Hyperlipidemia Disrupts Cerebrovascular Reflexes and Worsens Ischemic Perfusion Defect

Ayata, Cenk,Shin, Hwa Kyoung,Dilekö,z, Ergin,Atochin, Dmitriy N,Kashiwagi, Satoshi,Eikermann-Haerter, Katharina,Huang, Paul L SAGE Publications 2013 Journal of cerebral blood flow and metabolism Vol.33 No.6

<P> Hyperlipidemia is a highly prevalent risk factor for coronary and cervical atherosclerosis and stroke. However, even in the absence of overt atherosclerosis, hyperlipidemia disrupts endothelial and smooth muscle function. We investigated the impact of hyperlipidemia on resting-brain perfusion, fundamental cerebrovascular reflexes, and dynamic perfusion defect during acute focal ischemia in hyperlipidemic apolipoprotein E knockout mice before the development of flow-limiting atherosclerotic stenoses. Despite elevated blood pressures, absolute resting cerebral blood flow was reduced by 20% in apolipoprotein E knockout compared with wild type when measured by [<SUP>14</SUP>C]-iodoamphetamine technique. Noninvasive, high spatiotemporal resolution laser speckle flow imaging revealed that the lower autoregulatory limit was elevated in apolipoprotein E knockout mice (60 vs. 40 mm Hg), and cortical hyperemic responses to hypercapnia and functional activation were attenuated by 30% and 64%, respectively. Distal middle cerebral artery occlusion caused significantly larger perfusion defects and infarct volumes in apolipoprotein E knockout compared with wild type. Cerebrovascular dysfunction showed a direct relationship to the duration of high-fat diet. These data suggest that hyperlipidemia disrupts cerebral blood flow regulation and diminishes collateral perfusion in acute stroke in the absence of hemodynamically significant atherosclerosis. </P>

바우하우스 뮤지엄, 베셀 콜렉티브

영 & 아야타(YOUNG & AYATA) 현대건축사 2016 월간 CONCEPT Vol.- No.201

Effect of Strontium and Magnesium Additions on the Microstructure and Mechanical Properties of Al–12Si Alloys

Ali Paşa Hekimoğlu,Merve Çalış,Gizem Ayata 대한금속·재료학회 2019 METALS AND MATERIALS International Vol.25 No.6

In this study, a binary Al–12Si, eight ternary Al–12Si–Sr, and six quaternary Al–12Si–0.1Sr–(0.2–1)Mg alloys were producedby permanent mold casting. It was observed that microstructure of the binary alloy consisted of the phases of aluminum richα grains (dendrites), primary silicon, plate like β and eutectic Al–Si containing needle like silicon particles. The ternaryalloys have fine and globular (modified) eutectic silicon particles and higher volume fraction of α (Al) dendrites than binaryalloys. They also contained Al4Srphase after 0.02 wt% Sr, in addition to the phases in the binary alloy. This phase got coarsewhen the strontium ratio exceeded 0.1%. It was observed that the plate like β phase seen in the binary alloys transformed intothe fibrous form δ phase in the ternary alloys. Magnesium addition resulted in transformation of δ phase into script like πphase, and the formation of lamellar like Mg2Siphase when the ratio of it in the quaternary alloys reached the 0.6 wt%. Thelamellar like form of Mg2Siphase changed to Chinese-script type after the 0.6 wt% Mg. The results showed that hardness,yield and tensile strength of the Al–12Si–Sr alloys increased with increasing strontium content up to 0.1 wt%. The resultsalso showed that hardness of the quaternary alloys increased with increasing magnesium content, while yield and tensilestrength increased only up to 0.6 wt% Mg.

