Publications by authors named "Seong-Jin Yu"

39 Publications

Protective Effect of CXCR4 Antagonist CX807 in a Rat Model of Hemorrhagic Stroke.

Int J Mol Sci 2020 Sep 25;21(19). Epub 2020 Sep 25.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan 35053, Taiwan.

Intracerebral hemorrhage (ICH) is a major cause of stroke, with high mortality and morbidity. There is no effective pharmacological therapy for ICH. Previous studies have indicated that CXCR4 antagonists reduced microglia activation, attenuated infiltration of T cells, and improved functional recovery in ischemic stroke animals. The interaction of CXCR4 antagonists and ICH has not been characterized. The purpose of this study is to examine the neuroprotective action of a novel CXCR4 antagonist CX807 against ICH. In primary cortical neuronal and BV2 microglia co-culture, CX807 reduced glutamate-mediated neuronal loss and microglia activation. Adult rats were locally administered with collagenase VII to induce ICH. CX807 was given systemically after the ICH. Early post-treatment with CX807 improved locomotor activity in ICH rats. Brain tissues were collected for qRTPCR and histological staining. ICH upregulated the expression of CXCR4, CD8, TNFα, IL6, and TLR4. The immunoreactivity of IBA1 and CD8, as well as TUNEL labeling, were enhanced in the perilesioned area. CX807 significantly mitigated these responses. In conclusion, our data suggest that CX807 is neuroprotective and anti-inflammatory against ICH. CX807 may have clinical implications for the treatment of hemorrhagic stroke.
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http://dx.doi.org/10.3390/ijms21197085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582767PMC
September 2020

PT320, Sustained-Release Exendin-4, Mitigates L-DOPA-Induced Dyskinesia in a Rat 6-Hydroxydopamine Model of Parkinson's Disease.

Front Neurosci 2020 11;14:785. Epub 2020 Aug 11.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

Background: We previously demonstrated that subcutaneous administration of PT320, a sustained-release (SR) form of exendin-4, resulted in the long-term maintenance of steady-state exenatide (exendin-4) plasma and target levels in 6-hydroxydopamine (6-OHDA)-pretreated animals. Additionally, pre- or post-treatment with PT320 mitigated the early stage of 6-OHDA-induced dopaminergic neurodegeneration. The purpose of this study was to evaluate the effect of PT320 on L-3,4-dihydroxyphenylalanine (L-DOPA)-induced abnormal involuntary movements (AIMs) in the rat 6-OHDA model of Parkinson's disease.

Methods: Adult male Sprague-Dawley rats were unilaterally lesioned in the right medial forebrain bundle by 6-OHDA. L-DOPA and benserazide were given daily for 22 days, starting from 4 weeks after lesioning. PT320 was co-administered weekly for 3 weeks. AIM was evaluated on days 1, 16, and 22 after initiating L-DOPA/benserazide + PT320 treatment. Brain tissues were subsequently collected for HPLC measurements of dopamine (DA) and metabolite concentrations.

Results: L-DOPA/benserazide increased AIMs of limbs and axial as well as the sum of all dyskinesia scores (ALO) over 3 weeks. PT320 significantly reduced the AIM scores of limbs, orolingual, and ALO. Although PT320 did not alter DA levels in the lesioned striatum, PT320 significantly attenuated 6-OHDA-enhanced DA turnover.

Conclusion: PT320 attenuates L-DOPA/benserazide-induced dyskinesia in a 6-OHDA rat model of PD and warrants clinical evaluation to mitigate Parkinson's disease in humans.
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http://dx.doi.org/10.3389/fnins.2020.00785DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7431885PMC
August 2020

Downregulation of α-Synuclein Protein Levels by an Intracellular Single-Chain Antibody.

J Parkinsons Dis 2020 ;10(2):573-590

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

Background: Accumulation of α-synuclein (αSyn) in the dopaminergic neurons is a common pathology seen in patients with Parkinson's disease (PD). Overproduction of αSyn potentiates the formation of oligomeric αSyn aggregates and enhances dopaminergic neuron degeneration. Downregulating intracellular monomeric αSyn prevents the formation of αSyn oligomers and is a potential therapeutic strategy to attenuate the progression of PD.

Objective: The purpose of this study is to investigate the efficacy of gene delivery of αSyn-specific single-chain antibodies in vitro and in vivo.

Methods And Results: The plasmids for αSyn and selective antibodies (NAC32, D10, and VH14) were constructed and were transfected to HEK293 and SH-SY5Y cells. Co-expression of αSyn with NAC32, but not D10 or VH14, profoundly downregulated αSyn protein, but not αSyn mRNA levels in these cells. The interaction of αSyn and NAC32 antibody was next examined in vivo. Adeno-associated virus (AAV)-αSyn combined with AAV-NAC32 or AAV-sc6H4 (a negative control virus) were stereotactically injected into the substantia nigra of adult rats. AAV-NAC32 significantly reduced AAV-encoded αSyn levels in the substantia nigra and striatum and increased tyrosine hydroxylase immunoreactivity in the striatum. Also, in the animals injected with AAV-NAC32 alone, endogenous αSyn protein levels were significantly downregulated in the substantia nigra.

Conclusion: Our data suggest that AAV-mediated gene transfer of NAC32 is a feasible approach for reducing the expression of target αSyn protein in brain.
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http://dx.doi.org/10.3233/JPD-191787DOI Listing
January 2020

Post-treatment with Posiphen Reduces Endoplasmic Reticulum Stress and Neurodegeneration in Stroke Brain.

iScience 2020 Feb 28;23(2):100866. Epub 2020 Jan 28.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan. Electronic address:

Acetylcholinesterase (AChE) inhibitors have protective and anti-inflammatory actions against brain injury, mediated by nicotinic α7 cholinergic receptor activation. The use of AChE inhibitors in patients is limited by systemic cholinergic side effects. Posiphen, a stereoisomer of the AChE inhibitor Phenserine, lacks AChE inhibitor activity. The purpose of this study is to determine the protective effect of Posiphen in cellular and animal models of stroke. Both Posiphen and Phenserine reduced glutamate-mediated neuronal loss in co-cultures of primary cortical cells and microglia. Phenserine-, but not Posiphen-, mediated neuroprotection was diminished by the nicotinic α7 receptor antagonist methyllycaconitine. Posiphen antagonized NMDA-mediated Ca influx, thapsigargin-mediated neuronal loss and ER stress in cultured cells. Early post-treatment with Posiphen reduced ER stress signals, IBA1 immunoreactivity, TUNEL and infarction in the ischemic cortex, as well as neurological deficits in stroke rats. These findings indicate that Posiphen is neuroprotective against stroke through regulating Cai and ER stress.
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http://dx.doi.org/10.1016/j.isci.2020.100866DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7013187PMC
February 2020

Human Milk Oligosaccharide 2'-Fucosyllactose Reduces Neurodegeneration in Stroke Brain.

