Neurovascular Mechanisms in Stroke, Neurodegeneration and Recovery

Lo, Eng-H. The Korean Society of Pharmacology 2006 The Korean Journal of Physiology & Pharmacology Vol.10 No.5

The emerging concept of the 'neurovascular unit' may enable a powerful paradigm shift for neuroscience. Instead of a pure focus on the 'neurobiology' of disease, an opportunity now exists to return to a more integrative approach. The neurovascular unit emphasizes that signaling between vascular and neuronal compartments comprise the basis for both function and dysfunction in brain. Hence, brain disorders are not just due to death of neurons, but instead manifested as cell signaling perturbations at the neurovascular interface. In this mini-review, we will examine 3 examples of this hypothesis: neurovascular mechanisms involved in the thrombolytic therapy of stroke, the crosstalk between neurogenesis and angiogenesis, and the link between vascular dysfunction and amyloid pathology in Alzheimer's disease. An understanding of cell-cell and cell-matrix signaling at the neurovascular interface may yield new approaches for targeting CNS disorders.

Role of A-Kinase Anchoring Protein 12 in the Central Nervous System

Shintaro Kimura,Josephine Lok,Irwin H. Gelman,Eng H. Lo,Ken Arai 대한신경과학회 2023 Journal of Clinical Neurology Vol.19 No.4

A-kinase anchoring protein (AKAP) 12 is a scaffolding protein that anchors various signaling proteins to the plasma membrane. These signaling proteins include protein kinase A, protein kinase C, protein phosphatase 2B, Src-family kinases, cyclins, and calmodulin, which regulate their respective signaling pathways. AKAP12 expression is observed in the neurons, astrocytes, endothelial cells, pericytes, and oligodendrocytes of the central nervous system (CNS). Its physiological roles include promoting the development of the blood–brain barrier, maintaining white-matter homeostasis, and even regulating complex cognitive functions such as long-term memory formation. Under pathological conditions, dysregulation of AKAP12 expression levels may be involved in the pathology of neurological diseases such as ischemic brain injury and Alzheimer’s disease. This minireview aimed to summarize the current literature on the role of AKAP12 in the CNS.

Neurovascular Mechanisms in Stroke, Neurodegeneration and Recovery

Eng H. Lo 대한약리학회 2006 The Korean Journal of Physiology & Pharmacology Vol.10 No.5

The emerging concept of theneurovascular unitmay enable a powerful paradigm shift for neuroscience. Instead of a pure focus on theneurobiologyof disease, an opportunity now exists to return to a more integrative approach. The neurovascular unit emphasizes that signaling between vascular and neuronal compartments comprise the basis for both function and dysfunction in brain. Hence, brain disorders are not just due to death of neurons, but instead manifested as cell signaling perturbations at the neurovascular interface. In this mini-review, we will examine 3 examples of this hypothesis: neurovascular mechanisms involved in the thrombolytic therapy of stroke, the crosstalk between neurogenesis and angiogenesis, and the link between vascular dysfunction and amyloid pathology in Alzheimer's disease. An understanding of cell-cell and cell-matrix signaling at the neurovascular interface may yield new approaches for targeting CNS disorders.

The Role of the PI3K Pathway in the Regeneration of the Damaged Brain by Neural Stem Cells after Cerebral Infarction

Koh, Seong-Ho,Lo, Eng H. 대한신경과학회 2015 Journal of Clinical Neurology Vol.11 No.4

<P>Neurologic deficits resulting from stroke remain largely intractable, which has prompted thousands of studies aimed at developing methods for treating these neurologic sequelae. Endogenous neurogenesis is also known to occur after brain damage, including that due to cerebral infarction. Focusing on this process may provide a solution for treating neurologic deficits caused by cerebral infarction. The phosphatidylinositol-3-kinase (PI3K) pathway is known to play important roles in cell survival, and many studies have focused on use of the PI3K pathway to treat brain injury after stroke. Furthermore, since the PI3K pathway may also play key roles in the physiology of neural stem cells (NSCs), eliciting the appropriate activation of the PI3K pathway in NSCs may help to improve the sequelae of cerebral infarction. This review describes the PI3K pathway, its roles in the brain and NSCs after cerebral infarction, and the therapeutic possibility of activating the pathway to improve neurologic deficits after cerebral infarction.</P>

