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Ayinla MT, Asuku AO. The neurotoxic effects of lead acetate and the abrogating actions of 6-gingerol-rich extract of ginger via modulation of antioxidant defence system, pro-inflammatory markers, and apoptotic cascade. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2025:10.1007/s00210-025-03873-x. [PMID: 39937255 DOI: 10.1007/s00210-025-03873-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Accepted: 02/01/2025] [Indexed: 02/13/2025]
Abstract
Lead exposure is a public health concern and it has been linked to cognitive deficit, memory impairment, and neurotoxicity. This study was designed to investigate the effect of 6-gingerol-rich extract of ginger (6-GREG) on oxidative stress, inflammation, and apoptosis in lead acetate (PbAc)-induced neurotoxicity in male Wistar rats. Twenty-five (25) male Wistar rats in total were divided into five groups at random (n = 5). The control group received 0.5 ml of normal saline, the PbAc-treated group received 7.5 mg/kg of PbAc, the vitamin C, 6-GREG (100), and 6-GREG (200) groups received 7.5 mg/kg of PbAc followed by administration of vitamin C (100 mg/kg), 6-GREG (100 mg/kg), and 6-GREG (200 mg/kg) respectively for 2 weeks. Following behavioral tests, the rats were euthanized, and their brain tissues were homogenized for biochemical analysis. When compared to the control group, the administration of PbAc caused behavioral alterations as well as a significant (p < 0.05) decrease in the activities of catalase, glutathione peroxidase, as well as reduced glutathione and Bcl-2 levels in the PbAc-treated group. Furthermore, the PbAc-treated group showed a statistically significant rise (p < 0.05) in brain acetylcholinesterase, malondialdehyde, nitric oxide, interleukin-1-beta, tumor necrosis factor-α, and caspase-9 levels in comparison to the control. Administration of both 100 mg/kg and 200 mg/kg of 6-GREG effectively reversed these behavioral and biochemical changes in 6-GREG (100)- and 6-GREG (200)-treated groups respectively compared to the PbAc-treated group. Consequently, the study reveals the role of 6-GREG in attenuating PbAc-induced neurotoxicity and brain damage via antioxidative, anti-inflammatory, and anti-apoptotic mechanisms.
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Affiliation(s)
- Maryam Tayo Ayinla
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Ilorin, Nigeria
| | - Abraham Olufemi Asuku
- Department of Physiology, Faculty of Basic Medical Sciences, College of Health Sciences, University of Ilorin, Ilorin, Ilorin, Nigeria.
- Bioresources Development Centre, National Biotechnology Research and Development Agency (NBRDA), Ogbomoso, Nigeria.
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Salman M, Ismael S, Ishrat T. A modified murine photothrombotic stroke model: a minimally invasive and reproducible cortical and sub-cortical infarct volume and long-term deficits. Exp Brain Res 2023; 241:2487-2497. [PMID: 37656197 DOI: 10.1007/s00221-023-06696-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 08/22/2023] [Indexed: 09/02/2023]
Abstract
Ischemic stroke is one of the major causes of devastating neurological disabilities and mortality worldwide. Despite extensive research for treatment approaches, there remains limited therapy in the stroke field. Therefore, more research is required for reproducibility to understand stroke pathology in pre-clinical studies. In the current modified method, mice were subjected to photothrombotic stroke (pt-MCA; proximal-middle cerebral artery was exposed with a 532 nm laser beam for 4 min) by retro-orbital injection of photosensitive dye, Rose Bengal (15 mg/kg) before the laser light exposure. Sensorimotor deficits were assessed by rotarod and catwalk test at 72 h following post-pt-MCAO, and brain samples were collected for infarct volume and hemorrhagic transformation (HT) assessments. Cognitive impairments were assessed by a novel objective recognition and Morris's water maze tests at the end of the follow-up. pt-MCAO animals significantly reduced body weight and impaired motor and cognitive functions. Furthermore, pt-MCAO animals showed apparent infarction, brain edema, and increased HT compared to the sham animals. Additionally, this method enables concurrent measurement of short-term and long-term neurological dysfunction with relatively larger cortical and sub-cortical infarct volume following pt-MCAO. With respect to the other models, this modified model offers enhanced reproducibility regarding infarct volume and cognitive/functional outcomes and avoids complications associated with critical surgeries and craniotomy. In conclusion, this modified model helps to understand stroke pathogenesis and minimize the animals' numbers which help to increase the scientific and statistical potential in pre-clinical studies.
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Affiliation(s)
- Mohd Salman
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-228, Memphis, TN, 38163, USA
| | - Saifudeen Ismael
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-228, Memphis, TN, 38163, USA
| | - Tauheed Ishrat
- Department of Anatomy and Neurobiology, College of Medicine, The University of Tennessee Health Science Center, 875 Monroe Avenue, Wittenborg Bldg, Room-228, Memphis, TN, 38163, USA.
- Neuroscience Institute, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
- Department of Pharmaceutical Sciences, The University of Tennessee Health Science Center, Memphis, TN, 38163, USA.
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Zhang K, He K, Xu J, Nie L, Li S, Liu J, Long D, Dai Z, Yang X. Manganese exposure causes movement deficit and changes in the protein profile of the external globus pallidus in Sprague Dawley rats. Toxicol Ind Health 2021; 37:715-726. [PMID: 34706592 DOI: 10.1177/07482337211022223] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Manganese (Mn) is required for normal brain development and function. Excess Mn may trigger a parkinsonian movement disorder but the underlying mechanisms are incompletely understood. We explored changes in the brain proteomic profile and movement behavior of adult Sprague Dawley (SD) rats systemically treated with or without 1.0 mg/mL MnCl2 for 3 months. Mn treatment significantly increased the concentration of protein-bound Mn in the external globus pallidus (GP), as demonstrated by inductively coupled plasma mass spectrometry. Behavioral study showed that Mn treatment induced movement deficits, especially of skilled movement. Proteome analysis by two-dimensional fluorescence difference gel electrophoresis coupled with mass spectrometry revealed 13 differentially expressed proteins in the GP of Mn-treated versus Mn-untreated SD rats. The differentially expressed proteins were mostly involved in glycolysis, metabolic pathways, and response to hypoxia. Selected pathway class analysis of differentially expressed GP proteins, which included phosphoglycerate mutase 1 (PGAM1), primarily identified enrichment in glycolytic process and innate immune response. In conclusion, perturbation of brain energy production and innate immune response, in which PGAM1 has key roles, may contribute to the movement disorder associated with Mn neurotoxicity.
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Affiliation(s)
- Kaiqin Zhang
- School of Public Health, University of South China, Hunan Hengyang, China.,Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Kaiwu He
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China.,School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Jia Xu
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Lulin Nie
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Shupeng Li
- School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, China
| | - Jianjun Liu
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Dingxin Long
- School of Public Health, University of South China, Hunan Hengyang, China
| | - Zhongliang Dai
- The department of Anesthesiology, Shenzhen People's Hospital, The Second Clinical Medical College, Jinan University, Shenzhen, China
| | - Xifei Yang
- Key Laboratory of Modern Toxicology of Shenzhen, Shenzhen Medical Key Discipline of Health Toxicology, Shenzhen Center for Disease Control and Prevention, Shenzhen, China
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Nalamolu KR, Chelluboina B, Fornal CA, Challa SR, Pinson DM, Wang DZ, Klopfenstein JD, Veeravalli KK. Stem cell treatment improves post stroke neurological outcomes: a comparative study in male and female rats. Stroke Vasc Neurol 2021; 6:519-527. [PMID: 33741744 PMCID: PMC8717804 DOI: 10.1136/svn-2020-000834] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/12/2021] [Accepted: 02/18/2021] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND AND PURPOSE The therapeutic potential of different stem cells for ischaemic stroke treatment is intriguing and somewhat controversial. Recent results from our laboratory have demonstrated the potential benefits of human umbilical cord blood-derived mesenchymal stem cells (MSC) in a rodent stroke model. We hypothesised that MSC treatment would effectively promote the recovery of sensory and motor function in both males and females, despite any apparent sex differences in post stroke brain injury. METHODS Transient focal cerebral ischaemia was induced in adult Sprague-Dawley rats by occlusion of the middle cerebral artery. Following the procedure, male and female rats of the untreated group were euthanised 1 day after reperfusion and their brains were used to estimate the resulting infarct volume and tissue swelling. Additional groups of stroke-induced male and female rats were treated with MSC or vehicle and were subsequently subjected to a battery of standard neurological/neurobehavioral tests (Modified Neurological Severity Score assessment, adhesive tape removal, beam walk and rotarod). The tests were administered at regular intervals (at days 1, 3, 5, 7 and 14) after reperfusion to determine the time course of neurological and functional recovery after stroke. RESULTS The infarct volume and extent of swelling of the ischaemic brain were similar in males and females. Despite similar pathological stroke lesions, the clinical manifestations of stroke were more pronounced in males than females, as indicated by the neurological scores and other tests. MSC treatment significantly improved the recovery of sensory and motor function in both sexes, and it demonstrated efficacy in both moderate stroke (females) and severe stroke (males). CONCLUSIONS Despite sex differences in the severity of post stroke outcomes, MSC treatment promoted the recovery of sensory and motor function in male and female rats, suggesting that it may be a promising treatment for stroke.
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Affiliation(s)
- Koteswara Rao Nalamolu
- Cancer Biology and Pharmacology, College of Medicine, University of Illinois, Peoria, Illinois, USA.,Pharmaceutical and Biomedical Sciences, California Health Sciences University, Clovis, California, USA
| | - Bharath Chelluboina
- Cancer Biology and Pharmacology, College of Medicine, University of Illinois, Peoria, Illinois, USA.,Neurological Surgery, University of Wisconsin-Madison, Madison, Wisconsin, USA
| | - Casimir A Fornal
- Cancer Biology and Pharmacology, College of Medicine, University of Illinois, Peoria, Illinois, USA
| | - Siva Reddy Challa
- Cancer Biology and Pharmacology, College of Medicine, University of Illinois, Peoria, Illinois, USA
| | - David M Pinson
- Health Sciences Education, College of Medicine, University of Illinois, Peoria, Illinois, USA
| | - David Z Wang
- Neurology, College of Medicine, University of Illinois, Peoria, Illinois, USA.,Neurology, Barrow Neurological Institute, Phoenix, Arizona, USA
| | - Jeffrey D Klopfenstein
- Cancer Biology and Pharmacology, College of Medicine, University of Illinois, Peoria, Illinois, USA.,Neurosurgery, College of Medicine, University of Illinois, Peoria, Illinois, USA.,OSF HealthCare Illinois Neurological Institute, Peoria, Illinois, USA
| | - Krishna Kumar Veeravalli
- Cancer Biology and Pharmacology, College of Medicine, University of Illinois, Peoria, Illinois, USA .,Neurology, College of Medicine, University of Illinois, Peoria, Illinois, USA.,Neurosurgery, College of Medicine, University of Illinois, Peoria, Illinois, USA.,Pediatrics, College of Medicine, University of Illinois, Peoria, Illinois, USA
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Nalamolu KR, Challa SR, Fornal CA, Grudzien NA, Jorgenson LC, Choudry MM, Smith NJ, Palmer CJ, Pinson DM, Klopfenstein JD, Veeravalli KK. Attenuation of the Induction of TLRs 2 and 4 Mitigates Inflammation and Promotes Neurological Recovery After Focal Cerebral Ischemia. Transl Stroke Res 2021; 12:923-936. [PMID: 33426628 DOI: 10.1007/s12975-020-00884-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 10/16/2020] [Accepted: 12/22/2020] [Indexed: 12/17/2022]
Abstract
The intense inflammatory response triggered in the brain after focal cerebral ischemia is detrimental. Recently, we showed that the suppression of toll-like receptors (TLRs) 2 and 4 attenuates infarct size and reduces the expression of pro-inflammatory cytokines in the ischemic brain. In this study, we further examined the effect of unsuppressed induction of TLRs 2 and 4 on the expression of its downstream signaling molecules and pro-inflammatory cytokines 1 week after reperfusion. The primary purpose of this study was to investigate the effect of simultaneous knockdown of TLRs 2 and 4 on M1/M2 microglial polarization dynamics and post-stroke neurological deficits and the recovery. Transient focal cerebral ischemia was induced in young adult male Sprague-Dawley rats by the middle cerebral artery occlusion (MCAO) procedure using a monofilament suture. Appropriate cohorts of rats were treated with a nanoparticle formulation of TLR2shRNA and TLR4shRNA (T2sh+T4sh) expressing plasmids (1 mg/kg each of T2sh and T4sh) or scrambled sequence inserted vector (vehicle control) expressing plasmids (2 mg/kg) intravenously via tail vein immediately after reperfusion. Animals from various cohorts were euthanized during reperfusion, and the ischemic brain tissue was isolated and utilized for PCR followed by agarose gel electrophoresis, real-time PCR, immunoblot, and immunofluorescence analysis. Appropriate groups were subjected to a battery of standard neurological tests at regular intervals until 14 days after reperfusion. The increased expression of both TLRs 2 and 4 and their downstream signaling molecules including the pro-inflammatory cytokines was observed even at 1-week after reperfusion. T2sh+T4sh treatment immediately after reperfusion attenuated the post-ischemic inflammation, preserved the motor function, and promoted recovery of the sensory and motor functions. We conclude that the post-ischemic induction of TLRs 2 and 4 persists for at least 7 days after reperfusion, contributes to the severity of acute inflammation, and impedes neurological recovery. Unlike previous studies in TLRs 2 or 4 knockout models, results of this study in a pharmacologically relevant preclinical rodent stroke model have translational significance.