Transl Stroke Res 2020 10 2;11(5):1001-1011. Epub 2020 Jan 2.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli, Taiwan.

2'-Fucosyllactose (2'-FL) is a major oligosaccharide in human milk and is present at trace levels in cow milk. 2'-FL reduces inflammation in the gastrointestinal tract. Its action in the central nervous system has not been well characterized. The purpose of this study is to determine 2'-FL-mediated neural protection and repair in culture and stroke brain. In rat primary cortical neuronal cultures, 2'-FL significantly antagonized N-methyl-D-aspartate (NMDA) or glutamate-mediated changes in ATP production, MAP2 immunoreactivity, and TUNEL. The influx of Ca (Cai) was examined in primary cortical neurons expressing GCaMP5, an endogenous calcium probe. NMDA increased Cai; 2'-FL significantly attenuated this reaction. In a rat middle cerebral artery occlusion model of stroke, we found that intracerebroventricular pretreatment or oral posttreatment with 2'-FL significantly reduced brain infarction, mitigated microglial activation, improved locomotor activity, and upregulated brain-derived neurotrophic factor (BDNF) expression. Post-stroke delivery of 2'-FL increased bromodeoxyuridine (BrdU) labeling in the perilesioned area. These BrdU cells co-expressed NeuN, or nestin, or GFAP. Using subventricular Matrigel cultures, we demonstrated that 2'-FL increased cell migration from subventricular zone explant. This response was reduced by anti-BDNF blocking antibody. In conclusion, our data suggest that 2'-FL has neuroprotective action through inhibition of Cai, inflammation, and apoptosis. Posttreatment with 2'-FL facilitates neural repair in stroke brain.
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http://dx.doi.org/10.1007/s12975-019-00774-zDOI Listing
October 2020

Translating intracarotid artery transplantation of bone marrow-derived NCS-01 cells for ischemic stroke: Behavioral and histological readouts and mechanistic insights into stem cell therapy.

Stem Cells Transl Med 2020 02 18;9(2):203-220. Epub 2019 Nov 18.

Center of Excellence for Aging and Brain Repair, Department of Neurosurgery and Brain Repair, University of South Florida College of Medicine, Tampa, Florida.

The present study used in vitro and in vivo stroke models to demonstrate the safety, efficacy, and mechanism of action of adult human bone marrow-derived NCS-01 cells. Coculture with NCS-01 cells protected primary rat cortical cells or human neural progenitor cells from oxygen glucose deprivation. Adult rats that were subjected to middle cerebral artery occlusion, transiently or permanently, and subsequently received intracarotid artery or intravenous transplants of NCS-01 cells displayed dose-dependent improvements in motor and neurological behaviors, and reductions in infarct area and peri-infarct cell loss, much better than intravenous administration. The optimal dose was 7.5 × 10 cells/mL when delivered via the intracarotid artery within 3 days poststroke, although therapeutic effects persisted even when administered at 1 week after stroke. Compared with other mesenchymal stem cells, NCS-01 cells ameliorated both the structural and functional deficits after stroke through a broad therapeutic window. NCS-01 cells secreted therapeutic molecules, such as basic fibroblast growth factor and interleukin-6, but equally importantly we observed for the first time the formation of filopodia by NCS-01 cells under stroke conditions, characterized by cadherin-positive processes extending from the stem cells toward the ischemic cells. Collectively, the present efficacy readouts and the novel filopodia-mediated mechanism of action provide solid lab-to-clinic evidence supporting the use of NCS-01 cells for treatment of stroke in the clinical setting.
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http://dx.doi.org/10.1002/sctm.19-0229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6988762PMC
February 2020

Enhanced survival of human-induced pluripotent stem cell transplant in parkinsonian rat brain by locally applied cyclosporine.

Brain Circ 2019 Jul-Sep;5(3):130-133. Epub 2019 Sep 30.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan.

A major limitation with cell transplantation in patients is the unimpressive number of cells survived. The death of grafted cells involves apoptosis and immunorejection. In this review, we encapsulate the recent preclinical development that improves the survival of grafted cells and mitigates the immunorejection of human-induced pluripotent stem cells (iPSCs) through co-grating nanoparticles-containing cyclosporine A (NanoCsA) in hemiparkinsonian rats. The study supported the notion that NanoCsA allows for long-lasting CsA discharge and limits immunorejection of human iPSC xenograft in a 6-hydroxydopamine Parkinson's disease rat model.
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http://dx.doi.org/10.4103/bc.bc_40_19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6785947PMC
September 2019

NanoCsA improves the survival of human iPSC transplant in hemiparkinsonian rats.