Role of matrix metalloproteinases in delayed cortical responses after stroke

Zhao, Bing-Qiao,Wang, Sophia,Kim, Hahn-Young,Storrie, Hannah,Rosen, Bruce R,Mooney, David J,Wang, Xiaoying,Lo, Eng H Nature Publishing Group 2006 Nature medicine Vol.12 No.4

Matrix metalloproteinases (MMPs) are zinc-endopeptidases with multifactorial actions in central nervous system (CNS) physiology and pathology. Accumulating data suggest that MMPs have a deleterious role in stroke. By degrading neurovascular matrix, MMPs promote injury of the blood-brain barrier, edema and hemorrhage. By disrupting cell-matrix signaling and homeostasis, MMPs trigger brain cell death. Hence, there is a movement toward the development of MMP inhibitors for acute stroke therapy. But MMPs may have a different role during delayed phases after stroke. Because MMPs modulate brain matrix, they may mediate beneficial plasticity and remodeling during stroke recovery. Here, we show that MMPs participate in delayed cortical responses after focal cerebral ischemia in rats. MMP-9 is upregulated in peri-infarct cortex at 7–14 days after stroke and is colocalized with markers of neurovascular remodeling. Treatment with MMP inhibitors at 7 days after stroke suppresses neurovascular remodeling, increases ischemic brain injury and impairs functional recovery at 14 days. MMP processing of bioavailable VEGF may be involved because inhibition of MMPs reduces endogenous VEGF signals, whereas additional treatment with exogenous VEGF prevents MMP inhibitor–induced worsening of infarction. These data suggest that, contrary to MMP inhibitor therapies for acute stroke, strategies that modulate MMPs may be needed for promoting stroke recovery.

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>

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>

Crosstalk between oligodendrocytes and cerebral endothelium contributes to vascular remodeling after white matter injury

Pham, Loc‐,Duyen D.,Hayakawa, Kazuhide,Seo, Ji Hae,Nguyen, Minh‐,Nguyet,Som, Angel T.,Lee, Brian J.,Guo, Shuzhen,Kim, Kyu‐,Won,Lo, Eng H.,Arai, Ken Wiley Subscription Services, Inc., A Wiley Company 2012 GLIA Vol.60 No.6

<P><B>Abstract</B></P><P>After stroke and brain injury, cortical gray matter recovery involves mechanisms of neurovascular matrix remodeling. In white matter, however, the mechanisms of recovery remain unclear. In this study, we demonstrate that oligodendrocytes secrete matrix metalloproteinase‐9 (MMP‐9), which accelerates the angiogenic response after white matter injury. In primary oligodendrocyte cultures, treatment with the proinflammatory cytokine interleukin‐1β (IL‐1β) induced an upregulation and secretion of MMP‐9. Conditioned media from IL‐1β‐stimulated oligodendrocytes significantly amplified matrigel tube formation in brain endothelial cells, indicating that MMP‐9 from oligodendrocytes can promote angiogenesis <I>in vitro</I>. Next, we asked whether similar signals and substrates operate after white matter injury <I>in vivo</I>. Focal white matter injury and demyelination was induced in mice via stereotactic injection of lysophosphatidylcholine into corpus callosum. Western blot analysis showed that IL‐1β expression was increased in damaged white matter. Immunostaining demonstrated MMP‐9 signals in myelin‐associated oligodendrocytic basic protein‐positive oligodendrocytes. Treatment with an IL‐1β‐neutralizing antibody suppressed the MMP‐9 response in oligodendrocytes. Finally, we confirmed that the broad spectrum MMP inhibitor GM6001 inhibited angiogenesis around the injury area in this white matter injury model. In gray matter, a neurovascular niche promotes cortical recovery after brain injury. Our study suggests that an analogous oligovascular niche may mediate recovery in white matter. © 2012 Wiley Periodicals, Inc.</P>

Dual effects of carbon monoxide on pericytes and neurogenesis in traumatic brain injury

Choi, Yoon Kyung,Maki, Takakuni,Mandeville, Emiri T,Koh, Seong-Ho,Hayakawa, Kazuhide,Arai, Ken,Kim, Young-Myeong,Whalen, Michael J,Xing, Changhong,Wang, Xiaoying,Kim, Kyu-Won,Lo, Eng H Nature Publishing Group 2016 Nature medicine Vol. No.