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Affiliation(s)
- Koteswara Rao Nalamolu
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
- Department of Pharmaceutical and Biomedical Sciences, California Health Sciences University, Clovis, CA, USA
| | - Siva Reddy Challa
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
| | - Casimir A Fornal
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
| | - Natalia A Grudzien
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
| | - Laura C Jorgenson
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
| | - Mouneeb M Choudry
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
| | - Nathan J Smith
- Department of Surgery, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Cassandra J Palmer
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
| | - David M Pinson
- Department of Health Sciences Education, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Jeffrey D Klopfenstein
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA
- Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA
| | - Krishna Kumar Veeravalli
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, 1 Illini Dr, Peoria, IL, 61605, USA.
- Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
- Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA.
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Wang C, Cao J, Duan S, Xu R, Yu H, Huo X, Qian Y. Effect of MicroRNA-126a-3p on Bone Marrow Mesenchymal Stem Cells Repairing Blood-brain Barrier and Nerve Injury after Intracerebral Hemorrhage. J Stroke Cerebrovasc Dis 2020; 29:104748. [PMID: 32160957 DOI: 10.1016/j.jstrokecerebrovasdis.2020.104748] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 01/10/2020] [Accepted: 02/09/2020] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE Intracerebral hemorrhage (ICH) is a disease that threatens human health due to its high morbidity and mortality. On behalf of finding the better methods in the treatment of ICH, researchers pay more attention to a new technology which is finding effective genes to modify stem cells. METHODS In this study, we isolated, cultured and identified bone marrow mesenchymal stem cells (MSCs) in vitro. Further, the MSCs (transfected with lentivirus expressing microRNA-126a-3p (miR-126)) were injected into the type Ⅶ collagenase-induced ICH rats to investigate the recovery effects of blood-brain barrier (BBB) and nerve damage in vivo. RESULTS The MSCs surface marker molecules (CD29: 98.5%; CD90: 96.5%) were highly expressed, and the blood cell surface molecule was negatively expressed (CD45: 2%). Meanwhile, it was verified that miR-126 facilitated the differentiation of MSCs into vascular endothelial cells, owing to the rise of markers (CD31 and VE-cadherin). The modified neurological severity score, modified limb placing test score, brain water content and evans blue content were reduced after transplanted miR-126-modified MSCs. It was found that miR-126 accelerated the differentiation of MSCs into vascular endothelial cells via immunohistochemical staining in vivo. HE staining indicated the area of edema was obviously decreased compared with that in ICH + vector-MSCs group. MiR-126-modified MSCs alleviated the cell apoptosis in brain tissues by TUNEL assay. In addition, the mRNA and protein expression of protease activated receptor-1 and matrix metalloproteinase-9 were diminished, whilst the expression of zonula occludens-1 (ZO-1) and claudin-5 were enhanced in ICH+miR-126-MSCs group. Immunofluorescence assay revealed that miR-126-modified MSCs decreased the disruption of tight junction (ZO-1 and claudin-5). CONCLUSIONS All data illustrate that miR-126-modified MSCs repair BBB and nerve injury after ICH.
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Affiliation(s)
- Chunyan Wang
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China.
| | - Jingwei Cao
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Shurong Duan
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Ran Xu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Hongli Yu
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Xin Huo
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
| | - Yuanyuan Qian
- Department of Neurology, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China
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Li Z, Gao Y, Yang C, Xiang Y, Zhang W, Zhang T, Su R, Lu C, Zhuang X. Assessment and Confirmation of Species Difference in Nonlinear Pharmacokinetics of Atipamezole with Physiologically Based Pharmacokinetic Modeling. Drug Metab Dispos 2020; 48:41-51. [PMID: 31699808 DOI: 10.1124/dmd.119.089151] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Accepted: 10/24/2019] [Indexed: 11/22/2022] Open
Abstract
Atipamezole, an α 2-adrenoceptor antagonist, displayed nonlinear pharmacokinetics (PK) in rats. The aim of this study was to understand the underlying mechanisms of nonlinear PK in rats and linear PK in humans and develop physiologically based PK models (PBPK) to capture and validate this phenomenon. In vitro and in vivo data were generated to show that metabolism is the main clearance pathway of atipamezole and species differences exist. Where cytochrome P450 (P450) was responsible for the metabolism in rats with a low Michaelis constant, human-specific UDP-glucuronosyltransferase 2B10- and 1A4-mediated N-glucuronidation was identified as the leading contributor to metabolism in humans with a high V max capacity. Saturation of metabolism was observed in rats at pharmacologically relevant doses, but not in humans at clinically relevant doses. PBPK models were developed using GastroPlus software to predict the PK profile of atipamezole in rats after intravenous or intramuscular administration of 0.1 to 3 mg/kg doses. The model predicted the nonlinear PK of atipamezole in rats and predicted observed exposures within 2-fold across dose levels. Under the same model structure, a human PBPK model was developed using human in vitro metabolism data. The PBPK model well described human concentration-time profiles at 10-100 mg doses showing dose-proportional increases in exposure. This study demonstrated that PBPK is a useful tool to predict human PK when interspecies extrapolation is not applicable. The nonlinear PK in rat and linear PK in human were characterized in vitro and allowed the prospective human PK via intramuscular dosing to be predicted at the preclinical stage. SIGNIFICANCE STATEMENT: This study demonstrated that PBPK is a useful tool for predicting human PK when interspecies extrapolation is not applicable due to species unique metabolism. Atipamezole, for example, is metabolized by P450 in rats and by N-glucuronidation in humans that were hypothesized to be the underlying reasons for a nonlinear PK in rats and linear PK in humans. This was testified by PBPK simulation in this study.
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Affiliation(s)
- Zheng Li
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - You Gao
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Chunmiao Yang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Yanan Xiang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Wenpeng Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Tianhong Zhang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Ruibin Su
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Chuang Lu
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
| | - Xiaomei Zhuang
- State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing, China (Z.L., Y.G., C.Y., Y.X., W.Z., T.Z., R.S., X.Z.); and Department of DMPK, Sanofi Company, Waltham, Massachusetts (C.L.)
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Song J, Kim YS, Lee DH, Lee SH, Park HJ, Lee D, Kim H. Neuroprotective effects of oleic acid in rodent models of cerebral ischaemia. Sci Rep 2019; 9:10732. [PMID: 31341184 PMCID: PMC6656890 DOI: 10.1038/s41598-019-47057-z] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Accepted: 06/06/2019] [Indexed: 01/02/2023] Open
Abstract
Oleic acid (OA) is released from brain phospholipids after cerebral ischaemia; however, its role in ischaemic injury remains unknown. We hypothesised that OA has neuroprotective effects after cerebral ischaemia, which may be exerted through peroxisome proliferator-activated receptor gamma (PPAR-γ) activation, since OA is an endogenous ligand of PPAR-γ. The effects of OA administration were evaluated in rodent models of middle cerebral artery occlusion (MCAO), photothrombosis, and four-vessel occlusion (4-VO). We determined the time window of therapeutic opportunity and examined the ability of the PPAR-γ antagonist GW9662 to reverse OA’s protective effects after MCAO. We found that OA administration decreased the MCAO-induced infarct volume and functional deficits, photothrombosis-induced infarct volume, and 4-VO-induced hippocampal neuronal death. Additionally, OA was highly efficacious when administered up to 3 h after MCAO. Pre-treatment with GW9662 abolished the inhibitory effects of OA on the infarct volume and immunoreactivity of key inflammatory mediators in the ischaemic cortex. Our results indicate that OA has neuroprotective effects against transient and permanent focal cerebral ischaemia, as well as global cerebral ischaemia. It may have therapeutic value for the ischaemic stroke treatment with a clinically feasible therapeutic window. The OA-mediated neuroprotection might be attributable to its anti-inflammatory actions through PPAR-γ activation.
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Affiliation(s)
- Jungbin Song
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Young-Sik Kim
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Dong Hwan Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea
| | - Sung Hyun Lee
- Korea Institute of Science and Technology for Eastern Medicine (KISTEM) NeuMed Inc., 88 Imun-ro, Dongdaemun-gu, Seoul, 02440, Republic of Korea
| | - Hyo Jin Park
- Korea Institute of Science and Technology for Eastern Medicine (KISTEM) NeuMed Inc., 88 Imun-ro, Dongdaemun-gu, Seoul, 02440, Republic of Korea
| | - Donghun Lee
- Department of Herbal Pharmacology, College of Korean Medicine, Gachon University, 1342 Seongnamdae-ro, Sujeong-gu, Seongnam-si, Gyeonggi-do, 13120, Republic of Korea.
| | - Hocheol Kim
- Department of Herbal Pharmacology, College of Korean Medicine, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
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Neuroprotective Effects of Musk of Muskrat on Transient Focal Cerebral Ischemia in Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2019; 2019:9817949. [PMID: 31341507 PMCID: PMC6614976 DOI: 10.1155/2019/9817949] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/12/2019] [Accepted: 06/11/2019] [Indexed: 11/18/2022]
Abstract
Musk of musk deer has been one of the most precious traditional medicinal materials for treatment of stroke, but trading is prohibited. Musk of muskrat, Ondatra zibethicus, is an accessible substitute for musk of musk deer. However, neuroprotective effects of the musk of muskrat on stroke model are so far unclear. Aim of the study is to determine neuroprotective effects of the musk of muskrat on focal cerebral ischemia. The protective effects against focal cerebral ischemia were evaluated using a model of middle cerebral artery occlusion (90-minute occlusion followed by 24-hour reperfusion). Musk of muskrat was collected from scent bag of muskrat and orally administered at doses of 100 and 300 mg/kg twice at times of 0 and 90 min after occlusion. The effects on sensorimotor dysfunction were investigated by using balance beam test and rotarod test after brain ischemia. The expression of cyclooxygenase-2 (COX-2) was investigated by immunohistochemistry. Oral administration of musk at 300 mg/kg significantly reduced (p<0.001) the infarct volume by 32.4% compared with a vehicle-treated group. Oral administration of musk at 300 mg/kg also ameliorated ischemia-induced spontaneous and vestibule sensorimotor dysfunction in balance beam test and rotarod test compared with control group and COX-2 upregulation. Musk of muskrat may have neuroprotective effects against transient focal cerebral ischemia with recovery of sensorimotor dysfunction. Regarding the immunohistochemistry, the effects of muskrat may be due to anti-inflammatory properties through inhibition of COX-2 expressions.
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10
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Nalamolu KR, Venkatesh I, Mohandass A, Klopfenstein JD, Pinson DM, Wang DZ, Veeravalli KK. Exosomes Treatment Mitigates Ischemic Brain Damage but Does Not Improve Post-Stroke Neurological Outcome. Cell Physiol Biochem 2019; 52:1280-1291. [PMID: 31026391 PMCID: PMC6996798 DOI: 10.33594/000000090] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Accepted: 04/23/2019] [Indexed: 12/16/2022] Open
Abstract
Background/Aims: Recent studies demonstrated that the treatment with mesenchymal stem cells (MSCs) obtained from the human umbilical cord blood improved survival, reduced brain damage, prevented apoptosis, suppressed inflammatory responses, downregulated the DNA damage-inducing genes, upregulated the DNA repair genes, and facilitated neurological recovery in stroke-induced animals. Emerging stroke literature supports the concept that the exosomes released from MSCs are the primary biological principles underlying the post-stroke neuroprotection offered by MSCs treatment. Methods: Because the treatment with exosomes has a great potential to overcome the limitations associated with cell-based therapies, we tested the efficacy of exosomes secreted from HUCB-MSCs under standard culture conditions on post-stroke brain damage and neurological outcome in a rat model of ischemic stroke by performing TTC staining as well as the modified neurological severity scores, modified adhesive removal, beam-walking, and accelerating Rotarod performance tests before ischemia and at regular intervals until seven days reperfusion. Results: Exosomes treatment attenuated the infarct size. Treatment with exosomes did not affect the post-stroke survival rate and body weight changes, but exacerbated the somatosensory and motor dysfunction and adversely affected the natural recovery that occurs without any treatment. Conclusion: Treatment with exosomes secreted from HUCB-MSCs under standard culture conditions attenuates the ischemic brain damage but does not improve the post-stroke neurological outcome.