Brain Res 2019 09 30;1719:124-132. Epub 2019 May 30.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan. Electronic address:

Increasing evidence has supported that transplantation of human stem cells induces neuroprotective and reparative effects in animal models of Parkinson's disease (PD). However, without systemic immunosuppressive therapy, most of these grafted cells are rejected by the hosts. Long term and systemic injection of cyclosporine-A (CsA) is required to maintain the survival of grafted cells. The purpose this study is to examine a new treatment strategy to suppress the immunorejection by locally co-grafting of polylactic/glycolic acid nanoparticles containing CsA (NanoCsA) with differentiated human induced pluripotent stem cells (iPSCs). In the in vitro media, NanoCsA provided sustained release of CsA for >6 weeks. The differentiated human iPSCs were co-grafted with NanoCsA or NanoVeh (nanoparticle without CsA) to the striatum of unilaterally 6-hydroxydopamine -lesioned rats. NanoCsA/iPSCs co-graft significantly improved locomotor activity compared to NanoVeh/iPSCs co-grafts or iPSC grafts + sytemic CsA at 1 month after transplantation. Brain tissues were collected for measurements of tyrosine hydroxylase (TH) and human marker Stem121 immunoreactivity. Cografting with NanoCsA/iPSCs, compared to NanoVeh/iPSCs, significantly increased TH and Stem121 immunoreactivity as well as tumor formation in the lesioned striatum. Taken together, our study supports that NanoCsA provides long-lasting CsA release and reduces immunorejection of human iPSCs xenograft in a 6-hydroxydopamine rat model of PD.
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http://dx.doi.org/10.1016/j.brainres.2019.05.040DOI Listing
September 2019

Pifithrin-Alpha Reduces Methamphetamine Neurotoxicity in Cultured Dopaminergic Neurons.

Neurotox Res 2019 Aug 8;36(2):347-356. Epub 2019 May 8.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

Methamphetamine (Meth) is a widely abused stimulant. High-dose Meth induces degeneration of dopaminergic neurons through p53-mediated apoptosis. A recent study indicated that treatment with the p53 inhibitor, pifithrin-alpha (PFT-α), antagonized Meth-mediated behavioral deficits in mice. The mechanisms underpinning the protective action of PFT-α against Meth have not been identified, and hence, their investigation is the focus of this study. Primary dopaminergic neuronal cultures were prepared from rat embryonic ventral mesencephalic tissue. High-dose Meth challenge reduced tyrosine hydroxylase immunoreactivity and increased terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling. PFT-α significantly antagonized these responses. PFT-α also reduced Meth-activated translocation of p53 to the nucleus, an initial step before transcription. Previous studies have indicated that p53 can also activate cell death through transcription-independent pathways. We found that PFT-α attenuated endoplasmic reticulum (ER) stressor thapsigargin (Tg)-mediated loss of dopaminergic neurons. ER stress was further monitored through the release of Gaussia luciferase (GLuc) from SH-SY5Y cells overexpressing GLuc-based Secreted ER Calcium-Modulated Protein (GLuc-SERCaMP). Meth or Tg significantly increased GLuc release in to the media, with PFT-α significantly reducing GLuc release. Additionally, PFT-α significantly attenuated Meth-induced CHOP expression. In conclusion, our data indicate that PFT-α is neuroprotective against Meth-mediated neurodegeneration via transcription-dependent nuclear and -independent cytosolic ER stress pathways.
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http://dx.doi.org/10.1007/s12640-019-00050-wDOI Listing
August 2019

Wharton' jelly mesenchymal stromal cell therapy for ischemic brain injury.

Brain Circ 2018 Jul-Sep;4(3):124-127. Epub 2018 Oct 9.

Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli County, Taiwan.

Increasing evidence have supported that Wharton's jelly mesenchymal stem cell (WJ-MSCs) have immunomodulatory and protective effects against several diseases including kidney, liver pathologies, and heart injury. Few studies have reported that WJ-MSCs reduced inflammation in hippocampal slices after oxygen-glucose deprivation. We recently reported the neuroprotective effects of human WJ-MSCs (hWJ-MSCs) in rats exposed to a transient right middle cerebral artery occlusion. hWJ-MSCs transplantation significantly reduced brain infarction and microglia activation in the penumbra leading with a significant reduction of neurological deficits. Interestingly, the grafted hWJ-MSCs in the ischemic core were mostly incorporated into IBA1 (+) cells, suggesting that hWJ-MSCs were immunorejected by the host. The immune rejection of hWJ-MSCs was reduced in after cyclosporine A treatment. Moreover, the glia cell line-derived neurotrophic factor expression was significantly increased in the host brain after hWJ-MSCs transplantation. In conclusion, these results suggest that the protective effect of hWJ-MSCs may be due to the secretion of trophic factors rather than to the survival of grafted cells. This paper is a review article. Referred literature in this paper has been listed in the references section. The data sets supporting the conclusions of this article are available online by searching various databases, including PubMed. Some original points in this article come from the laboratory practice in our research center and the authors' experiences.
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http://dx.doi.org/10.4103/bc.bc_16_18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6187942PMC
October 2018

Neuroprotective Action of Human Wharton's Jelly-Derived Mesenchymal Stromal Cell Transplants in a Rodent Model of Stroke.

Cell Transplant 2018 Nov 4;27(11):1603-1612. Epub 2018 Oct 4.

Center for Neuropsychiatric Research, National Health Research Institutes (NHRI), Miaoli, Taiwan.

Wharton's jelly-derived mesenchymal stromal cells (WJ-MSCs) have distinct immunomodulatory and protective effects against kidney, liver, or heart injury. Limited studies have shown that WJ-MSCs attenuates oxygen-glucose deprivation-mediated inflammation in hippocampal slices. The neuroprotective effect of intracerebral WJ-MSC transplantation against stroke has not been well characterized. The purpose of this study was to examine the neuroprotective effect of human WJ-MSC (hWJ-MSC) transplants in an animal model of stroke. Adult male Sprague-Dawley rats were anesthetized and placed in a stereotaxic frame. hWJ-MSCs, pre-labeled with chloromethyl benzamide 1,1'-dioctadecyl-3,3,3'3'- tetramethylindocarbocyanine perchlorate (CM-Dil), were transplanted to the right cerebral cortex at 10 min before a transient (60 min) right middle cerebral artery occlusion (MCAo). Transplantation of hWJ-MSCs significantly reduced neurological deficits at 3 and 5 days after MCAo. hWJ-MSC transplants also significantly reduced brain infarction and microglia activation in the penumbra. Grafted cells carrying CM-Dil fluorescence were identified at the grafted site in the ischemic core; these cells were mostly incorporated into ionized calcium-binding adaptor molecule (+) cells, suggesting these xenograft cells were immuno-rejected by the host. In another set of animals, hWJ-MSCs were transplanted in cyclosporine (CsA)-treated rats. hWJ-MSC transplants significantly reduced brain infarction, improved neurological function, and reduced neuroinflammation. Less phagocytosis of CM-dil-labeled grafted cells was found in the host brain after CsA treatment. Transplantation of hWJ-MSC significantly increased glia cell line-derived neurotrophic factor expression in the host brain. Taken together, our data support that intracerebral transplantation of hWJ-MSCs reduced neurodegeneration and inflammation in the stroke brain. The protective effect did not depend on the survival of grafted cells but may be indirectly mediated through the production of protective trophic factors from the transplants.
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http://dx.doi.org/10.1177/0963689718802754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6299196PMC
November 2018

Author Correction: Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson's disease.