<P>At low levels, carbon monoxide (CO) has physiological roles as a second messenger and neuromodulator(1,2). Here we assess the effects of CO in a mouse model of traumatic brain injury (TBI). Treatment with CO-releasing molecule (CORM)-3 reduced pericyte death and ameliorated the progression of neurological deficits. In contrast, although treatment with the radical scavenger N-tert-butyl-a-phenylnitrone (PBN) also reduced pericyte death, neurological outcomes were not rescued. As compared to vehicle-treated control and PBN-treated mice, CORM-3-treated mice showed higher levels of phosphorylated neural nitric oxide synthase within neural stem cells (NSCs). Inhibition of nitric oxide synthase diminished the CORM-3-mediated increase in the number of cells that stained positive for both the neuronal marker NeuN and 5-bromo-2'-deoxyuridine (BrdU; a marker for proliferating cells) in vivo, consequently interfering with neurological recovery after TBI. Because NSCs seemed to be in close proximity to pericytes, we asked whether cross-talk between pericytes and NSCs was induced by CORM-3, thereby promoting neurogenesis. In pericyte cultures that were undergoing oxygen and glucose deprivation, conditioned cell culture medium collected after CORM-3 treatment enhanced the in vitro differentiation of NSCs into mature neurons. Taken together, these findings suggest that CO treatment may provide a therapeutic approach for TBI by preventing pericyte death, rescuing cross-talk with NSCs and promoting neurogenesis.</P>

Oxidative Stress Interferes With White Matter Renewal After Prolonged Cerebral Hypoperfusion in Mice

Miyamoto, Nobukazu,Maki, Takakuni,Pham, Loc-Duyen D.,Hayakawa, Kazuhide,Seo, Ji Hae,Mandeville, Emiri T.,Mandeville, Joseph B.,Kim, Kyu-Won,Lo, Eng H.,Arai, Ken American Heart Association, Inc. 2013 Stroke Vol.44 No.12

<P><B>Background and Purpose—</B></P><P>White matter injury caused by cerebral hypoperfusion may contribute to the pathophysiology of vascular dementia and stroke, but the underlying mechanisms remain to be fully defined. Here, we test the hypothesis that oxidative stress interferes with endogenous white matter repair by disrupting renewal processes mediated by oligodendrocyte precursor cells (OPCs).</P><P><B>Methods—</B></P><P>In vitro, primary rat OPCs were exposed to sublethal CoCl<SUB>2</SUB> for 7 days to induce prolonged chemical hypoxic stress. Then, OPC proliferation/differentiation was assessed. In vivo, prolonged cerebral hypoperfusion was induced by bilateral common carotid artery stenosis in mice. Then, reactive oxygen species production, myelin density, oligodendrocyte versus OPC counts, and cognitive function were evaluated. To block oxidative stress, OPCs and mice were treated with the radical scavenger edaravone.</P><P><B>Results—</B></P><P>Prolonged chemical hypoxic stress suppressed OPC differentiation in vitro. Radical scavenging with edaravone ameliorated these effects. After 28 days of cerebral hypoperfusion in vivo, reactive oxygen species levels were increased in damaged white matter, along with the suppression of OPC-to-oligodendrocyte differentiation and loss of myelin staining. Concomitantly, mice showed functional deficits in working memory. Radical scavenging with edaravone rescued OPC differentiation, ameliorated myelin loss, and restored working memory function.</P><P><B>Conclusions—</B></P><P>Our proof-of-concept study demonstrates that after prolonged cerebral hypoperfusion, oxidative stress interferes with white matter repair by disrupting OPC renewal mechanisms. Radical scavengers may provide a potential therapeutic approach for white matter injury in vascular dementia and stroke.</P>