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Affiliation(s)
- Koteswara Rao Nalamolu
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, USA
| | - Ishwarya Venkatesh
- Department of Internal Medicine, Rush University Medical Center, Chicago, USA
| | - Adithya Mohandass
- School of Pharmacy, College of Health Sciences, University of Wyoming, Laramie, USA
| | - Jeffrey D Klopfenstein
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, USA.,Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, USA.,Comprehensive Stroke Center, OSF Illinois Neurological Institute, Peoria, USA
| | - David M Pinson
- Department of Pathology, University of Illinois College of Medicine at Peoria, Peoria, USA
| | - David Z Wang
- Comprehensive Stroke Center, OSF Illinois Neurological Institute, Peoria, USA.,Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, USA
| | - Krishna Kumar Veeravalli
- Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, USA.,Department of Neurosurgery, University of Illinois College of Medicine at Peoria, Peoria, USA.,Department of Neurology, University of Illinois College of Medicine at Peoria, Peoria, USA.,Department of Health Sciences Education, University of Illinois College of Medicine at Rockford, Rockford, USA,
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11
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Adrenergic receptor antagonism induces neuroprotection and facilitates recovery from acute ischemic stroke. Proc Natl Acad Sci U S A 2019; 116:11010-11019. [PMID: 31097598 DOI: 10.1073/pnas.1817347116] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Spontaneous waves of cortical spreading depolarization (CSD) are induced in the setting of acute focal ischemia. CSD is linked to a sharp increase of extracellular K+ that induces a long-lasting suppression of neural activity. Furthermore, CSD induces secondary irreversible damage in the ischemic brain, suggesting that K+ homeostasis might constitute a therapeutic strategy in ischemic stroke. Here we report that adrenergic receptor (AdR) antagonism accelerates normalization of extracellular K+, resulting in faster recovery of neural activity after photothrombotic stroke. Remarkably, systemic adrenergic blockade before or after stroke facilitated functional motor recovery and reduced infarct volume, paralleling the preservation of the water channel aquaporin-4 in astrocytes. Our observations suggest that AdR blockers promote cerebrospinal fluid exchange and rapid extracellular K+ clearance, representing a potent potential intervention for acute stroke.
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12
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Löscher W. The holy grail of epilepsy prevention: Preclinical approaches to antiepileptogenic treatments. Neuropharmacology 2019; 167:107605. [PMID: 30980836 DOI: 10.1016/j.neuropharm.2019.04.011] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 04/03/2019] [Accepted: 04/09/2019] [Indexed: 02/06/2023]
Abstract
A variety of acute brain insults can induce epileptogenesis, a complex process that results in acquired epilepsy. Despite advances in understanding mechanisms of epileptogenesis, there is currently no approved treatment that prevents the development or progression of epilepsy in patients at risk. The current concept of epileptogenesis assumes a window of opportunity following acute brain insults that allows intervention with preventive treatment. Recent results suggest that injury-induced epileptogenesis can be a much more rapid process than previously thought, suggesting that the 'therapeutic window' may only be open for a brief period, as in stroke therapy. However, experimental data also suggest a second, possibly delayed process ("secondary epileptogenesis") that influences the progression and refractoriness of the epileptic state over time, allowing interfering with this process even after onset of epilepsy. In this review, both methodological issues in preclinical drug development and novel targets for antiepileptogenesis will be discussed. Several promising drugs that either prevent epilepsy (antiepileptogenesis) or slow epilepsy progression and alleviate cognitive or behavioral comorbidities of epilepsy (disease modification) have been described in recent years, using diverse animal models of acquired epilepsy. Promising agents include TrkB inhibitors, losartan, statins, isoflurane, anti-inflammatory and anti-oxidative drugs, the SV2A modulator levetiracetam, and epigenetic interventions. Research on translational target validity and on prognostic biomarkers that can be used to stratify patients (or experimental animals) at high risk of developing epilepsy will hopefully soon lead to proof-of-concept clinical trials with the most promising drugs, which will be essential to make prevention of epilepsy a reality. This article is part of the special issue entitled 'New Epilepsy Therapies for the 21st Century - From Antiseizure Drugs to Prevention, Modification and Cure of Epilepsy'.
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Affiliation(s)
- Wolfgang Löscher
- Department of Pharmacology, Toxicology, and Pharmacy, University of Veterinary Medicine, Hannover, Germany; Center for Systems Neuroscience, Hannover, Germany.
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13
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Selakovic V, Arsenijevic L, Jovanovic M, Sivcev S, Jovanovic N, Leontijevic M, Stojanovic M, Radenkovic M, Andjus P, Radenovic L. Functional and pharmacological analysis of agmatine administration in different cerebral ischemia animal models. Brain Res Bull 2019; 146:201-212. [PMID: 30641119 DOI: 10.1016/j.brainresbull.2019.01.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 12/18/2018] [Accepted: 01/03/2019] [Indexed: 11/17/2022]
Abstract
Agmatine (AgM, 100 mg/kg i.p.) effect was tested in parallel at two animal models of cerebral ischemia - rat MCAO model (60'/24 h, 60'/48 h, 90'/24 h, 90'/48 h) and gerbil global ischemia (10') model, administrated 5 min after reperfusion. Aim was to evaluate AgM effect on functional outcome 24 and 48 h after MCAO on neurological and sensor-motor function, and coordination in rats. AgM administration significantly reduced infarct volume, improved neurological score and improved post-ischemic oxidative status. Results of behavioral tests (cylinder test, beam walking test, and adhesive removal test) have shown very effective functional recovery after AgM administration. Efficiency of AgM administration in gerbils was observed in forebrain cortex, striatum, hippocampus, and cerebellum at the level of each examined oxidative stress parameter (nitric oxide level, superoxide production, superoxide dismutase activity, and index of lipid peroxidation) measured in four different time points starting at 3 h up to 48 h after reperfusion. The highest levels were obtained 6 h after the insult. The most sensitive oxidative stress parameter to AgM was nitric oxide. Additionally, we performed pharmacological analysis of AgM on rat isolated common carotid arteries. The findings imply that mixed population of potassium channels located on the smooth muscle cells was involved in common carotid artery response to AgM, with predominance of inward rectifying K+ channels. In our comparative experimental approach, judged by behavioral, biochemical, as well as pharmacological data, the AgM administration showed an effective reduction of ischemic neurological damage and oxidative stress, hence indicating a direction towards improving post-stroke recovery.
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Affiliation(s)
- V Selakovic
- Institute of Medical Research, Medical Faculty Military Medical Academy, University of Defense, Serbia
| | | | - M Jovanovic
- Faculty of Biology, University of Belgrade, Serbia
| | - S Sivcev
- Faculty of Biology, University of Belgrade, Serbia
| | - N Jovanovic
- Faculty of Biology, University of Belgrade, Serbia
| | | | - M Stojanovic
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Serbia
| | - M Radenkovic
- Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Serbia
| | - P Andjus
- Faculty of Biology, University of Belgrade, Serbia
| | - L Radenovic
- Faculty of Biology, University of Belgrade, Serbia.
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14
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McDonald MW, Hayward KS, Rosbergen ICM, Jeffers MS, Corbett D. Is Environmental Enrichment Ready for Clinical Application in Human Post-stroke Rehabilitation? Front Behav Neurosci 2018; 12:135. [PMID: 30050416 PMCID: PMC6050361 DOI: 10.3389/fnbeh.2018.00135] [Citation(s) in RCA: 96] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2018] [Accepted: 06/14/2018] [Indexed: 11/13/2022] Open
Abstract
Environmental enrichment (EE) has been widely used as a means to enhance brain plasticity mechanisms (e.g., increased dendritic branching, synaptogenesis, etc.) and improve behavioral function in both normal and brain-damaged animals. In spite of the demonstrated efficacy of EE for enhancing brain plasticity, it has largely remained a laboratory phenomenon with little translation to the clinical setting. Impediments to the implementation of enrichment as an intervention for human stroke rehabilitation and a lack of clinical translation can be attributed to a number of factors not limited to: (i) concerns that EE is actually the "normal state" for animals, whereas standard housing is a form of impoverishment; (ii) difficulty in standardizing EE conditions across clinical sites; (iii) the exact mechanisms underlying the beneficial actions of enrichment are largely correlative in nature; (iv) a lack of knowledge concerning what aspects of enrichment (e.g., exercise, socialization, cognitive stimulation) represent the critical or active ingredients for enhancing brain plasticity; and (v) the required "dose" of enrichment is unknown, since most laboratory studies employ continuous periods of enrichment, a condition that most clinicians view as impractical. In this review article, we summarize preclinical stroke recovery studies that have successfully utilized EE to promote functional recovery and highlight the potential underlying mechanisms. Subsequently, we discuss how EE is being applied in a clinical setting and address differences in preclinical and clinical EE work to date. It is argued that the best way forward is through the careful alignment of preclinical and clinical rehabilitation research. A combination of both approaches will allow research to fully address gaps in knowledge and facilitate the implementation of EE to the clinical setting.
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Affiliation(s)
- Matthew W McDonald
- Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.,Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada
| | - Kathryn S Hayward
- Stroke Division, Florey Institute of Neuroscience and Mental Health, Heidelberg, VIC, Australia.,NHMRC Centre for Research Excellence in Stroke Rehabilitation and Brain Recovery, Heidelberg, VIC, Australia
| | - Ingrid C M Rosbergen
- Division of Physiotherapy, School of Health and Rehabilitation Sciences, The University of Queensland, Brisbane, QLD, Australia.,Allied Health Services, Sunshine Coast Hospital and Health Service, Birtinya, QLD, Australia
| | - Matthew S Jeffers
- Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.,Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada
| | - Dale Corbett
- Department of Cellular & Molecular Medicine, University of Ottawa, Ottawa, ON, Canada.,Canadian Partnership for Stroke Recovery, Ottawa, ON, Canada
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15
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Nissinen J, Andrade P, Natunen T, Hiltunen M, Malm T, Kanninen K, Soares JI, Shatillo O, Sallinen J, Ndode-Ekane XE, Pitkänen A. Disease-modifying effect of atipamezole in a model of post-traumatic epilepsy. Epilepsy Res 2017; 136:18-34. [DOI: 10.1016/j.eplepsyres.2017.07.005] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Revised: 06/30/2017] [Accepted: 07/06/2017] [Indexed: 12/25/2022]
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16
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Pan M, Wang P, Zheng C, Zhang H, Lin S, Shao B, Zhuge Q, Jin K. Aging Systemic Milieu Impairs Outcome after Ischemic Stroke in Rats. Aging Dis 2017; 8:519-530. [PMID: 28966798 PMCID: PMC5614318 DOI: 10.14336/ad.2017.0710] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2017] [Accepted: 07/10/2017] [Indexed: 11/26/2022] Open
Abstract
Compelling evidence indicates that factors in the blood can profoundly reverse aging-related impairments, as exposure of aged mice to young blood rejuvenates adult stem cell function, improves cognition, and ameliorates cardiac hypertrophy. Systemic factors from mice can also extend the life span of a partner exposed to a lethal treatment or disease. These findings suggest that the systemic milieu of a healthy young partner may be beneficial for an aged organism. However, it is unknown whether a healthy young systemic milieu can improve functional recovery after ischemic stroke. Intraperitoneal administration of young plasma into aged rats after ischemic stroke induced by distal middle cerebral artery occlusion (dMCAO) reduced infarct volume and motor impairment, compared with vehicle group. On the contrary, intraperitoneal administration of plasma from aged rats into young ischemic rats worsened brain injury and motor deficits. Using a proteomic approach, we found that haptoglobin levels were significantly increased in serum of aged rats and that intraperitoneal administration of haptoglobin impaired outcome after ischemic stroke in young rats. Our data suggest that the aging systemic milieu plays a critical role in functional outcome after ischemic stroke.
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Affiliation(s)
- Mengxiong Pan
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.,2Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
| | - Peng Wang
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Chengcai Zheng
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Hongxia Zhang
- 2Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
| | - Siyang Lin
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Bei Shao
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Qichuan Zhuge
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China
| | - Kunlin Jin
- 1Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325000, China.,2Institute for Healthy Aging, University of North Texas Health Science Center, Fort Worth, Texas 76107, USA
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17
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Hylin MJ, Brenneman MM, Corwin JV. Noradrenergic antagonists mitigate amphetamine-induced recovery. Behav Brain Res 2017; 334:61-71. [PMID: 28756213 DOI: 10.1016/j.bbr.2017.07.035] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2017] [Revised: 07/18/2017] [Accepted: 07/25/2017] [Indexed: 11/16/2022]
Abstract
Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment.