Sci Rep 2018 Sep 12;8(1):13953. Epub 2018 Sep 12.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.
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http://dx.doi.org/10.1038/s41598-018-31455-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6135809PMC
September 2018

Post-treatment with PT302, a long-acting Exendin-4 sustained release formulation, reduces dopaminergic neurodegeneration in a 6-Hydroxydopamine rat model of Parkinson's disease.

Sci Rep 2018 Jul 16;8(1):10722. Epub 2018 Jul 16.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

We previously demonstrated that pretreatment with Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -mediated dopaminergic neurodegeneration. The use of GLP-1 or Exendin-4 for Parkinson's disease (PD) patients is limited by their short half-lives. The purpose of this study was to evaluate a new extended release Exendin-4 formulation, PT302, in a rat model of PD. Subcutaneous administration of PT302 resulted in sustained elevations of Exendin-4 in plasma for >20 days in adult rats. To define an efficacious dose within this range, rats were administered PT302 once every 2 weeks either before or following the unilaterally 6-hydroxydopamine lesioning. Pre- and post-treatment with PT302 significantly reduced methamphetamine-induced rotation after lesioning. For animals given PT302 post lesion, blood and brain samples were collected on day 47 for measurements of plasma Exendin-4 levels and brain tyrosine hydroxylase immunoreactivity (TH-IR). PT302 significantly increased TH-IR in the lesioned substantia nigra and striatum. There was a significant correlation between plasma Exendin-4 levels and TH-IR in the substantia nigra and striatum on the lesioned side. Our data suggest that post-treatment with PT302 provides long-lasting Exendin-4 release and reduces neurodegeneration of nigrostriatal dopaminergic neurons in a 6-hydroxydopamine rat model of PD at a clinically relevant dose.
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http://dx.doi.org/10.1038/s41598-018-28449-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048117PMC
July 2018

9-cis retinoic acid induces neurorepair in stroke brain.

Sci Rep 2017 07 3;7(1):4512. Epub 2017 Jul 3.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan.

The purpose of this study was to examine the neurorestorative effect of delayed 9 cis retinoic acid (9cRA) treatment for stroke. Adult male rats received a 90-min right distal middle cerebral artery occlusion (dMCAo). Animals were separated into two groups with similar infarction sizes, based on magnetic resonance imaging on day 2 after dMCAo. 9cRA or vehicle was given via an intranasal route daily starting from day 3. Stroke rats receiving 9cRA post-treatment showed an increase in brain 9cRA levels and greater recovery in motor function. 9cRA enhanced the proliferation of bromodeoxyuridine (+) cells in the subventricular zone (SVZ) and lesioned cortex in the stroke brain. Using subventricular neurosphere and matrigel cultures, we demonstrated that proliferation and migration of SVZ neuroprogenitor cells were enhanced by 9cRA. Our data support a delayed and non-invasive drug therapy for stroke. Intranasal 9cRA can facilitate the functional recovery and endogenous repair in the ischemic brain.
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http://dx.doi.org/10.1038/s41598-017-04048-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5495771PMC
July 2017

A Novel CXCR4 Antagonist CX549 Induces Neuroprotection in Stroke Brain.

Cell Transplant 2017 04 27;26(4):571-583. Epub 2016 Oct 27.

C-X-C chemokine receptor type 4 (CXCR4) is a receptor for a pleiotropic chemokine CXCL12. Previous studies have shown that the acute administration of the CXCR4 antagonist AMD3100 reduced neuroinflammation in stroke brain and mobilized bone marrow hematopoietic stem cells (HSCs). The purpose of this study was to characterize the neuroprotective and neurotrophic effect of a novel CXCR4 antagonist CX549. We demonstrated that CX549 had a higher affinity for CXCR4 and was more potent than AMD3100 to inhibit CXCL12-mediated chemotaxis in culture. CX549 effectively reduced the activation of microglia and improved neuronal survival after injury in neuron/microglia cocultures. Early poststroke treatment with CX549 significantly improved behavioral function, reduced brain infarction, and suppressed the expression of inflammatory markers. Compared to AMD3100, CX549 has a higher affinity for CXCR4, is more efficient to mobilize HSCs for transplantation, and induces behavioral improvement. Our data support that CX549 is a potent anti-inflammatory agent, is neuroprotective against ischemic brain injury, and may have clinical implications for the treatment of stroke.
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http://dx.doi.org/10.3727/096368916X693563DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5661213PMC
April 2017

Neurotrophic and neuroprotective effects of oxyntomodulin in neuronal cells and a rat model of stroke.

