, clear and pragmatic preferences were given regarding publication and financing, suggesting the establishing of writing committees similar to large-scale clinical trials and global funding resources for financial support. The broad acceptance among research community encourages phase III preclinical trial implementation. Electronic supplementary material The online version of this article (doi:10.1007/s12975-016-0474-6) contains supplementary material, which is available to authorized users.Publication Selective ROCK2 inhibition in focal cerebral ischemia(BlackWell Publishing Ltd, 2013) Hyun Lee, Jeong; Zheng, Yi; von Bornstadt, Daniel; Wei, Ying; Balcioglu, Aygul; Daneshmand, Ali; Yalcin, Nilufer; Yu, Esther; Herisson, Fanny; Atalay, Yahya B; Kim, Maya H; Ahn, Yong-Joo; Balkaya, Mustafa; Sweetnam, Paul; Schueller, Olivier; Poyurovsky, Masha V; Kim, Hyung-Hwan; Lo, Eng; Furie, Karen L; Ayata, CenkObjective: 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.Publication The Sirtuin-2 Inhibitor AK7 Is Neuroprotective in Models of Parkinson’s Disease but Not Amyotrophic Lateral Sclerosis and Cerebral Ischemia(Public Library of Science, 2015) Chen, Xiqun; Wales, Pauline; Quinti, Luisa; Zuo, Fuxing; Moniot, Sébastien; Herisson, Fanny; Rauf, Nazifa Abdul; Wang, Hua; Silverman, Richard B.; Ayata, Cenk; Maxwell, Michelle M.; Steegborn, Clemens; Schwarzschild, Michael; Outeiro, Tiago F.; Kazantsev, Aleksey G.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.Publication Soluble Guanylate Cyclase 1 1 Limits Stroke Size and Attenuates Neurological Injury(Ovid Technologies (Wolters Kluwer Health), 2010) Atochin, Dmitriy; Yuzawa, Izumi; Li, Qian; Rauwerdink, Kristen M.; Malhotra, Rajeev; Chang, Junlei; Brouckaert, Peter; Ayata, Cenk; Moskowitz, Michael; Bloch, Kenneth; Huang, Paul; Buys, EmmanuelBackground and Purpose— Nitric oxide mediates endothelium-dependent vasodilation, modulates cerebral blood flow, and determines stroke outcome. Nitric oxide signals in part by stimulating soluble guanylate cyclase (sGC) to synthesize cGMP. To study the role of sGC in stroke injury, we compared the outcome of cerebral ischemia and reperfusion in mice deficient in the α1 subunit of sGC (sGCα1−/−) with that in wild-type mice. Methods— Blood pressure, cerebrovascular anatomy, and vasoreactivity of pressurized carotid arteries were compared in both mouse genotypes. Cerebral blood flow was measured before and during middle cerebral artery occlusion and reperfusion. We then assessed neurological deficit and infarct volume after 1 hour of occlusion and 23 hours of reperfusion and after 24 hours of occlusion. Results— Blood pressure and cerebrovascular anatomy were similar between genotypes. We found that vasodilation of carotid arteries in response to acetylcholine or sodium nitroprusside was diminished in sGCα1−/− compared with wild-type mice. Cerebral blood flow deficits did not differ between the genotypes during occlusion, but during reperfusion, cerebral blood flow was 45% less in sGCα1−/− mice. Infarct volumes and neurological deficits were similar after 24 hours of occlusion in both genotypes. After 1 hour of ischemia and 23 hours of reperfusion, infarct volumes were 2-fold larger and neurological deficits were worse in sGCα1−/− than in the wild-type mice. Conclusion— sGCα1 deficiency impairs vascular reactivity to nitric oxide and is associated with incomplete reperfusion, larger infarct size, and worse neurological damage, suggesting that cGMP generated by sGCα1β1 is protective in ischemic stroke.Publication Endovascular thrombectomy and post-procedural headache(Springer Milan, 2017) Khan, Sabrina; Amin, Faisal Mohammad; Holtmannspötter, Markus; Hansen, Klaus; Florescu, Anna Maria; Fakhril-Din, Zainab; Petersen, Julie Falkenberg; Ghanizada, Hashmat; Ayata, Cenk; Gaist, David; Ashina, MessoudBackground: We investigated the prevalence of post-procedural headache in patients who have undergone thrombectomy for ischemic stroke, and correlated history of migraine with risk of peri-procedural complications. A total of 314 patients underwent thrombectomy at the Danish National Hospital from January 2012 to December 2014. Eligible subjects were phone-interviewed using a purpose-developed semi-structured questionnaire according to the International Classification of Headache Disorders 3, beta version criteria. Findings: Among 96 eligible subjects, there was a significant decrease in migraine (p = 0.022) within the first 3 months after EVT compared to 1 year before treatment, which was further evident at interview time (on average 1.6 years after EVT, p = 0.013). A minority of patients experienced headaches for the first time within 3 months of their EVT (migraine 2, TTH 9), which persisted at interview time for subjects with migraine. Out of 12 subjects with peri-procedural complications, 2 had a history of migraine with aura. Conclusion: Thrombectomy leads to a significant decrease in previously known migraine, and new onset of headache in a small subset of patients. A history of migraine does not appear to predispose to peri-procedural complications. Electronic supplementary material The online version of this article (doi:10.1186/s10194-017-0719-0) contains supplementary material, which is available to authorized users.Publication Etomidate and Ketamine: Residual Motor and Adrenal Dysfunction that Persist beyond Recovery from Loss of Righting Reflex in Rats(MDPI, 2014) Diaz-Gil, Daniel; Mueller, Noomi; Moreno-Duarte, Ingrid; Lin, Hsin; Ayata, Cenk; Cusin, Cristina; Cotten, Joseph; Eikermann, MatthiasWe tested the hypothesis that etomidate and ketamine produce residual effects that modify functional mobility (measured by the balance beam test) and adrenal function (adrenocorticotropic hormone (ACTH) stimulation) immediately following recovery from loss of righting reflex in rats. Intravenous etomidate or ketamine was administered in a randomized, crossover fashion (2 or 4 mg/kg and 20 or 40 mg/kg, respectively) on eight consecutive days. Following recovery of righting reflex, animals were assessed for residual effects on functional mobility on the balance beam, motor behavior in the open field and adrenal function through ACTH stimulation. We evaluated the consequences of the effects of the anesthetic agent-induced motor behavior on functional mobility. On the balance beam, etomidate-treated rats maintained their grip longer than ketamine-treated rats, indicating greater balance abilities (mean ± SD, 21.5 ± 25.1 s vs. 3.0 ± 4.3 s respectively, p < 0.021). In the open field test, both dosages of etomidate and ketamine had opposite effects on travel behavior, showing ketamine-induced hyperlocomotion and etomidate-induced hypolocomotion. There was a significant interaction between anesthetic agent and motor behavior effects for functional mobility effects (p < 0.001). Corticosterone levels were lower after both 40 mg/kg ketamine and 4 mg/kg etomidate anesthesia compared to placebo, an effect stronger with etomidate than ketamine (p < 0.001). Following recovery from anesthesia, etomidate and ketamine have substantial side effects. Ketamine-induced hyperlocomotion with 20 and 40 mg/kg has stronger effects on functional mobility than etomidate-induced hypolocomotion with 2 and 4 mg/kg. Etomidate (4 mg/kg) has stronger adrenal suppression effects than ketamine (40 mg/kg).