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Affiliation(s)
- M J Hylin
- Neurotrauma and Rehabilitation Laboratory, Department of Psychology, Southern Illinois University, Carbondale, IL, United States.
| | - M M Brenneman
- Department of Psychology, Coastal Carolina University, P.O. Box 261954, Conway, SC, United States
| | - J V Corwin
- Department of Psychology, Northern Illinois University, DeKalb, IL, United States
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18
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Hu Y, Liu N, Zhang P, Pan C, Zhang Y, Tang Y, Deng H, Aimaiti M, Zhang Y, Zhou H, Wu G, Tang Z. Preclinical Studies of Stem Cell Transplantation in Intracerebral Hemorrhage: a Systemic Review and Meta-Analysis. Mol Neurobiol 2016; 53:5269-77. [PMID: 26409481 PMCID: PMC5012148 DOI: 10.1007/s12035-015-9441-6] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 09/10/2015] [Indexed: 01/15/2023]
Abstract
To comprehensively evaluate the therapeutic effects on both functional and structural outcomes, we performed a meta-analysis of preclinical data on stem cell therapy in intracranial hemorrhage, thus providing optimal evidence and instruction for clinical translation. We searched online databases to identify eligible studies based on unmodified stem cell transplantation in intracranial hemorrhage (ICH). From each study, we extracted data regarding neurobehavioral and histological outcomes in order to analyze the comprehensive effective sizes according to the most important clinical parameters (seven indices) and to explore any potential correlation through meta-regression. We analyzed 40 eligible studies including 1021 animals and found a significant improvement in both behavioral and structural outcomes with the median effect size of 1.77 for modified Neurological Severity Score, 1.16 for the modified placement test, 1.82 for the rotarod test, and 1.24 for tissue loss reduction. The meta-regression results revealed that intracerebral administration was the most effective for behavioral and structural recovery post-ICH; mesenchymal stem cells shared comparable therapeutic effects with neural stem cells. Delayed therapy, applied more than 1 week after ICH, showed the greatest improvement of structural outcomes. Stem cell therapy showed significant improvement on behavioral and structural outcomes of ICH animals with relatively large effect sizes. However, the practical efficacy of the therapy is likely to be lower considering poor study quality and non-negligible publication bias. Further, future research should interpret animal results cautiously considering the limited internal and external validity when referring to the design of both animal studies and clinical trials.
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Affiliation(s)
- Yang Hu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Na Liu
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Chao Pan
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Youping Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yingxin Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Hong Deng
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Miribanu Aimaiti
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Ye Zhang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Houguang Zhou
- Department of Geriatrics Neurology, Huashan Hospital, Fudan University, Shanghai, 200040, People's Republic of China
| | - Guofeng Wu
- Department of Neurology, Affiliated Hospital of Guizhou Medical University, Guizhou, 550004, People's Republic of China
| | - Zhouping Tang
- Department of Neurology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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19
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Motor Skills Training Improves Sensorimotor Dysfunction and Increases Microtubule-Associated Protein 2 mRNA Expression in Rats with Intracerebral Hemorrhage. J Stroke Cerebrovasc Dis 2016; 25:2071-7. [DOI: 10.1016/j.jstrokecerebrovasdis.2016.05.007] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Revised: 04/20/2016] [Accepted: 05/06/2016] [Indexed: 11/21/2022] Open
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20
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Jolkkonen J, Kwakkel G. Translational Hurdles in Stroke Recovery Studies. Transl Stroke Res 2016; 7:331-42. [PMID: 27000881 DOI: 10.1007/s12975-016-0461-y] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2015] [Revised: 02/11/2016] [Accepted: 03/09/2016] [Indexed: 12/20/2022]
Abstract
Emerging understanding of brain plasticity has opened new avenues for the treatment of stroke. The promising preclinical evidence with neuroprotective drugs has not been confirmed in clinical trials, thus nowadays, researchers, pharmaceutical companies, and funding bodies hesitate to initiate these expensive trials with restorative therapies. Since many of the previous failures can be traced to low study quality, a number of guidelines such as STAIR and STEPS were introduced to rectify these shortcomings. However, these guidelines stem from the study design for neuroprotective drugs and one may question whether they are appropriate for restorative approaches, which rely heavily on behavioral testing. Most of the recovery studies conducted in stroke patients have been small-scale, proof-of-concept trials. Consequently, the overall effect sizes of pooled phase II trials have proved unreliable and unstable in most meta-analyses. Although the methodological quality of trials in humans is improving, most studies still suffer from methodological flaws and do not meet even the minimum of evidence-based standards for reporting randomized controlled trials. The power problem of most phase II trials is mostly attributable to a lack of proper stratification with robust prognostic factors at baseline as well as the incorrect assumption that all patients will exhibit the same proportional amount of spontaneous neurological recovery poststroke. In addition, most trials suffer from insufficient treatment contrasts between the experimental and control arm and the outcomes have not been sufficiently responsive to detect small but clinically relevant changes in neurological impairments and activities. This narrative review describes the main factors that bias recovery studies, both in experimental animals and stroke patients.
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Affiliation(s)
- Jukka Jolkkonen
- Department of Neurology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland. .,Neurocenter, Neurology, University Hospital of Kuopio, Kuopio, Finland.
| | - Gert Kwakkel
- Department of Rehabilitation Medicine, VU University Medical Center, MOVE Research Institute Amsterdam, Amsterdam, The Netherlands.,Neurorehabilitation, Amsterdam Rehabilitation Research Center, Reade, Amsterdam, The Netherlands.,Neuroscience Campus Amsterdam, VU University Amsterdam, Amsterdam, The Netherlands.,Department of Physical Therapy and Human Movement Sciences, Northwestern University, Evanston, IL, USA
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21
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Chang CZ, Wu SC. 4'-O-β-D-Glucosyl-5-O-Methylvisamminol, A Natural Histone H3 Phosphorylation Epigenetic Suppressor, Exerts a Neuroprotective Effect Through PI3K/Akt Signaling Pathway on Focal Cerebral Ischemia in Rats. World Neurosurg 2016; 89:474-88. [PMID: 26868427 DOI: 10.1016/j.wneu.2016.01.061] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2015] [Revised: 01/15/2016] [Accepted: 01/19/2016] [Indexed: 11/16/2022]
Abstract
BACKGROUND A bursting inflammation has been observed that compromises neurologic function in patients who experience stroke. We sought to examine the neuroprotective efficacy of 4'-O-β-D-glucosyl-5-O-methylvisamminol (OGOMV), a novel histone H3 phosphorylation epigenetic suppressor) in a transient middle cerebral artery occlusion (tMCAO). METHODS A rodent tMCAO model was used. Administration with 400 μg/kg/day OGOMV was initiated 12 hours before (prevention) and 1 hour after animals were subjected to tMCAO (reversal). The cerebral cortex was harvested to examine protein kinase B (PI3D/Akt), 5-bromo-2'-deoxyuridine (Western blot), and caspases (reverse-transcription polymerase chain reaction). In addition, cerebrospinal fluid samples were collected to examine interleukin 1-β, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-α (reverse-transcription polymerase chain reaction). RESULTS Cortical 5-bromo-2'-deoxyuridine and phospho-PI3D/Akt were reduced in tMCAO animals, compared with the healthy controls but increased in the OGOMV treatment and prevention groups. Activated cortical caspase-3,-6, and -9a as well as increased IL-1β and TNF-α levels were observed in the tMCAO animals (P < 0.05). Both prevention and treatment with OGOMV significantly reduced cleaved caspase-3 and -9a groups, but no significant change in caspase-6 was noted. Perifosine, an Akt inhibitor, was added to reduce the bioexpression of phospho-P13D/Akt, and Bcl-2 level and increased cleaved caspase-9a level in both OGOMV prevention and treatment tMCAO groups (P > 0.05). CONCLUSION Our study suggests that OGOMV could exert a neuroprotective effect by inhibiting the P13D/Akt protein, attenuating inflammation, and cleaved caspase-3- and -9a-related apoptosis. This study also lends credence to support the notion that the prevention of OGOMV could attenuate proinflammatory cytokine mRNA and late-onset caspases in tMCAO and merits further study.
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Affiliation(s)
- Chih-Zen Chang
- Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan; Department of Surgery, Kaohsiung Municipal Ta Tung Hospital, Kaohsiung, Taiwan.
| | - Shu-Chuan Wu
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan
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22
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Chang CZ, Wu SC, Kwan AL, Lin CL. Rhinacanthin-C, A Fat-Soluble Extract from Rhinacanthus nasutus, Modulates High-Mobility Group Box 1-Related Neuro-Inflammation and Subarachnoid Hemorrhage-Induced Brain Apoptosis in a Rat Model. World Neurosurg 2016; 86:349-60. [DOI: 10.1016/j.wneu.2015.08.071] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2015] [Revised: 08/26/2015] [Accepted: 08/27/2015] [Indexed: 10/23/2022]
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Chang CZ, Wu SC, Kwan AL, Lin CL. 4'-O-β-D-glucosyl-5-O-methylvisamminol, an active ingredient of Saposhnikovia divaricata, attenuates high-mobility group box 1 and subarachnoid hemorrhage-induced vasospasm in a rat model. BEHAVIORAL AND BRAIN FUNCTIONS : BBF 2015; 11:28. [PMID: 26395442 PMCID: PMC4578329 DOI: 10.1186/s12993-015-0074-8] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/21/2015] [Accepted: 09/11/2015] [Indexed: 12/16/2022]
Abstract
BACKGROUND High-mobility group box 1 (HMGB1) was observed to be an important extracellular mediator involved in vascular inflammation associated with subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of 4'-O-β-D-glucosyl-5-O-methylvisamminol (4OGOMV), C22H28O10, on the alternation of cytokines and HMGB1 in an animal model. METHODS A rodent double hemorrhage SAH model was employed. Administration with 4OGOMV was initiated 1 h after animals were subjected to SAH. Basilar arteries (BAs) were harvested and cortexes examined for HMGB1 mRNA, protein expression (Western blot) and monocyte chemoattractant protein-1 (MCP-1) immunostaining. Cerebrospinal fluid samples were collected to examine IL-1β, IL-6, IL-8 and MCP-1 (rt-PCR). RESULTS Morphological findings revealed endothelial cell deformity, intravascular elastic lamina torture, and smooth muscle necrosis in the vessels of SAH groups. Correspondently, IL-1β, IL-6 and MCP-1 in the SAH-only and SAH-plus vehicle groups was also elevated. 4OGOMV dose-dependently reduced HMGB1 protein expression when compared with the SAH groups.(p < 0.01) Likewise, 400 μg/kg 4OGOMV reduced IL-1β, MCP-1 and HMGB1 mRNA levels as well as MCP-1(+) monocytes when compared with the SAH groups.. CONCLUSION 4OGOMV exerts its neuro-protective effect partly through the dual effect of inhibiting IL-6 and MCP-1 activation and also reduced HMGB1 protein, mRNA and MCP-1(+) leukocytes translocation. This study lends credence to validating 4OGOMV as able to attenuate pro-inflammatory cytokine mRNA, late-onset inflammasome, and cellular basis in SAH-induced vasospasm.
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Affiliation(s)
- Chih-Zen Chang
- Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, ROC.
- Department of Surgery, Kaohsiung Municipal Ta Tung Hospital, Kaohsiung, Taiwan.
| | - Shu-Chuan Wu
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, ROC.
| | - Aij-Lie Kwan
- Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, ROC.
| | - Chih-Lung Lin
- Department of Surgery, Faculty of Medicine, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
- Division of Neurosurgery, Department of Surgery, Kaohsiung Medical University Hospital, No.100, Tzyou 1st Road, Kaohsiung, Taiwan, ROC.
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Yang LC, Li J, Xu SF, Cai J, Lei H, Liu DM, Zhang M, Rong XF, Cui DD, Wang L, Peng Y, Wang XL. L-3-n-butylphthalide Promotes Neurogenesis and Neuroplasticity in Cerebral Ischemic Rats. CNS Neurosci Ther 2015. [PMID: 26215907 DOI: 10.1111/cns.12438] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
AIMS This study investigated whether anticerebral ischemia new drug, l-3-n-butylphthalide (l-NBP), improved behavioral recovery and enhanced hippocampal neurogenesis after cerebral ischemia in rats. METHODS AND RESULTS The middle cerebral artery of rats was blocked for 2 h. The daily oral administrations of 30 mg/kg l-NBP or vehicle were begun from the second day until the rats were sacrificed. L-NBP treatment markedly increased 5-bromo-2'-deoxyuridine (BrdU)-positive cells in the hippocampal dentate gyrus (DG) of injured hemisphere on day 28 after ischemia. The amount of newborn cells and newly mature neurons was also increased. The expressions of growth-associated protein-43 and synaptophysin were significantly elevated in l-NBP-treated rats. However, l-NBP markedly reduced the percentage of BrdU(+) /GFAP(+) cells. Additionally, the levels of catalytical subunit of protein kinase A (PKA), protein kinase B (Akt), and cAMP response element-binding protein (CREB) were significantly increased, and the activation of the signal transducer and activation of transcription 3 (STAT3) and the expressions of cleaved caspase-3 and Bax were obviously inhibited by l-NBP. Consequently, l-NBP attenuated the behavioral dysfunction. CONCLUSIONS It first demonstrates that l-NBP may improve the behavioral outcome of cerebral ischemia by promoting neurogenesis and neuroplasticity. Activation of CREB and Akt and inhibition of STAT3 signaling might be involved in.