Exp Neurol 2017 Feb 14;288:104-113. Epub 2016 Nov 14.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD, USA. Electronic address:

Proglucagon-derived peptides, especially glucagon-like peptide-1 (GLP-1) and its long-acting mimetics, have exhibited neuroprotective effects in animal models of stroke. Several of these peptides are in clinical trials for stroke. Oxyntomodulin (OXM) is a proglucagon-derived peptide that co-activates the GLP-1 receptor (GLP-1R) and the glucagon receptor (GCGR). The neuroprotective action of OXM, however, has not been thoroughly investigated. In this study, the neuroprotective effect of OXM was first examined in human neuroblastoma (SH-SY5Y) cells and rat primary cortical neurons. GLP-1R and GCGR antagonists, and inhibitors of various signaling pathways were used in cell culture to characterize the mechanisms of action of OXM. To evaluate translation in vivo, OXM-mediated neuroprotection was assessed in a 60-min, transient middle cerebral artery occlusion (MCAo) rat model of stroke. We found that OXM dose- and time-dependently increased cell viability and protected cells from glutamate toxicity and oxidative stress. These neuroprotective actions of OXM were mainly mediated through the GLP-1R. OXM induced intracellular cAMP production and activated cAMP-response element-binding protein (CREB). Furthermore, inhibition of the PKA and MAPK pathways, but not inhibition of the PI3K pathway, significantly attenuated the OXM neuroprotective actions. Intracerebroventricular administration of OXM significantly reduced cerebral infarct size and improved locomotor activities in MCAo stroke rats. Therefore, we conclude that OXM is neuroprotective against ischemic brain injury. The mechanisms of action involve induction of intracellular cAMP, activation of PKA and MAPK pathways and phosphorylation of CREB.
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http://dx.doi.org/10.1016/j.expneurol.2016.11.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5203805PMC
February 2017

Novel GLP-1R/GIPR co-agonist "twincretin" is neuroprotective in cell and rodent models of mild traumatic brain injury.

Exp Neurol 2017 Feb 11;288:176-186. Epub 2016 Nov 11.

Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, MD 21224, USA. Electronic address:

Several single incretin receptor agonists that are approved for the treatment of type 2 diabetes mellitus (T2DM) have been shown to be neuroprotective in cell and animal models of neurodegeneration. Recently, a synthetic dual incretin receptor agonist, nicknamed "twincretin," was shown to improve upon the metabolic benefits of single receptor agonists in mouse and monkey models of T2DM. In the current study, the neuroprotective effects of twincretin are probed in cell and mouse models of mild traumatic brain injury (mTBI), a prevalent cause of neurodegeneration in toddlers, teenagers and the elderly. Twincretin is herein shown to have activity at two different receptors, dose-dependently increase levels of intermediates in the neurotrophic CREB pathway and enhance viability of human neuroblastoma cells exposed to toxic concentrations of glutamate and hydrogen peroxide, insults mimicking the inflammatory conditions in the brain post-mTBI. Additionally, twincretin is shown to improve upon the neurotrophic effects of single incretin receptor agonists in these same cells. Finally, a clinically translatable dose of twincretin, when administered post-mTBI, is shown to fully restore the visual and spatial memory deficits induced by mTBI, as evaluated in a mouse model of weight drop close head injury. These results establish twincretin as a novel neuroprotective agent and suggest that it may improve upon the effects of the single incretin receptor agonists via dual agonism.
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http://dx.doi.org/10.1016/j.expneurol.2016.11.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5878017PMC
February 2017

Differential modulation of methamphetamine-mediated behavioral sensitization by overexpression of Mu opioid receptors in nucleus accumbens and ventral tegmental area.

Psychopharmacology (Berl) 2016 Feb 10;233(4):661-72. Epub 2015 Nov 10.

Center for Neuropsychiatric Research, National Health Research Institutes, Miaoli, Taiwan.

Rationale: Repeated administration of methamphetamine (Meth) induces behavioral sensitization which is characterized by a progressive increase in locomotor response after each injection. Previous studies have shown that Mu opioid receptors (MORs) can regulate Meth-mediated behavioral sensitization. However, the reported interactions are controversial; systemic activation of MORs either enhanced or suppressed Meth sensitization. It is possible that alteration of Meth sensitization after systemic administration of MOR ligands reflects the sum of distinct MOR reactions in multiple brain regions.

Objectives: The purpose of the present study was to examine the actions of MORs on Meth sensitization after regionally selective overexpression of human MOR through an AAV6-based gene delivery system.

Method: We demonstrated that adeno-associated virus (AAV)-MOR increased MOR immunoreactivity and binding in vitro. AAV-MOR or AAV-green fluorescent protein (GFP) was injected into the nucleus accumbens (NAc) or ventral tegmental area (VTA) of adult mice. Two weeks after viral infection, animals received Meth or saline for five consecutive days. Locomotor behavior and striatal dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) level were determined.

Results: Repeated administration of Meth progressively increased locomotor activity; this sensitization reaction was attenuated by intra-NAc AAV-MOR microinjections. Infusion of AAV-MOR to VTA enhanced Meth sensitization. AAV-MOR significantly enhanced DA levels in VTA after VTA infection but reduced DOPAC/DA turnover in the NAc after NAc injection.

Conclusion: Our data suggest a differential modulation of Meth sensitization by overexpression of MOR in NAc and VTA. Regional manipulation of MOR expression through AAV may be a novel approach to control Meth abuse and psychomimetic activity.
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http://dx.doi.org/10.1007/s00213-015-4134-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336502PMC
February 2016

Time-Dependent Protection of CB2 Receptor Agonist in Stroke.

PLoS One 2015 17;10(7):e0132487. Epub 2015 Jul 17.

Center for Neuropsychiatric Research, National Health Research Institutes, Zhunan, Taiwan; Neural Protective and Regeneration Section, National Institute on Drug Abuse, NIH, Baltimore, Maryland, United States of America.

Recent studies have indicated that type 2 cannabinoid receptor (CB2R) agonists reduce neurodegeneration after brain injury through anti-inflammatory activity. The purpose of this study was to examine the time-dependent interaction of CB2R and inflammation in stroke brain. Adult male rats were subjected to right middle cerebral artery occlusion (MCAo). CB2R mRNA expression was significantly elevated >20 fold on day 2, peaked >40-fold on day 5, and normalized on day 10 post-stroke. Inflammatory markers IBA1 and TLR4 were significantly upregulated 15 fold until day 5 after MCAo. Because of the delayed upregulation of CB2R and IBA1, we next treated animals daily with CB2R agonist AM1241 or anti-inflammatory PPAR-γ agonist pioglitazone from 2 to 5 days after MCAo. Delayed treatment with pioglitazone significantly reduced abnormal neurological scores and body asymmetry as well as brain infarction in stroke animals. No behavioral improvement or reduction in brain infarction was found in animals receiving AM1241. Pioglitazone, but not AM1241, significantly reduced IBA1 expression in the stroke cortex, suggesting that delayed treatment with AM1241 failed to alter ischemia-mediated IBA-1 upregulation. In contrast, pretreatment with AM1241 significantly reduced brain infarction and neurological deficits. In conclusion, our data support a time-dependent neuroprotection of CB2 agonist in an animal model of stroke. Delayed post- treatment with PPAR-γ agonist induced behavioral recovery and microglial suppression; early treatment with CB2R agonist suppressed neurodegeneration in stroke animals.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0132487PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4505877PMC
May 2016

Transplantation of human placenta-derived multipotent stem cells reduces ischemic brain injury in adult rats.

