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.

Inhibition of aluminum corrosion by phthalazinone and synergistic effect of halide ion in 1.0 M HCl

Ahmed Y. Musa,Abdul Amir H. Kadhum,Abu Bakar Mohamad,Mohd Sobri Takriff,Eng Pei Chee 한국물리학회 2012 Current Applied Physics Vol.12 No.1

The inhibitive effects of 1-(2H)-phthalazinone (PTO) for aluminum alloy (2024) corrosion in 1.0 M HCl solution and the synergistic effect of KI on the corrosion inhibition efficiency were assessed using electrochemical measurements. Results showed that the inhibition efficiency increased with an increase in concentration of the PTO and synergistically increased with addition of KI. Adsorption characteristic of PTO molecules in absence and presence of KI was approximated by Freundlich and Langmuir adsorption isotherm models, respectively. The synergistic effect is found to decrease with increase in the concentration of PTO and a competitive inhibition mechanism exists between KI and PTO cations.

Pomegranate Seed Extract Attenuates Chemotherapy-Induced Acute Nephrotoxicity and Hepatotoxicity in Rats

Kerim Çayır,Ali Karadeniz,Nejdet Şimşek,Serap Yıldırım,Emre Karakuş,Adem Kara,Hürrem Turan Akkoyun,Emin Şengül 한국식품영양과학회 2011 Journal of medicinal food Vol.14 No.10

Cisplatin (CDDP), one of the most active cytotoxic agents against cancer, has adverse side effects, such as nephrotoxicity and hepatotoxicity. The present study was designed to investigate the potential protective effect of pomegranate seed extract (PSE) against oxidative stress caused by CDDP injury of the kidneys and liver by measuring tissue biochemical and antioxidant variables and immunohistochemically testing caspase-3–positive cells. Twenty-four Sprague–Dawley rats were divided into 4 groups: control; CDDP: injected intraperitoneally with CDDP (7 mg/kg body weight, single dose); PSE: treated for 15 consecutive days by gavage with PSE (300 mg/kg per day); and PSE+CDDP: treated by gavage with PSE 15 days after a single injection of CDDP. The degree of protection against CDDP injury afforded by PSE was evaluated by determining the levels of malondialdehyde as a measure of lipid peroxidation. The levels of glutathione and activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase were estimated from liver and kidney homogenates; the liver and kidney were also histologically examined. PSE elicited a significant protective effect toward liver and kidney by decreasing the level of lipid peroxidation; elevating the levels of glutathione S-transferase; and increasing the activities of glutathione peroxidase, glutathione S-transferase, and superoxide dismutase. These biochemical observations were supported by immunohistochemical findings and suggested that PSE significantly attenuated nephrotoxicity and hepatotoxicity by the way of its antioxidant, radical-scavenging, and antiapoptotic effects. This PSE extract could be used as a dietary supplement in patients receiving chemotherapy medications.

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.

Mossbauer Study of Ti0.9957Fe0.01O₂

Eng Chan Kim,S. H. Moon,S. I. Woo,H. D. Kim,B. Y. Kim,J. H. Cho,Y. G. Joh,D. H. Kim 한국자기학회 2005 韓國磁氣學會誌 Vol.15 No.2

The rutile polycrystal Ti_(0.99)(57)^Fe_(0.01)O₂ prepared with (57)^Fe enriched iron have been studied by Mossbauer spectroscopy, X-ray diffraction and VSM. The Mossbauer spectrum of Ti_(0.99)(57)^Fe_(0.01)O₂ consists of a ferromagnetic and a paramagnetic phase over all temperature ranging from 4 to 300 K. Isomer shifts indicate Fe²+ for the ferromagnetic phase, but Fe³+ for the paramagneic phase of Ti_(0.99)(57)^Fe_(0.01)O₂ sample. It is noted that the magnetic hyperfine field of ferromagnetic phase had the value about 1.48 times as large as that of α-Fe. The XRD data for Ti_(0.99)(57)^Fe_(0.01)O₂ showed a pure rutile phase with tetragonal structures without any segregation of Fe into particulates within the instrumental resolution limit. The magnetic hysteresis (M-H) curve at room temperature showed an obvious ferromagnetic behavior and the magnetic moment per Fe atom under the applied field of 1T was estimated to be about 0.71 μ_B, suggesting a low spin configuration of Fe ions.

Mossbauer Study of Ti₁-x-yCoxFeyO₂

Eng Chan Kim,S. R. Lee,T. H. Kim,Y. S. Ryu,J. H. Cho,Y. G. Joh,D. H. Kim 한국자기학회 2006 韓國磁氣學會誌 Vol.16 No.1

Mossbauer spectra of Ti₁-x-yCoxFeyO₂ (0.01≤x, y≤0.05) prepared with (57)^Fe enriched iron have been taken at various temperatures ranging from 80 to 300 K. The Mossbauer spectrum of Ti0.94Co_(0.03)Fe_(0.03)O₂ consists of a ferromagnetic (six-Lorentzian), a paramagnetic phase (doublet) and armorphous phase over all temperature ranges. Isomer shifts indicate Fe³+ for the ferromagnetic phase and the paramagneic phase of Ti₁-x-yCoxFeyO₂ samples. It is noted that the magnetic hyperfine field of ferromagnetic phase had the value about 1.5 times as large as that of α-Fe. The XRD data for Ti₁-x-yCoxFeyO₂ showed mainly rutile phase with tetragonal structures without any segregation of Co and Fe into particulates within the instrumental resolution limit. The magnetic moment per (Co+Fe) atom in Ti_(0.94)Co_(0.03)Fe_(0.03)O₂ under the applied field of 1 T was estimated to be about 0.332μB which is ten times as large as that of Ti_(0.97)Co_(0.03)O₂, 0.024μB per Co atom, suggesting a high spin configuration of Co and Fe ions.

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>