Rho-Kinase Inhibition Improves Ischemic Perfusion Deficit in Hyperlipidemic Mice

Shin, Hwa Kyoung,Huang, Paul L,Ayata, Cenk SAGE Publications 2014 Journal of cerebral blood flow and metabolism Vol.34 No.2

<P> Hyperlipidemia is a major cardiovascular risk factor associated with progressive cerebrovascular dysfunction and diminished collateral perfusion in stroke. Rho-associated kinase (ROCK) may be an important mediator of hyperlipidemic vascular dysfunction. We tested the efficacy of acute or chronic ROCK inhibition on the size of dynamic perfusion defect using laser speckle flowmetry in hyperlipidemic apolipoprotein E knockout mice fed on a high-fat diet for 8 weeks. Mice were studied at an age before the development of flow-limiting atherosclerotic stenoses in aorta and major cervical arteries. Focal ischemia was induced by distal middle cerebral artery occlusion (dMCAO) during optical imaging. The ROCK inhibitor fasudil (10 mg/kg) was administered either as a single dose 1 hour before ischemia onset, or daily for 4 weeks. Fasudil decreased both baseline arterial blood pressure and cerebrovascular resistance (CVR) by ∼15%, and significantly improved tissue perfusion during dMCAO. Interestingly, peri-infarct depolarizations were also reduced. Chronic treatment did not further enhance these benefits compared with acute treatment with a single dose. These data show that ROCK inhibition improves CVR and ischemic tissue perfusion in hyperlipidemic mice. </P>

Endothelial Dysfunction Abrogates the Efficacy of Normobaric Hyperoxia in Stroke

Shin, Hwa Kyoung,Oka, Fumiaki,Kim, Ji Hyun,Atochin, Dmitriy,Huang, Paul L.,Ayata, Cenk Society for Neuroscience 2014 The Journal of neuroscience Vol.34 No.46

<P>Hyperoxia has been uniformly efficacious in experimental focal cerebral ischemia. However, pilot clinical trials have showed mixed results slowing its translation in patient care. To explain the discordance between experimental and clinical outcomes, we tested the impact of endothelial dysfunction, exceedingly common in stroke patients but under-represented in experimental studies, on the neuroprotective efficacy of normobaric hyperoxia. We used hyperlipidemic apolipoprotein E knock-out and endothelial nitric oxide synthase knock-out mice as models of endothelial dysfunction, and examined the effects of normobaric hyperoxia on tissue perfusion and oxygenation using high-resolution combined laser speckle and multispectral reflectance imaging during distal middle cerebral artery occlusion. In normal wild-type mice, normobaric hyperoxia rapidly and significantly improved tissue perfusion and oxygenation, suppressed peri-infarct depolarizations, reduced infarct volumes, and improved neurological function. In contrast, normobaric hyperoxia worsened perfusion in ischemic brain and failed to reduce infarct volumes or improve neurological function in mice with endothelial dysfunction. These data suggest that the beneficial effects of hyperoxia on ischemic tissue oxygenation, perfusion, and outcome are critically dependent on endothelial nitric oxide synthase function. Therefore, vascular risk factors associated with endothelial dysfunction may predict normobaric hyperoxia nonresponders in ischemic stroke. These data may have implications for myocardial and systemic circulation as well.</P>

Age-Related Decline in Oligodendrogenesis Retards White Matter Repair in Mice

Miyamoto, Nobukazu,Pham, Loc-Duyen D.,Hayakawa, Kazuhide,Matsuzaki, Toshinori,Seo, Ji Hae,Magnain, Caroline,Ayata, Cenk,Kim, Kyu-Won,Boas, David,Lo, Eng H.,Arai, Ken American Heart Association, Inc. 2013 Stroke Vol.44 No.9

<P><B>Background and Purpose—</B></P><P>Aging is one of the major risk factors for white matter injury in cerebrovascular disease. However, the effects of age on the mechanisms of injury/repair in white matter remain to be fully elucidated. Here, we ask whether, compared with young brains, white matter regions in older brains may be more vulnerable in part because of decreased rates of compensatory oligodendrogenesis after injury.</P><P><B>Methods—</B></P><P>A mouse model of prolonged cerebral hypoperfusion was prepared by bilateral common carotid artery stenosis in 2-month and 8-month-old mice. Matching in vitro studies were performed by subjecting oligodendrocyte precursor cells to sublethal 7-day CoCl<SUB>2</SUB> treatment to induce chemical hypoxic stress.</P><P><B>Results—</B></P><P>Baseline myelin density in the corpus callosum was similar in 2-month and 8-month-old mice. But after induction of prolonged cerebral hypoperfusion, older mice showed more severe white matter injury together with worse deficits in working memory. The numbers of newborn oligodendrocytes and their precursors were increased by cerebral hypoperfusion in young mice, whereas these endogenous responses were significantly dampened in older mice. Defects in cyclic AMP response element-binding protein signaling may be involved because activating cyclic AMP response element-binding protein with the type-III phosphodiesterase inhibitor cilostazol in older mice restored the differentiation of oligodendrocyte precursor cells, alleviated myelin loss, and improved cognitive dysfunction during cerebral hypoperfusion. Cell culture systems confirmed that cilostazol promoted the differentiation of oligodendrocyte precursor cells.</P><P><B>Conclusions—</B></P><P>An age-related decline in cyclic AMP response element-binding protein–mediated oligodendrogenesis may compromise endogenous white matter repair mechanisms, and therefore, drugs that activate cyclic AMP response element-binding protein signaling provide a potential therapeutic approach for treating white matter injury in aging brains.</P>