Cell Transplant 2015 9;24(3):459-70. Epub 2015 Feb 9.

Center for Neuropsychiatric Research, National Health Research Institutes (NHRI), Miaoli, Taiwan.

After the onset of stroke, a series of progressive and degenerative reactions, including inflammation, is activated, which leads to cell death. We recently reported that human placenta-derived multipotent stem cells (hPDMCs) process potent anti-inflammatory effects. In this study, we examined the protective effect of hPDMC transplants in a rodent model of stroke. Adult male Sprague-Dawley rats were anesthetized. hPDMCs labeled with a vital dye of fluorescing microparticles, DiI, or vehicle were transplanted into three cortical areas adjacent to the right middle cerebral artery (MCA). Five minutes after grafting, the right MCA was transiently occluded for 60 min. Stroke animals receiving hPDMCs showed a significant behavioral improvement and reduction in lesion volume examined by T2-weighted images 4 days poststroke. Brain tissues were collected 1 day later. Human-specific marker HuNu immunoreactivity and DiI fluorescence were found at the hPDMC graft sites, suggesting the survival of hPDMCs in host brain. Grafting of hPDMCs suppressed IBA1 immunoreactivity and deramification of IBA1(+) cells in the perilesioned area, suggesting activation of microglia was attenuated by the transplants. Taken together, our data indicate that hPDMC transplantation reduced cortical lesions and behavioral deficits in adult stroke rats, and these cells could serve as a unique anti-inflammatory reservoir for the treatment of ischemic brain injury.
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http://dx.doi.org/10.3727/096368915X686922DOI Listing
December 2015

Methamphetamine induces a rapid increase of intracellular Ca(++) levels in neurons overexpressing GCaMP5.

Addict Biol 2016 Mar 6;21(2):255-66. Epub 2014 Nov 6.

Center for Neuropsychiatric Research, National Health Research Institutes, Taiwan.

In this study, methamphetamine (Meth)- and glutamate (Glu)-mediated intracellular Ca(++) (Ca(++) i) signals were examined in real time in primary cortical neurons overexpressing an intracellular Ca(++) probe, GCaMP5, by adeno-associated viral (AAV) serotype 1. Binding of Ca(++) to GCaMP increased green fluorescence intensity in cells. Both Meth and Glu induced a rapid increase in Ca(++) i, which was blocked by MK801, suggesting that Meth enhanced Ca(++) i through Glu receptor in neurons. The Meth-mediated Ca(++) signal was also blocked by Mg(++) , low Ca(++) or the L-type Ca(++) channel inhibitor nifedipine. The ryanodine receptor inhibitor dantrolene did not alter the initial Ca(++) influx but partially reduced the peak of Ca(++) i. These data suggest that Meth enhanced Ca(++) influx through membrane Ca(++) channels, which then triggered the release of Ca(++) from the endoplasmic reticulum in the cytosol. AAV-GCaMP5 was also injected to the parietal cortex of adult rats. Administration of Meth enhanced fluorescence in the ipsilateral cortex. Using immunohistochemistry, Meth-induced green fluorescence was found in the NeuN-containing cells in the cortex, suggesting that Meth increased Ca(++) in neurons in vivo. In conclusion, we have used in vitro and in vivo techniques to demonstrate a rapid increase of Ca(++) i by Meth in cortical neurons through overexpression of GCaMP5. As Meth induces behavioral responses and neurotoxicity through Ca(++) i, modulation of Ca(++) i may be useful to reduce Meth-related reactions.
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http://dx.doi.org/10.1111/adb.12193DOI Listing
March 2016

Local administration of AAV-BDNF to subventricular zone induces functional recovery in stroke rats.

PLoS One 2013 2;8(12):e81750. Epub 2013 Dec 2.

Center for Neuropsychiatric Research, National Health Research Institute, Zhunan, Taiwan ; Neural Protection and Regeneration Section, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America.

Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV-BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0081750PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3847037PMC
September 2014

9-Cis retinoic acid protects against methamphetamine-induced neurotoxicity in nigrostriatal dopamine neurons.

Neurotox Res 2014 Apr 25;25(3):248-61. Epub 2013 Jul 25.

Neural Protection and Regeneration Section, Intramural Research Program, National Institute on Drug Abuse, NIH, Baltimore, MD, 21224, USA.

Methamphetamine (MA) is a drug of abuse as well as a dopaminergic neurotoxin. 9-Cis retinoic acid (9cRA), a biologically active derivative of vitamin A, has protective effects against damage caused by H(2)O(2) and oxygen-glucose deprivation in vitro as well as infarction and terminal deoxynucleotidyl transferase-mediated dNTP nick-end labeling (TUNEL) labeling in ischemic brain. The purpose of this study was to examine if there was a protective role for 9cRA against MA toxicity in nigrostriatal dopaminergic neurons. Primary dopaminergic neurons, prepared from rat embryonic ventral mesencephalic tissue, were treated with MA. High doses of MA decreased tyrosine hydroxylase (TH) immunoreactivity while increasing TUNEL labeling. These toxicities were significantly reduced by 9cRA. 9cRA also inhibited the export of Nur77 from nucleus to cytosol, a response that activates apoptosis. The interaction of 9cRA and MA in vivo was next examined in adult rats. 9cRA was delivered intracerebroventricularly; MA was given (5 mg/kg, 4×) one day later. Locomotor behavior was measured 2 days after surgery for a period of 48 h. High doses of MA significantly reduced locomotor activity and TH immunoreactivity in striatum. Administration of 9cRA antagonized these changes. Previous studies have shown that 9cRA can induce bone morphogenetic protein-7 (BMP7) expression and that administration of BMP7 attenuates MA toxicity. We demonstrated that MA treatment significantly reduced BMP7 mRNA expression in nigra. Noggin (a BMP antagonist) antagonized 9cRA-induced behavioral recovery and 9cRA-induced normalization of striatal TH levels. Our data suggest that 9cRA has a protective effect against MA-mediated neurodegeneration in dopaminergic neurons via upregulation of BMP.
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http://dx.doi.org/10.1007/s12640-013-9413-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902054PMC
April 2014