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Affiliation(s)
- Li-Chao Yang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jiang Li
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Shao-Feng Xu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Jie Cai
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Hui Lei
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dong-Mei Liu
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Man Zhang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xian-Fang Rong
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Dan-Dan Cui
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ling Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Ying Peng
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
| | - Xiao-Liang Wang
- State Key Laboratory of Bioactive Substances and Functions of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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Khabbal J, Kerkelä E, Mitkari B, Raki M, Nystedt J, Mikkonen V, Bergström K, Laitinen S, Korhonen M, Jolkkonen J. Differential Clearance of Rat and Human Bone Marrow-Derived Mesenchymal Stem Cells from the Brain after Intra-arterial Infusion in Rats. Cell Transplant 2015; 24:819-28. [DOI: 10.3727/096368914x679336] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Intra-arterial (IA) delivery of bone marrow-derived mesenchymal stem cells (BM-MSCs) has shown potential as a minimally invasive therapeutic approach for stroke. The aim of the present study was to determine the whole-body biodistribution and clearance of technetium-99m (99mTc)-labeled rat and human BM-MSCs after IA delivery in a rat model of transient middle cerebral artery occlusion (MCAO) using single-photon emission computed tomography (SPECT). Our hypothesis was that xenotransplantation has a major impact on the behavior of cells. Male RccHan: Wistar rats were subjected to sham operation or MCAO. Twenty-four hours after surgery, BM-MSCs (2×106 cells/animal) labeled with 99mTc were infused into the external carotid artery. Whole-body SPECT images were acquired 20 min, 3 h, and 6 h postinjection, after which rats were sacrificed, and organs were collected and weighed for measurement of radioactivity. The results showed that the majority of the cells were located in the brain and especially in the ipsilateral hemisphere immediately after cell infusion both in sham-operated and MCAO rats. This was followed by fast disappearance, particularly in the case of human cells. At the same time, the radioactivity signal increased in the spleen, kidney, and liver, the organs responsible for destroying cells. Further studies are needed to demonstrate whether differential cell behavior has any functional impact.
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Affiliation(s)
- Joonas Khabbal
- Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland
| | - Erja Kerkelä
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Bhimashankar Mitkari
- Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland
| | - Mari Raki
- Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
| | - Johanna Nystedt
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Ville Mikkonen
- Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland
| | - Kim Bergström
- Centre for Drug Research, Faculty of Pharmacy, University of Helsinki, Helsinki, Finland
- HUS Medical Imaging Centre, Helsinki University Central Hospital, Helsinki, Finland
| | - Saara Laitinen
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Matti Korhonen
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Jukka Jolkkonen
- Institute of Clinical Medicine - Neurology, University of Eastern Finland, Kuopio, Finland
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Cordeiro MF, Horn AP. Stem cell therapy in intracerebral hemorrhage rat model. World J Stem Cells 2015; 7:618-629. [PMID: 25914768 PMCID: PMC4404396 DOI: 10.4252/wjsc.v7.i3.618] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 12/03/2014] [Accepted: 12/19/2014] [Indexed: 02/06/2023] Open
Abstract
Intracerebral hemorrhage (ICH) is a very complex pathology, with many different not fully elucidated etiologies and prognostics. It is the most severe subtype of stroke, with high mortality and morbidity rates. Unfortunately, despite the numerous promising preclinical assays including neuroprotective, anti-hypertensive, and anti-inflammatory drugs, to this moment only symptomatic treatments are available, motivating the search for new alternatives. In this context, stem cell therapy emerged as a promising tool. However, more than a decade has passed, and there is still much to be learned not only about stem cells, but also about ICH itself, and how these two pieces come together. To date, rats have been the most widely used animal model in this research field, and there is much more to be learned from and about them. In this review, we first summarize ICH epidemiology, risk factors, and pathophysiology. We then present different methods utilized to induce ICH in rats, and examine how accurately they represent the human disease. Next, we discuss the different types of stem cells used in previous ICH studies, also taking into account the tested transplantation sites. Finally, we summarize what has been achieved in assays with stem cells in rat models of ICH, and point out some relevant issues where attention must be given in future efforts.
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27
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Mering S, Jolkkonen J. Proper housing conditions in experimental stroke studies-special emphasis on environmental enrichment. Front Neurosci 2015; 9:106. [PMID: 25870536 PMCID: PMC4378295 DOI: 10.3389/fnins.2015.00106] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Accepted: 03/12/2015] [Indexed: 12/20/2022] Open
Abstract
Environmental enrichment provides laboratory animals with novelty and extra space, allowing different forms of multisensory stimulation ranging from social grouping to enhanced motor activity. At the extreme end of the spectrum, one can have a super-enriched environment. Environmental enrichment is believed to result in improved cognitive and sensorimotor functions both in naïve rodents and in animals with brain lesions such as those occurring after a stroke. Robust behavioral effects in animals which have suffered a stroke are probably related not only to neuronal plasticity in the perilesional cortex but also in remote brain areas. There is emerging evidence to suggest that testing restorative therapies in an enriched environment can maximize treatment effects, e.g., the perilesional milieu seems to be more receptive to concomitant pharmacotherapy and/or cell therapy. This review provides an updated overview on the effect of an enriched environment in stroke animals from the practical points to be considered when planning experiments to the mechanisms explaining why combined therapies can contribute to behavioral improvement in a synergistic manner.
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Affiliation(s)
- Satu Mering
- Lab Animal Centre, University of Eastern Finland Kuopio, Finland
| | - Jukka Jolkkonen
- Institute of Clinical Medicine - Neurology, University of Eastern Finland Kuopio, Finland
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Cui LL, Kerkelä E, Bakreen A, Nitzsche F, Andrzejewska A, Nowakowski A, Janowski M, Walczak P, Boltze J, Lukomska B, Jolkkonen J. The cerebral embolism evoked by intra-arterial delivery of allogeneic bone marrow mesenchymal stem cells in rats is related to cell dose and infusion velocity. Stem Cell Res Ther 2015; 6:11. [PMID: 25971703 PMCID: PMC4429328 DOI: 10.1186/scrt544] [Citation(s) in RCA: 157] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2014] [Revised: 01/27/2015] [Accepted: 01/27/2015] [Indexed: 12/17/2022] Open
Abstract
Introduction Intra-arterial cell infusion is an efficient delivery route with which to target organs such as the ischemic brain. However, adverse events including microembolisms and decreased cerebral blood flow were recently reported after intra-arterial cell delivery in rodent models, raising safety concerns. We tested the hypothesis that cell dose, infusion volume, and velocity would be related to the severity of complications after intra-arterial cell delivery. Methods In this study, 38 rats were subjected to a sham middle cerebral artery occlusion (sham-MCAO) procedure before being infused with allogeneic bone-marrow mesenchymal stem cells at different cell doses (0 to 1.0 × 106), infusion volumes (0.5 to 1.0 ml), and infusion times (3 to 6 minutes). An additional group (n = 4) was infused with 1.0 × 106 cells labeled with iron oxide for in vivo tracking of cells. Cells were infused through the external carotid artery under laser Doppler flowmetry monitoring 48 hours after sham-MCAO. Magnetic resonance imaging (MRI) was performed 24 hours after cell infusion to reveal cerebral embolisms or hemorrhage. Limb placing, cylinder, and open field tests were conducted to assess sensorimotor functions before the rats were perfused for histology. Results A cell dose-related reduction in cerebral blood flow was noted, as well as an increase in embolic events and concomitant lesion size, and sensorimotor impairment. In addition, a low infusion velocity (0.5 ml/6 minutes) was associated with high rate of complications. Lesions on MRI were confirmed with histology and corresponded to necrotic cell loss and blood-brain barrier leakage. Conclusions Particularly cell dose but also infusion velocity contribute to complications encountered after intra-arterial cell transplantation. This should be considered before planning efficacy studies in rats and, potentially, in patients with stroke.
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Affiliation(s)
- Li-li Cui
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, 70211, Finland.
| | - Erja Kerkelä
- Finnish Red Cross Blood Services, Helsinki, 00310, Finland.
| | - Abdulhameed Bakreen
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, 70211, Finland.
| | - Franziska Nitzsche
- Fraunhofer Institute for Cell Therapy and Immunology and Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, 04103, Germany.
| | - Anna Andrzejewska
- NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, 02-106, Poland.
| | - Adam Nowakowski
- NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, 02-106, Poland.
| | - Miroslaw Janowski
- Division of MR Research, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Piotr Walczak
- Division of MR Research, Russell H Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.
| | - Johannes Boltze
- Fraunhofer Institute for Cell Therapy and Immunology and Translational Centre for Regenerative Medicine, University of Leipzig, Leipzig, 04103, Germany.
| | - Barbara Lukomska
- NeuroRepair Department, Mossakowski Medical Research Centre, Warsaw, 02-106, Poland.
| | - Jukka Jolkkonen
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Kuopio, 70211, Finland.
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Purpurogallin, a natural phenol, attenuates high-mobility group box 1 in subarachnoid hemorrhage induced vasospasm in a rat model. Int J Vasc Med 2014; 2014:254270. [PMID: 25485154 PMCID: PMC4251792 DOI: 10.1155/2014/254270] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2014] [Revised: 10/30/2014] [Accepted: 10/30/2014] [Indexed: 01/17/2023] Open
Abstract
High-mobility group box 1 (HMGB1) was shown to be an important extracellular mediator involved in vascular inflammation of animals following subarachnoid hemorrhage (SAH). This study is of interest to examine the efficacy of purpurogallin, a natural phenol, on the alternation of cytokines and HMGB1 in a SAH model. A rodent double hemorrhage SAH model was employed. Basilar arteries (BAs) were harvested to examine HMGB1 mRNA and protein expression (Western blot). CSF samples were to examine IL-1β, IL-6, IL-8, and TNF-α (rt-PCR). Deformed endothelial wall, tortuous elastic lamina, and necrotic smooth muscle were observed in the vessels of SAH groups but were absent in the purpurogallin group. IL-1β, IL-6, and TNF-α in the SAH only and SAH plus vehicle groups were significantly elevated (P < 0.01). Purpurgallin dose-dependently reduced HMGB1 protein expression. Likewise, high dose purpurogallin reduced TNF-α and HMGB1 mRNA levels. In conclusion, purpurogallin exerts its neuroinflammation effect through the dual effect of inhibiting IL-6 and TNF-α mRNA expression and reducing HMGB1 protein and mRNA expression. This study supports purpurogallin could attenuate both proinflammatory cytokines and late-onset inflammasome in SAH induced vasospasm.
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Yu K, Wu Y, Zhang Q, Xie H, Liu G, Guo Z, Li F, Jia J, Kuang S, Hu R. Enriched environment induces angiogenesis and improves neural function outcomes in rat stroke model. J Neurol Sci 2014; 347:275-80. [PMID: 25455300 DOI: 10.1016/j.jns.2014.10.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2014] [Revised: 09/18/2014] [Accepted: 10/13/2014] [Indexed: 12/18/2022]
Abstract
Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury has neuroprotective benefits in animal models, including enhancing functional recovery after ischemic stroke. However, the mechanism underlying this effect remains unclear. To clarify this critical issue, the current study investigated the effects of EE on the improvement of damaged neural function and the induction of angiogenesis. Adult rats were subjected to ischemia induced by middle cerebral artery occlusion followed by reperfusion. Neurological status scores were used to evaluate neural function on postoperative days 2, 7, and 14. A beam-walking task was used to test the recovery of motor behavior on postoperative days 2, 5, 10, and 15. We also used a Morris water maze task to examine whether EE protected learning and memory performance. The specific marker of angiogenesis of CD31 was examined by western blot. Angiogenesis around the peri-infarction region was assayed by laser scanning confocal microscopy (LSCM) after 14 days of EE exposure starting 24h after ischemia. Neurological status scores of animals in the EE group were significantly higher than those in the standard housing condition (SC) control group from the seventh day after ischemic. EE accelerated the recovery of motor coordination and integration and also improved learning and memory performance after cerebral ischemia. Furthermore, EE increased CD31 levels and promoted angiogenesis of cortex in the peri-infarction region compared to the SC group. Neural function outcomes are positively correlated with post-ischemia angiogenesis. These findings suggest that EE plays an important role in the recovery of damaged neural function via regulation of angiogenesis after ischemia.