Oligodendrocyte precursors induce early blood-brain barrier opening after white matter injury.

Seo, Ji Hae,Miyamoto, Nobukazu,Hayakawa, Kazuhide,Pham, Loc-Duyen D,Maki, Takakuni,Ayata, Cenk,Kim, Kyu-Won,Lo, Eng H,Arai, Ken American Society for Clinical Investigation 2013 The Journal of clinical investigation Vol.123 No.2

<P>Oligodendrocyte precursor cells (OPCs) are thought to maintain homeostasis and contribute to long-term repair in adult white matter; however, their roles in the acute phase after brain injury remain unclear. Mice that were subjected to prolonged cerebral hypoperfusion stress developed white matter demyelination over time. Prior to demyelination, we detected increased MMP9 expression, blood-brain barrier (BBB) leakage, and neutrophil infiltration in damaged white matter. Notably, at this early stage, OPCs made up the majority of MMP9-expressing cells. The standard MMP inhibitor GM6001 reduced the early BBB leakage and neutrophil infiltration, indicating that OPC-derived MMP9 induced early BBB disruption after white matter injury. Cell-culture experiments confirmed that OPCs secreted MMP9 under pathological conditions, and conditioned medium prepared from the stressed OPCs weakened endothelial barrier tightness in vitro. Our study reveals that OPCs can rapidly respond to white matter injury and produce MMP9 that disrupts the BBB, indicating that OPCs may mediate injury in white matter under disease conditions.</P>

Early Activation of Phosphatidylinositol 3-Kinase after Ischemic Stroke Reduces Infarct Volume and Improves Long-Term Behavior

Kim, Y. S.,Yoo, A.,Son, J. W.,Kim, H. Y.,Lee, Y. J.,Hwang, S.,Lee, K. Y.,Lee, Y. J.,Ayata, C.,Kim, H. H. Humana Press 2017 Molecular Neurobiology Vol. No.

<P>Phosphatidylinositol 3-kinases (PI3Ks) have recently been implicated in apoptosis and ischemic cell death. We tested the efficacy of early intervention with a peptide PI3K activator in focal cerebral ischemia. After determining the most effective dose (24 mu g/kg) and time window (2 h after MCAO) of treatment, a total of 48 rats were subjected to middle cerebral artery occlusion (MCAO). Diffusion weighted MRI (DWI) was performed 1 h after MCAO and rats with lesion sizes within a predetermined range were randomized to either PI3K activator or vehicle treatment arms. Fluid attenuated inversion recovery (FLAIR) MRI, neurological function, western blots, and immunohistochemistry were blindly assessed. Initial DWI lesion volumes were nearly identical between two groups prior to treatment. However, FLAIR showed significantly smaller infarct volumes in the PI3K activator group compared with vehicle (146 +/- 81 mm(3) and 211 +/- 96 mm(3), p = 0.045) at 48 h. The PI3K activator group also had better neurological function for up to 2 weeks. In addition, PI3K activator decreased the number of TUNEL-positive cells in the peri-infarct region compared with the control group. Western blot and immunohistochemistry showed increased expression of phosphorylated Akt (Ser473) and GSK-3 beta (Ser9) and decreased expression of cleaved caspase-9 and caspase-3. Our results suggest a neuroprotective role of early activation of PI3K in ischemic stroke. The use of DWI in the randomization of experimental groups may reduce bias.</P>