CART peptide induces neuroregeneration in stroke rats.

J Cereb Blood Flow Metab 2013 Feb 5;33(2):300-10. Epub 2012 Dec 5.

National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland 21224, USA.

Utilizing a classic stroke model in rodents, middle cerebral artery occlusion (MCAo), we describe a novel neuroregenerative approach using the repeated intranasal administration of cocaine- and amphetamine-regulated transcript (CART) peptide starting from day 3 poststroke for enhancing the functional recovery of injured brain. Adult rats were separated into two groups with similar infarction sizes, measured by magnetic resonance imaging on day 2 after MCAo, and were treated with CART or vehicle. The CART treatment increased CART level in the brain, improved behavioral recovery, and reduced neurological scores. In the subventricular zone (SVZ), CART enhanced immunolabeling of bromodeoxyuridine, a neural progenitor cell marker Musashi-1, and the proliferating cell nuclear antigen, as well as upregulated brain-derived neurotrophic factor (BDNF) mRNA. AAV-GFP was locally applied to the SVZ to examine migration of SVZ cells. The CART enhanced migration of GFP(+) cells from SVZ toward the ischemic cortex. In SVZ culture, CART increased the size of neurospheres. The CART-mediated cell migration from SVZ explants was reduced by anti-BDNF blocking antibody. Using (1)H-MRS (proton magnetic resonance spectroscopy), increases in N-acetylaspartate levels were found in the lesioned cortex after CART treatment in stroke brain. Cocaine- and amphetamine-regulated transcript increased the expression of GAP43 and fluoro-ruby fluorescence in the lesioned cortex. In conclusion, our data suggest that intranasal CART treatment facilitates neuroregeneration in stroke brain.
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http://dx.doi.org/10.1038/jcbfm.2012.172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3564201PMC
February 2013

Early post-treatment with 9-cis retinoic acid reduces neurodegeneration of dopaminergic neurons in a rat model of Parkinson's disease.

BMC Neurosci 2012 Oct 6;13:120. Epub 2012 Oct 6.

Neural Protection and Regeneration Section, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD, USA.

Background: Retinoic acid (RA) is a biologically active derivative of vitamin A. Previous studies have demonstrated that RA has protective effects against damage caused by H2O2 or oxygen-glucose deprivation in mesangial and PC12 cells. Pretreatment with 9-cis-retinoic acid (9cRA) reduced infarction and TUNEL labeling in cerebral cortex as well as attenuated neurological deficits after distal middle cerebral artery occlusion in rats. The purpose of this study was to examine a protective role of 9cRA in dopaminergic (DA) neurons in a typical rodent model of Parkinson's disease (PD).

Results: The protective role of 9cRA was first examined in rat primary ventromesencephalic culture. Treatment with 9cRA significantly reduced 6-hydroxydopamine (6-OHDA)-mediated cell death and TUNEL labeling in cultured dopaminergic neurons. The protective effect was also examined in adult male rats. Animals received unilateral 6-OHDA lesioning at the left medial forebrain bundle on day 0. Methamphetamine -induced rotational behavior was examined on days 6, 20 and 30 after lesioning. Animals were separated into 2 groups to balance rotational behavior and lesion extent on day 6 and were treated with either 9cRA or vehicle (i.c.v. on day 7 + intra-nasal from day 8 to day 14). Post-treatment with 9cRA significantly reduced methamphetamine -mediated ipislateral rotation at 20 and 30 days after lesioning. In vivo voltammetry was used to examine DA overflow in striatum. Treatment with 9cRA significantly increased KCl -evoked DA release in the lesioned striatum. 9cRA also increased tyrosine hydroxylase (+) cell number in the lesioned nigra as determined by unbiased stereology.

Conclusion: Our data suggests that early post-treatment with 9cRA has a protective effect against neurodegeneration in nigrostriatal DA neurons in an animal model of PD.
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http://dx.doi.org/10.1186/1471-2202-13-120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3523975PMC
October 2012

Suppression of endogenous PPARγ increases vulnerability to methamphetamine-induced injury in mouse nigrostriatal dopaminergic pathway.

Psychopharmacology (Berl) 2012 Jun 13;221(3):479-92. Epub 2011 Dec 13.

National Institute on Drug Abuse, IRP, Neural Protection and Regeneration Section, 251 Bayview Boulevard, 06-721A, Baltimore, MD 21224, USA.

Rationale: Methamphetamine is a commonly abused drug and dopaminergic neurotoxin. Repeated administration of high doses of methamphetamine induces programmed cell death, suppression of dopamine release, and reduction in locomotor activity. Previous studies have shown that pretreatment with peroxisome proliferator-activated receptor gamma (PPARγ) agonist reduced methamphetamine-induced neurodegeneration.

Objectives: The purpose of this study was to examine the role of endogenous PPARγ in protecting against methamphetamine toxicity.

Methods: Adeno-associated virus (AAV) encoding the Cre recombinase gene was unilaterally injected into the left substantia nigra of loxP-PPARγ or control wild-type mice. Animals were treated with high doses of methamphetamine 1 month after viral injection. Behavioral tests were examined using rotarod and rotometer. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection.