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Affiliation(s)
- Kewei Yu
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
| | - Yi Wu
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China; The Yonghe Branch of Huashan Hospital, Fudan University, Shanghai 200436, China; Department of Sports Medicine and Rehabilitation, Shanghai Medical College, Fudan University, Shanghai 200032, China; Department of Rehabilitation Medicine, Jing'an District Centre Hospital of Shanghai, 200040, China.
| | - Qi Zhang
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
| | - Hongyu Xie
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
| | - Gang Liu
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; The Yonghe Branch of Huashan Hospital, Fudan University, Shanghai 200436, China
| | - Zhenzhen Guo
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China
| | - Fang Li
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Rehabilitation Medicine, Jing'an District Centre Hospital of Shanghai, 200040, China
| | - Jie Jia
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai 200032, China; Department of Sports Medicine and Rehabilitation, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Shenyi Kuang
- Department of Clinical Medicine, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Ruiping Hu
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai 200040, China; Department of Sports Medicine and Rehabilitation, Shanghai Medical College, Fudan University, Shanghai 200032, China.
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Lipsanen A, Parkkinen S, Khabbal J, Mäkinen P, Peräniemi S, Hiltunen M, Jolkkonen J. KB-R7943, an inhibitor of the reverse Na+/Ca2+ exchanger, does not modify secondary pathology in the thalamus following focal cerebral stroke in rats. Neurosci Lett 2014; 580:173-7. [DOI: 10.1016/j.neulet.2014.08.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 06/17/2014] [Accepted: 08/04/2014] [Indexed: 11/29/2022]
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Song M, Kim YJ, Kim YH, Roh J, Kim EC, Lee HJ, Kim SU, Yoon BW. Long-term effects of magnetically targeted ferumoxide-labeled human neural stem cells in focal cerebral ischemia. Cell Transplant 2013; 24:183-90. [PMID: 24380414 DOI: 10.3727/096368913x675755] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The long-term effect of magnetically targeted neural stem cells in a rat focal cerebral ischemia model was investigated. In middle cerebral artery occlusion (MCAO) stroke model rats, ferumoxide-labeled human neural stem cells (hNSCs) were injected into the tail vein. MCAO rats were divided into three groups: ischemia only (IO), ischemia with NSC injection (IC), and ischemia with NSC injection and the use of magnet targeting (IM). Four weeks after MCAO and 3 weeks posttransplantation, a greater number of hNSCs were found in ischemic lesion sites in IM rat brain compared with IO and IC animals. In addition, differentiation of hNSCs into neurons or astrocytes and angiogenesis were markedly increased. In IM rats, infarct volume was considerably reduced, and function was significantly improved. The present study indicates that long-term use of magnetic fields may be a useful way to improve the efficacy of targeted migration of stem cells and functional deficits in stem cell-based therapy for ischemic brain injury.
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Affiliation(s)
- Miyeoun Song
- Department of Neurology, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea
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Mitkari B, Nitzsche F, Kerkelä E, Kuptsova K, Huttunen J, Nystedt J, Korhonen M, Jolkkonen J. Human bone marrow mesenchymal stem/stromal cells produce efficient localization in the brain and enhanced angiogenesis after intra-arterial delivery in rats with cerebral ischemia, but this is not translated to behavioral recovery. Behav Brain Res 2013; 259:50-9. [PMID: 24177208 DOI: 10.1016/j.bbr.2013.10.030] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2013] [Revised: 10/16/2013] [Accepted: 10/18/2013] [Indexed: 02/07/2023]
Abstract
Intravascular cell therapy is a promising approach for the treatment of stroke. However, high accumulation of cells to lungs and other filtering organs is a major concern after intravenous (i.v.) cell transplantation. This can be circumvented by intra-arterial (i.a.) cell infusion, which improves homing of cells to the injured brain. We studied the effect of i.a. delivery of human bone marrow-derived mesenchymal cells (BMMSCs) on behavioral and histological outcome in rats after middle cerebral artery occlusion (MCAO). Sixty male Wistar rats were subjected to transient MCAO (60 min) or sham-operation. BMMSCs (1×10(6)) were infused into the external carotid artery on postoperative day 2 or 7. Histology performed after a 42-day follow-up did not detect any human cells (MAB1281) in the ischemic brain. Endothelial cell staining with RECA-1 revealed a significant increase in the number of blood vessels in the perilesional cortex in MCAO rats treated with cells on postoperative day 7. Behavioral recovery as assessed in three tests, sticky label, cylinder and Montoya's staircase, was not improved by human BMMSCs during the follow-up. In conclusion, human BMMSCs did not improve functional recovery in MCAO rats despite effective initial homing to the ischemic hemisphere and enhanced angiogenesis, when strict behavioral tests not affected by repeated testing and compensation were utilized.
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Affiliation(s)
- Bhimashankar Mitkari
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Yliopistonranta 1 C, Kuopio, Finland
| | - Franziska Nitzsche
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Yliopistonranta 1 C, Kuopio, Finland
| | - Erja Kerkelä
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Kristina Kuptsova
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Yliopistonranta 1 C, Kuopio, Finland
| | - Joanna Huttunen
- A. I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland
| | - Johanna Nystedt
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Matti Korhonen
- Finnish Red Cross Blood Service, Advanced Therapies and Product Development, Helsinki, Finland
| | - Jukka Jolkkonen
- Institute of Clinical Medicine-Neurology, University of Eastern Finland, Yliopistonranta 1 C, Kuopio, Finland.
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Yu K, Wu Y, Hu Y, Zhang Q, Xie H, Liu G, Chen Y, Guo Z, Jia J. Neuroprotective effects of prior exposure to enriched environment on cerebral ischemia/reperfusion injury in rats: the possible molecular mechanism. Brain Res 2013; 1538:93-103. [PMID: 24084470 DOI: 10.1016/j.brainres.2013.09.036] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2013] [Revised: 09/10/2013] [Accepted: 09/23/2013] [Indexed: 01/03/2023]
Abstract
Increasing evidence shows that exposure to an enriched environment (EE) after cerebral ischemia/reperfusion injury is neuroprotective in animal models. Recent studies have demonstrated that animals housed in an enriched environment condition after an experimental stroke obtained a better functional outcome than those housed in a standard condition. However, little is known about the underlying mechanisms of neuroprotective effects of enriched environment exposure prior to injury. The current study examined the neuroprotective effects of prior enriched environment exposure after transient middle cerebral artery occlusion (MCAO) in rats. Male Sprague Dawley (SD) rats, weighing 55-65g at the beginning of the experiment, were randomly assigned to a pre-ischemic enriched environment (PIEE) or pre-ischemic standard condition (PISC) group for 1 month. They were weighed on days1, 7, 18, and 28, and their locomotor activity was tracked during the period between 9:00am and 3:00pm daily. After 1 month, ischemia was induced by occluding the middle cerebral artery for 90min, followed by reperfusion. After approximately 24h of the operation, functional outcomes were assessed using the beam-walking test and a neurological evaluation scale in all rats. We measured the expression of extracellular signal regulated protein kinases1/2 (ERK1/2) by western blotting and gene expression levels of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthasen (iNOS) by Real-Time PCR in the cortical area affected by ischemia. Finally, we measured the level of malondialdehyde (MDA) content, which is a biomarker of oxidative stress. The results showed that rats in the PIEE group had lighter weight than those in the PISC group. The functional outcomes of rats in the PIEE group were better than those in the PISC group, and substances associated with inflammation, such as MDA, nNOS, iNOS, and phospho-ERK1/2, were lower in the PIEE group compared with the PISC group. These results indicate that enriched environment may provide neuroprotection via ischemic preconditioning and enhance resilience to cerebral ischemia.
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Affiliation(s)
- Kewei Yu
- Department of Rehabilitation, Huashan Hospital, Fudan University, Shanghai, 200040, China; State Key Laboratory of Medical Neurobiology, Fudan University, Shanghai, 200032, China
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Qin J, Song B, Zhang H, Wang Y, Wang N, Ji Y, Qi J, Chandra A, Yang B, Zhang Y, Gong G, Xu Y. Transplantation of human neuro-epithelial-like stem cells derived from induced pluripotent stem cells improves neurological function in rats with experimental intracerebral hemorrhage. Neurosci Lett 2013; 548:95-100. [PMID: 23680458 DOI: 10.1016/j.neulet.2013.05.007] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2013] [Revised: 04/22/2013] [Accepted: 05/06/2013] [Indexed: 01/27/2023]
Abstract
Specific targeted therapy for intracerebral hemorrhage (ICH), which has high disability and case-fatality rate, is currently not available. Induced pluripotent stem cells (iPSCs) generated from somatic cells of ICH patients have therapeutic potential for individualized cerebral protection. While, whether ICH patient-originated iPSCs could differentiate into neuro-epithelial-like stem (NES) cells and whether such NES cells could improve functional recovery in the hemorrhage-injured brain are unclear. Here, we showed that fibroblasts from an ICH patient can be efficiently reprogrammed to iPSCs by lentiviral vectors carrying defined transcription factors (OCT4, SOX2, KLF4, and c-MYC). These iPSCs have the typical morphology, surface antigens, capability of self-renewal and differentiating into cell types of all three embryonic germ layers that are similar to human embryonic stem cells (hESCs). Using defined serum-free neural differentiation medium, we induced the iPSCs differentiate into NES cells. Subsequently, the NES cells from ICH patient-originated iPSCs were transplanted into the perihematoma of rats with experimental ICH injury. Intriguingly, recovery of neurological dysfunction in experimental ICH rats was observed post-NES cells graftage. Transplanted NES cells migrated to the surrounding area of hematoma, survived and differentiated into neuron-like cells. Our study demonstrates that the transplantation of human iPS-originated NES cells is an effective approach of treating ICH injury and the improvement of neural function is partially due to neuronal replacement and regeneration.
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Affiliation(s)
- Jie Qin
- Third Department of Neurology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, Henan, PR China
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Kwon HM, Kim Y, Yang SI, Kim YJ, Lee SH, Yoon BW. Geldanamycin protects rat brain through overexpression of HSP70 and reducing brain edema after cerebral focal ischemia. Neurol Res 2013; 30:740-5. [DOI: 10.1179/174313208x289615] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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Glibenclamide enhances neurogenesis and improves long-term functional recovery after transient focal cerebral ischemia. J Cereb Blood Flow Metab 2013; 33:356-64. [PMID: 23149556 PMCID: PMC3587805 DOI: 10.1038/jcbfm.2012.166] [Citation(s) in RCA: 84] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Glibenclamide is neuroprotective against cerebral ischemia in rats. We studied whether glibenclamide enhances long-term brain repair and improves behavioral recovery after stroke. Adult male Wistar rats were subjected to transient middle cerebral artery occlusion (MCAO) for 90 minutes. A low dose of glibenclamide (total 0.6 μg) was administered intravenously 6, 12, and 24 hours after reperfusion. We assessed behavioral outcome during a 30-day follow-up and animals were perfused for histological evaluation. In vitro specific binding of glibenclamide to microglia increased after pro-inflammatory stimuli. In vivo glibenclamide was associated with increased migration of doublecortin-positive cells in the striatum toward the ischemic lesion 72 hours after MCAO, and reactive microglia expressed sulfonylurea receptor 1 (SUR1) and Kir6.2 in the medial striatum. One month after MCAO, glibenclamide was also associated with increased number of NeuN-positive and 5-bromo-2-deoxyuridine-positive neurons in the cortex and hippocampus, and enhanced angiogenesis in the hippocampus. Consequently, glibenclamide-treated MCAO rats showed improved performance in the limb-placing test on postoperative days 22 to 29, and in the cylinder and water-maze test on postoperative day 29. Therefore, acute blockade of SUR1 by glibenclamide enhanced long-term brain repair in MCAO rats, which was associated with improved behavioral outcome.
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Sarajärvi T, Lipsanen A, Mäkinen P, Peräniemi S, Soininen H, Haapasalo A, Jolkkonen J, Hiltunen M. Bepridil decreases Aβ and calcium levels in the thalamus after middle cerebral artery occlusion in rats. J Cell Mol Med 2012; 16:2754-67. [PMID: 22805236 PMCID: PMC4118244 DOI: 10.1111/j.1582-4934.2012.01599.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2012] [Accepted: 07/09/2012] [Indexed: 11/27/2022] Open
Abstract
Alzheimer's disease (AD) and cerebral ischaemia share similar features in terms of altered amyloid precursor protein (APP) processing and β-amyloid (Aβ) accumulation. We have previously shown that Aβ and calcium deposition, and β-secretase activity, are robustly increased in the ipsilateral thalamus after transient middle cerebral artery occlusion (MCAO) in rats. Here, we investigated whether the non-selective calcium channel blocker bepridil, which also inhibits β-secretase cleavage of APP, affects thalamic accumulation of Aβ and calcium and in turn influences functional recovery in rats subjected to MCAO. A 27-day bepridil treatment (50 mg/kg, p.o.) initiated 2 days after MCAO significantly decreased the levels of soluble Aβ40, Aβ42 and calcium in the ipsilateral thalamus, as compared with vehicle-treated MCAO rats. Expression of seladin-1/DHCR24 protein, which is a potential protective factor against neuronal damage, was decreased at both mRNA and protein levels in the ipsilateral thalamus of MCAO rats. Conversely, bepridil treatment restored seladin-1/DHCR24 expression in the ipsilateral thalamus. Bepridil treatment did not significantly affect heme oxygenase-1- or NAD(P)H quinone oxidoreductase-1-mediated oxidative stress or inflammatory responses in the ipsilateral thalamus of MCAO rats. Finally, bepridil treatment mitigated MCAO-induced alterations in APP processing in the ipsilateral thalamus and improved contralateral forelimb use in MCAO rats. These findings suggest that bepridil is a plausible therapeutic candidate in AD or stroke owing to its multifunctional role in key cellular events that are relevant for the pathogenesis of these diseases.
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Affiliation(s)
- Timo Sarajärvi
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
| | - Anu Lipsanen
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
| | - Petra Mäkinen
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
| | - Sirpa Peräniemi
- School of Pharmacy, Biocenter Kuopio, University of Eastern FinlandKuopio, Finland
| | - Hilkka Soininen
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
- Department of Neurology, Kuopio University HospitalKuopio, Finland
| | - Annakaisa Haapasalo
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
| | - Jukka Jolkkonen
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
| | - Mikko Hiltunen
- Institute of Clinical Medicine – Neurology, University of Eastern FinlandKuopio, Finland
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Park S, Shin J, Hong Y, Kim S, Lee S, Park K, Lkhagvasuren T, Lee SR, Chang KT, Hong Y. Forced exercise enhances functional recovery after focal cerebral ischemia in spontaneously hypertensive rats. Brain Sci 2012; 2:483-503. [PMID: 24961257 PMCID: PMC4061815 DOI: 10.3390/brainsci2040483] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 09/03/2012] [Accepted: 10/03/2012] [Indexed: 11/16/2022] Open
Abstract
Caveolin is the principal protein of caveolae and has been implicated in the pathogenesis of cerebral ischemia. To investigate whether changed expression of caveolins has a pivotal role in focal cerebral ischemia, we induced middle cerebral artery occlusion (MCAo)-reperfusion and examined expression of caveolins, inflammatory activation markers, and mediators of autophagic cell death. We also treated MCAo rats with forced exercise to determine its effects on neurological outcome. Particularly, spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used to compare the effects of hypertension on focal cerebral ischemia. All MCAo groups showed neurological deficiencies, motor dysfunction, and disruption of balancing ability; however, these pathological changes were more severe in SHR than WKY rats. Expression of caveolins was decreased in MCAo brain tissue, whereas the levels of iNOS and glial fibrillary acidic protein (GFAP) increased. Additionally, LC3-II and beclin-1 levels were elevated in the MCAo groups. Forced exercise attenuated both molecular and behavioral changes in MCAo animals, but SHR rats showed delayed functional recovery and residual molecular changes when compared to WKY rats. These results suggest that forced exercise may be beneficial for promoting functional recovery following cerebral ischemia through caveolin-dependent mechanisms or interactions between caveolins and these signaling molecules in ischemic brain regions.
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Affiliation(s)
- Sookyoung Park
- Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae 621-749, Korea.
| | - Jinhee Shin
- Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae 621-749, Korea.
| | - Yunkyung Hong
- Department of Rehabilitation Science in Interdisciplinary PhD Program, Graduate School of Inje University, Gimhae 621-749, Korea.
| | - Sunmi Kim
- Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae 621-749, Korea.
| | - Seunghoon Lee
- Department of Rehabilitation Science in Interdisciplinary PhD Program, Graduate School of Inje University, Gimhae 621-749, Korea.
| | - Kanghui Park
- Department of Rehabilitation Science in Interdisciplinary PhD Program, Graduate School of Inje University, Gimhae 621-749, Korea.
| | - Tserentogtokh Lkhagvasuren
- Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae 621-749, Korea.
| | - Sang-Rae Lee
- National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang 363-883, Korea.
| | - Kyu-Tae Chang
- National Primate Research Center (NPRC), Korea Research Institute of Bioscience and Biotechnology (KRIBB), Ochang 363-883, Korea.
| | - Yonggeun Hong
- Cardiovascular & Metabolic Disease Center, College of Biomedical Science & Engineering, Inje University, Gimhae 621-749, Korea.
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Intra-arterial infusion of human bone marrow-derived mesenchymal stem cells results in transient localization in the brain after cerebral ischemia in rats. Exp Neurol 2012; 239:158-62. [PMID: 23059455 DOI: 10.1016/j.expneurol.2012.09.018] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 09/21/2012] [Accepted: 09/27/2012] [Indexed: 12/13/2022]
Abstract
Cell therapies from various sources have been under intense research in stroke. Efficient homing of the cells to the injured brain without complications is necessary to realize the therapeutic potential of cell therapy. Intra-arterial (IA) infusion of cells bypasses the filtering organs and directs the cells to the target area more efficiently. Here we studied the biodistribution of human bone marrow-derived mesenchymal stromal/stem cells (BMMSCs) after a direct infusion into the external carotid artery (ECA) in rats. Cells, which were cultured without animal-derived agents and also treated with a proteolytic enzyme to transiently modify cell surface adhesion proteins, were infused 24 h after transient middle cerebral artery occlusion (MCAO). SPECT imaging was used immediately after cell infusion and 24 h thereafter to track (111)In-oxine-labeled BMMSC in sham-operated and MCAO rats. IA infusion of BMMSCs in rats resulted in immediate cell entrapment in the brain, but the majority of the signal disappeared during the next 24 h and relocated to the internal organs. In MCAO rats, radioactivity counts 24 h after infusion were higher in the ischemic hemisphere compared to the contralateral hemisphere. Our results showed that IA infusion through ECA is a safe and efficient administration route for BMMSCs resulting in a transient localization of cells in the rat brain.
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Lee K, Lee JS, Jang HJ, Kim SM, Chang MS, Park SH, Kim KS, Bae J, Park JW, Lee B, Choi HY, Jeong CH, Bu Y. Chlorogenic acid ameliorates brain damage and edema by inhibiting matrix metalloproteinase-2 and 9 in a rat model of focal cerebral ischemia. Eur J Pharmacol 2012; 689:89-95. [PMID: 22659584 DOI: 10.1016/j.ejphar.2012.05.028] [Citation(s) in RCA: 92] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2011] [Revised: 05/08/2012] [Accepted: 05/16/2012] [Indexed: 11/18/2022]
Abstract
Chlorogenic acid (CGA) has been reported to have various beneficial effects on the cardiovascular and central nervous systems. The purpose of the current study was to investigate whether CGA has protective effects against cerebral ischemia and whether these effects are due to modification of brain edema-related vascular factors. In a rat model of transient middle cerebral artery occlusion (MCAo, 2h of occlusion followed by 22 h of reperfusion), we measured infarct volume and performed behavioral test to evaluate the effects of CGA on brain damage and sensory-motor functional deficits. Brain water content and Evans blue extravasation were measured to evaluate brain edema and blood brain barrier (BBB) damage. Lipid peroxidation (LPO) and the expressions and activities of matrix metalloproteinase (MMP)-2 and MMP-9 were measured to investigate the mechanisms of action. Intraperitoneal injection of CGA (3, 10, and 30 mg/kg) at 0 h and 2h after MCAo dose-dependently reduced infarct volume and sensory-motor functional deficits. It also reduced brain water content and Evans blue extravasation. Mechanistically, CGA reduced LPO and MMPs expressions and activities. These results suggest that CGA reduces brain damage, BBB damage and brain edema by radical scavenging activity and the inhibitory effects on MMP-2 and MMP-9.
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Affiliation(s)
- Kyungjin Lee
- College of Oriental Medicine, Kyung Hee University, Seoul 130 701, Republic of Korea
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Zvejniece L, Svalbe B, Liepinsh E, Pulks E, Dambrova M. The sensorimotor and cognitive deficits in rats following 90- and 120-min transient occlusion of the middle cerebral artery. J Neurosci Methods 2012; 208:197-204. [PMID: 22640751 DOI: 10.1016/j.jneumeth.2012.05.018] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2012] [Revised: 05/16/2012] [Accepted: 05/17/2012] [Indexed: 01/08/2023]
Abstract
Middle cerebral artery occlusion (MCAO) is the most commonly used method to study the neurological and histological outcomes and the pathological mechanisms of ischaemic stroke. The current work compares sensorimotor and cognitive deficits and the infarct volume in rats following a transient 90- or 120-min MCAO, which allows the appropriate behavioural tests to be chosen based on the goal and design of the experiment. In the beam-walking test, we found significant differences between the 90- and 120-min MCAO groups in the number of foot faults made with the impaired hindlimb on post-stroke days 3, 7 and 14. In the cylinder test, a difference between the 90- and 120-min groups was observed on post-operation day 14. The responses to tactile and proprioceptive stimulation were impaired to a similar extent after 90- and 120-min MCAO in the vibrissae-evoked forelimb-placing and limb-placing tests. Moreover, we found significant memory impairment in the 120-min MCAO group 6 days after the acquisition trial. The brain tissue damage was significantly higher after 120-min occlusion of the MCA compared with 90-min occlusion; the infarct volumes were 13% and 25% of the contralateral hemispheres, respectively. In conclusion, both the 90- and 120-min occlusion models result in a significant impairment of sensorimotor, tactile and proprioceptive function, but memory impairment is only observed in the 120-min MCAO group. The beam-walking and cylinder tests detected neurological dysfunction after the 120-min MCAO, whereas the limb-placing and vibrissae-evoked forelimb-placing tests were able to evaluate the neurological dysfunction in rats after 90- and 120-min MCAO.
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Affiliation(s)
- Liga Zvejniece
- Latvian Institute of Organic Synthesis, Laboratory of Pharmaceutical Pharmacology, Aizkraukles str 21, Riga, Latvia.
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Goyagi T, Tobe Y, Nishikawa T. Long-term and spatial memory effects of selective β1-antagonists after transient focal ischaemia in rats. Br J Anaesth 2012; 109:399-406. [PMID: 22581807 DOI: 10.1093/bja/aes134] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Although various reports have shown that β-antagonists provide neuroprotective effects after cerebral ischaemia, their effect on spatial memory after transient focal ischaemia is not known. We investigated the treatment of β1-antagonists on neurological outcome spatial memory for 1 month after focal cerebral ischaemia in rats. METHODS Male rats randomly received an i.v. infusion of saline 0.5 ml h(-1), esmolol 200 μg kg(-1) min(-1), or landiolol 50 μg kg(-1) min(-1). Infusion was initiated 30 min before middle cerebral artery occlusion and continued for 24 h. The infarct areas in the hippocampus and striatum were measured after the final retention trial and neurological examinations. RESULTS Neurological deficit scores in the landiolol- and esmolol-treated rats were significantly lower than in the control rats at 1, 4, 7, and 11 days after ischaemia (P<0.05). Using the Morris water maze to assess spatial memory, we found that escape latency and swimming path length to the platform were significantly shorter in the landiolol-treated rats, compared with the saline-treated rats at 4 and 11 days after ischaemia (P<0.05). The mean (SD) infarct area was 19.1 (8.0)% in the striatum and 18.6 (10.0)% in the hippocampus of the landiolol-treated rats, and 16.8 (14.0)% and 16.8 (15.0)% in the striatum and hippocampus, respectively, of esmolol-treated rats. This was significantly less than in control rats [striatum 31.7 (14.0)% and hippocampus 29.8 (13.0)%, P<0.05]. CONCLUSIONS The current study indicates that although esmolol and landiolol provided long-term neuroprotection in terms of histological outcome, they had no effect on neurological outcome and spatial memory retention.
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Affiliation(s)
- T Goyagi
- Department of Anaesthesia and Intensive Care Medicine, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita-city, Akita 010-8543, Japan.
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Wang Z, Cui C, Li Q, Zhou S, Fu J, Wang X, Zhuge Q. Intracerebral transplantation of foetal neural stem cells improves brain dysfunction induced by intracerebral haemorrhage stroke in mice. J Cell Mol Med 2012; 15:2624-33. [PMID: 21251212 PMCID: PMC4373431 DOI: 10.1111/j.1582-4934.2011.01259.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Intracerebral haemorrhage (ICH) can lead to secondary insults and severe neurological deficits. Transplantation of neural stem cells (NSCs) was suggested as an alternative to improve ICH-induced neurological dysfunction. The present study aimed at investigating the therapeutic role and long-term survival of foetal NSCs and potential role of foetal NSCs-produced factors in ICH. Our results demonstrated that foetal NSCs could differentiate into neural axons and dendrites and astrocytes in both in vitro and in vivo conditions, demonstrated by positive double or triple staining with Hoechst, neuronal specific nuclear protein, neurofilaments and glial fibrillary acidic protein. Intracerebral transplantation of foetal NSCs 3 days after ICH induction by intrastriatal administration of bacterial collagenase could improve the functional performance in the limb-placing test and shorten the duration of the recovery from ICH-induced neural disorders. The foetal NSCs may also produce neurotrophic and/or neuroprotective factors during culture, because the culture medium alone could partially improve functional performance. Thus, our data suggest that the foetal NSCs may be one of the therapeutic candidates for ICH.
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Affiliation(s)
- Zhenzhong Wang
- Department of Neurosurgery, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China
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Lee K, Kim J, Lee BJ, Park JW, Leem KH, Bu Y. Protective effects of Galla Rhois, the excrescence produced by the sumac aphid, Schlechtendalia chinensis, on transient focal cerebral ischemia in the rat. JOURNAL OF INSECT SCIENCE (ONLINE) 2012; 12:10. [PMID: 22954153 PMCID: PMC3465921 DOI: 10.1673/031.012.0110] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/19/2010] [Accepted: 05/05/2011] [Indexed: 06/01/2023]
Abstract
Galla Rhois is formed by aphids, primarily Schlechtendalia chinensis Bell (Homoptera: Pemphigidae), on the leaf of sumac, Rhus javanica L. (Sapindales: Anacardiaceae). It is a tannin-rich herb that is widely used in traditional Korean medicine. Its various pharmacological effects, including its radical-scavenging effects, have been reported. The purpose of the current study was to determine if these radical-scavenging effects can be confirmed using in vitro assays and to investigate its neuroprotective effects, optimal dosage, mechanisms, and therapeutic time window in an animal model of stroke. Galla Rhois 85% methanol extract (GRE) exhibited potent and dose-dependent radical-scavenging effects on various radicals. Oral administration of GRE (300 mg/kg) in a transient focal cerebral ischemia rat model (two hours of occlusion followed by 22 hours of reperfusion) reduced the brain infarct volume by 37.5%. It also improved sensory motor function and reduced lipid-peroxidation in middle cerebral artery occlusion. However, it did not have any inhibitory effects on brain edema. The time window study revealed that pre- and co-treatment with GRE had protective effects, but post-treatment with GRE (three or six hours after ischemia) did not have protective effects. In conclusion, GRE had potent radical-scavenging activities and neuroprotective effects in a rat model of stroke when it was pre- and co-administered. The optimal dosage may be around 300 mg/kg for oral administration.
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Affiliation(s)
- Kyungjin Lee
- Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, 130–701, South Korea
| | - Jinmo Kim
- Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, 130–701, South Korea
| | - Beom-joon Lee
- Kangnam Korean Hospital, Kyung Hee University, Seoul, 135–501, South Korea
| | - Jea-Woo Park
- Internal Medicine, Kyung Hee Oriental Medical Hospital, Seoul, 130–701, South Korea
| | - Kang-Hyun Leem
- Department of Herbal Pharmacology, College of Oriental Medicine, Semyung University, Jechon, 390–711, South Korea
| | - Youngmin Bu
- Department of Herbal Pharmacology, College of Oriental Medicine, Kyung Hee University, Seoul, 130–701, South Korea
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Choi BI, Park D, Lee SH, Bae DK, Yang G, Yang YH, Kim TK, Choi EK, Lee HJ, Choi KC, Nahm SS, Kim YB. Neurobehavioural deficits correlate with the cerebral infarction volume of stroke animals: a comparative study on ischaemia-reperfusion and photothrombosis models. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2012; 33:60-69. [PMID: 22134000 DOI: 10.1016/j.etap.2011.11.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Revised: 10/25/2011] [Accepted: 11/07/2011] [Indexed: 05/31/2023]
Abstract
The study investigated the correlation between infarction areas and behavioural deficits in middle cerebral artery occlusion (MCAO) and photothrombosis stroke models. In the MCAO model, a 0.38 mm-diameter silicone-coated thread was introduced through the left external carotid artery and advanced 18 mm via the internal carotid artery to the origin of middle cerebral artery of male Sprague-Dawley rats weighing 300-350 g. The thread was removed for reperfusion after occlusion for 0.5, 1 or 2h. In the photothrombosis model, after a midline incision on the scalp, a focused light (10,000 lux, 6 mm-diameter) was delivered 1mm anterior to the bregma and 3mm left of the midline for 5, 10 or 20 min. During the first 2 min of irradiation, Rose Bengal dye (30 mg/kg) was injected intravenously. Twenty four hours post-surgery, the animals were subjected to neurological scoring and behavioural performances, and were sacrificed for macroscopic and microscopic examinations of brain injury. Total infarction volumes in the MCAO model rats increased in an occlusion time-dependent manner, while the infarction volumes in photothrombosis model rats plateaued relatively quickly with no time-dependent increase. The MCAO model displayed neurological scores and behavioural deficits that correlated well with infarction volumes, while relatively poor correlation between infarction volume and neurobehavioural abnormalities was evident in the photothrombosis model. The results indicate the suitability of the MCAO model for studies on preventive or therapeutic compounds related to functional recovery, although the photothrombosis model might be useful to generate focused lesions leading to the location-related behavioural changes.
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Affiliation(s)
- Byong-il Choi
- College of Veterinary Medicine and Research Institute of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea
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Jwa CS, Yi HJ, Oh SJ, Hwang SJ. Prior use of 3-hydroxy-3-methyl-glutaryl-coenzyme a reductase inhibitor, simvastatin fails to improve outcome after experimental intracerebral hemorrhage. J Korean Neurosurg Soc 2011; 50:403-8. [PMID: 22259685 DOI: 10.3340/jkns.2011.50.5.403] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2011] [Revised: 08/08/2011] [Accepted: 11/21/2011] [Indexed: 01/21/2023] Open
Abstract
OBJECTIVE Contrary to some clinical belief, there were quite a few studies regarding animal models of intracerebral hemorrhage (ICH) in vivo suggesting that prior use of statins may improve outcome after ICH. This study reports the effect of 3-hydroxy-3-methyl-glutaryl-coenzyme A (HMG CoA) reductase inhibitor, simvastatin given before experimental ICH. METHODS Fifty-one rats were subjected to collagenase-induced ICH, subdivided in 3 groups according to simvastatin treatment modality, and behavioral tests were done. Hematoma volume, brain water content and hemispheric atrophy were analyzed. Immunohistochemical staining for microglia (OX-42) and endothelial nitric oxide synthase (eNOS) was performed and caspase-3 activity was also measured. RESULTS Pre-simvastatin therapy decreased inflammatory reaction and perihematomal cell death, but resulted in no significant reduction of brain edema and no eNOS expression in the perihematomal region. Finally, prior use of simvastatin showed less significant improvement of neurological outcome after experimental ICH when compared to post-simvastatin therapy. CONCLUSION The present study suggests that statins therapy after ICH improves neurological outcome, but prior use of statins before ICH might provide only histological improvement, providing no significant impact on neurological outcome against ICH.
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Affiliation(s)
- Cheol-Su Jwa
- Department of Neurosurgery, National Medical Center, Seoul, Korea
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Lipsanen A, Hiltunen M, Jolkkonen J. Chronic ibuprofen treatment does not affect the secondary pathology in the thalamus or improve behavioral outcome in middle cerebral artery occlusion rats. Pharmacol Biochem Behav 2011; 99:468-74. [PMID: 21557963 DOI: 10.1016/j.pbb.2011.04.019] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2011] [Revised: 04/13/2011] [Accepted: 04/24/2011] [Indexed: 01/06/2023]
Abstract
Anti-inflammatory drug ibuprofen decreases the β-amyloid (Aβ) deposition and associated inflammation in transgenic Alzheimer disease mice. Based on this, we studied whether ibuprofen could modulate the secondary pathology described in the thalamus of middle cerebral artery occlusion (MCAO) rats. Our hypothesis was that ibuprofen could decrease inflammatory reaction and Aβ load in the thalamus of MCAO rats, which in turn is reflected in improved behavioral outcome. Forty male Wistar rats (250-340 g) were subjected to sham-operation or transient occlusion of the right middle cerebral artery (120 min). Ibuprofen (4 0mg/kg/day, per os) was administrated for 27 days beginning the treatment on post-operative day 2. MCAO controls were given vehicle. Sensorimotor impairment was assessed using the limb-placing, tapered ledged beam-walking and cylinder tests during the follow-up. The rats were perfused for histology on postoperative day 29. Histological data showed that ibuprofen did not affect Aβ or calcium load in the thalamus of MCAO rats. In addition, behavioral tests did not show significant difference between vehicle- and ibuprofen-treated MCAO rats. The present data do not support the idea that ibuprofen reduces the secondary Aβ/calcium pathology in the thalamus or associated sensorimotor impairment following cerebral ischemia.
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Affiliation(s)
- Anu Lipsanen
- Institute of Clinical Medicine, Neurology, University of Eastern Finland, Kuopio, Finland
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Svalbe B, Zvejniece L, Vavers E, Pugovics O, Muceniece R, Liepinsh E, Dambrova M. Mildronate treatment improves functional recovery following middle cerebral artery occlusion in rats. Behav Brain Res 2011; 222:26-32. [PMID: 21420440 DOI: 10.1016/j.bbr.2011.03.027] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Revised: 03/10/2011] [Accepted: 03/11/2011] [Indexed: 11/18/2022]
Abstract
Mildronate (3-(2,2,2-trimethylhydrazinium) propionate) is an inhibitor of l-carnitine biosynthesis and an anti-ischemic drug. In the present study, we investigated the effects of mildronate in rats following focal cerebral ischemia. Male Wistar rats were subjected to transient occlusion of the middle cerebral artery (MCAO) for 90min, followed by the intraperitoneal administration of mildronate at doses of 100 and 200mg/kg 2h after reperfusion and then daily for an additional 14days. The beam-walking, rota-rod and cylinder tests were used to assess sensorimotor function, and vibrissae-evoked forelimb-placing and limb-placing tests examined responses to tactile and proprioceptive stimulation. Following behavioural testing, the infarct volume was measured. The cerebellar concentrations of l-carnitine, γ-butyrobetaine (GBB) and mildronate were also measured. The results showed that saline-treated MCAO rats had minor or no spontaneous recovery in sensorimotor and proprioceptive function up to 14days post-stroke. Treatment with mildronate at a dose of 200mg/kg was found to accelerate recovery of motor and proprioceptive deficits in limb-placing, cylinder and beam-walking tests. Analysis of rat cerebellar tissue extracts revealed that l-carnitine and GBB concentrations changed with mildronate treatment; the concentration of l-carnitine was significantly decreased by mildronate treatment, whereas the concentration of GBB was significantly increased. Cerebellar concentrations of mildronate also increased in a dose-dependent manner following systemic administration. Infarct size did not differ among the experimental groups on post-stroke day 14. The present study suggests that mildronate treatment improves the functional outcome in MCAO rats without influencing infarct size.
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Affiliation(s)
- Baiba Svalbe
- Latvian Institute of Organic Synthesis, Riga, Latvia; University of Latvia, Riga, Latvia.
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Lee HJ, Lim IJ, Lee MC, Kim SU. Human neural stem cells genetically modified to overexpress brain-derived neurotrophic factor promote functional recovery and neuroprotection in a mouse stroke model. J Neurosci Res 2011; 88:3282-94. [PMID: 20818776 DOI: 10.1002/jnr.22474] [Citation(s) in RCA: 117] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Intracerebral hemorrhage (ICH) is a lethal stroke type; mortality approaches 50%, and current medical therapy against ICH shows only limited effectiveness, so an alternative approach is required, such as stem cell-based cell therapy. Previously we have shown that intravenously transplanted human neural stem cells (NSCs) selectively migrate to the brain and promote functional recovery in rat ICH model, and others have shown that intracerebral infusion of brain-derived neurotrophic factor (BDNF) results in improved structural and functional outcome from cerebral ischemia. We postulated that human NSCs overexpressing BDNF transplanted into cerebral cortex overlying ICH lesion could provide improved survival of grafted NSCs and increased angiogenesis and behavioral recovery in mouse ICH model. ICH was induced in adult mice by injection of bacterial collagenase into striatum. The HB1.F3.BDNF (F3.BDNF) human NSC line produces sixfold higher amounts of BDNFF over the parental F3 cell line in vitro, induces behavioral improvement, and produces a threefold increase in cell survival at 2 weeks and 8 weeks posttransplantation. Brain transplantation of human NSCs overexpressing BDNF provided differentiation and survival of grafted human NSCs and renewed angiogenesis of host brain and functional recovery of ICH animals. These results indicate that the F3.BDNF human NSCs should be of great value as a cellular source for experimental studies involving cellular therapy for human neurological disorders, including ICH.
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Affiliation(s)
- Hong J Lee
- Medical Research Institute, Chung-Ang University College of Medicine, Seoul, Korea
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