Results: Administration of AAV-Cre selectively removed PPARγ in left nigra in loxP-PPARγ mice but not in the wild-type mice. The loxP-PPARγ/AAV-Cre mice that received methamphetamine showed a significant reduction in time on the rotarod and exhibited increased ipsilateral rotation using a rotometer. The peak of dopamine release induced by local application of KCl and the rate of dopamine clearance were significantly attenuated in the left striatum of loxP-PPARγ/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra, and dorsal striatum in loxP-PPARγ/AAV-Cre mice receiving high doses of methamphetamine.

Conclusion: A deficiency in PPARγ increases vulnerability to high doses of methamphetamine. Endogenous PPARγ may play an important role in reducing methamphetamine toxicity in vivo.
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http://dx.doi.org/10.1007/s00213-011-2595-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351577PMC
June 2012

p-Hydroxybenzyl alcohol prevents brain injury and behavioral impairment by activating Nrf2, PDI, and neurotrophic factor genes in a rat model of brain ischemia.

Mol Cells 2011 Mar 6;31(3):209-15. Epub 2011 Jan 6.

Department of Occupational Therapy, Inje University, Gimhae, 621-749, Korea.

The therapeutic goal in treating cerebral ischemia is to reduce the extent of brain injury and thus minimize neurological impairment. We examined the effects of p-hydroxybenzyl alcohol (HBA), an active component of Gastrodia elata Blume, on transient focal cerebral ischemia-induced brain injury with respect to the involvement of protein disulphide isomerase (PDI), nuclear factor-E2-related factor 2 (Nrf2), and neurotrophic factors. All animals were ovariectomized 14 days before ischemic injury. Ischemic injury was induced for 1 h by middle cerebral artery occlusion (MCAO) followed by 24-h reperfusion. Three days before MCAO, the vehicle-treated and the HBA-treated groups received intramuscular sesame oil and HBA (25 mg/kg BW), respectively. 2,3,5-Triphenyltetrazolium chloride (TTC) staining showed decreased infarct volume in the ischemic lesion of HBA-treated animals. HBA pretreatment also promoted functional recovery, as measured by the modified neurological severity score (mNSS; p < 0.05). Moreover, expression of PDI, Nrf2, BDNF, GDNF, and MBP genes increased by HBA treatment. In vitro, H(2)O(2)-induced PC12 cell death was prevented by 24 h HBA treatment, but bacitracin, a PDI inhibitor, attenuated this cytoprotective effect in a dose-dependent manner. HBA treatment for 2 h also induced nuclear translocation of Nrf2, possibly activating the intracellular antioxidative system. These results suggest that HBA protects against brain damage by modulating cytoprotective genes, such as Nrf2 and PDI, and neurotrophic factors.
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http://dx.doi.org/10.1007/s10059-011-0028-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3932695PMC
March 2011

Injectable VEGF hydrogels produce near complete neurological and anatomical protection following cerebral ischemia in rats.

Cell Transplant 2010 21;19(9):1063-71. Epub 2010 Apr 21.

InCytu, Inc., Lincoln, RI 02865, USA.

Vascular endothelial growth factor (VEGF) is a potent proangiogenic peptide and its administration has been considered as a potential neuroprotective strategy following cerebral stroke. Because VEGF has a short half-life and limited access to the brain parenchyma following systemic administration, approaches are being developed to deliver it directly to the site of infarction. In the present study, VEGF was incorporated into a sustained release hydrogel delivery system to examine its potential benefits in a rat model of cerebral ischemia. The hydrogel loaded with VEGF (1 μg) was stereotaxically injected into the striatum of adult rats 15 min prior to a 1-h occlusion of the middle cerebral artery. Two days after surgery, animals were tested for motor function using the elevated bias swing test (EBST) and Bederson neurological battery. Control animals received either stroke alone, stroke plus injections of a blank gel, or a single bolus injection of VEGF (1 μg). Behavioral testing confirmed that the MCA occlusion resulted in significant deficits in the the EBST and Bederson tests. In contrast, the performance of animals receiving VEGF gels was significantly improved relative to controls, with only modest impairments observed. Cerebral infarction analyzed using 2,3,5-triphenyl-tetrazolium chloride staining confirmed that the VEGF gels significantly and potently reduced the lesion volume. No neurological or histological benefits were conferred by either blank gel or bolus VEGF injections. These data demonstrate that VEGF, delivered from a hydrogel directly to the brain, can induce significant functional and structural protection from ischemic damage in a rat model of stroke.
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http://dx.doi.org/10.3727/096368910X498278DOI Listing
May 2011

Menstrual blood cells display stem cell-like phenotypic markers and exert neuroprotection following transplantation in experimental stroke.

Stem Cells Dev 2010 Apr;19(4):439-52

Department of Neurosurgery and Brain Repair, Center of Excellence for Aging and Brain Repair, University of South Florida College of Medicine, Tampa, Florida 33612, USA.

Cell therapy remains an experimental treatment for neurological disorders. A major obstacle in pursuing the clinical application of this therapy is finding the optimal cell type that will allow benefit to a large patient population with minimal complications. A cell type that is a complete match of the transplant recipient appears as an optimal scenario. Here, we report that menstrual blood may be an important source of autologous stem cells. Immunocytochemical assays of cultured menstrual blood reveal that they express embryonic-like stem cell phenotypic markers (Oct4, SSEA, Nanog), and when grown in appropriate conditioned media, express neuronal phenotypic markers (Nestin, MAP2). In order to test the therapeutic potential of these cells, we used the in vitro stroke model of oxygen glucose deprivation (OGD) and found that OGD-exposed primary rat neurons that were co-cultured with menstrual blood-derived stem cells or exposed to the media collected from cultured menstrual blood exhibited significantly reduced cell death. Trophic factors, such as VEGF, BDNF, and NT-3, were up-regulated in the media of OGD-exposed cultured menstrual blood-derived stem cells. Transplantation of menstrual blood-derived stem cells, either intracerebrally or intravenously and without immunosuppression, after experimentally induced ischemic stroke in adult rats also significantly reduced behavioral and histological impairments compared to vehicle-infused rats. Menstrual blood-derived cells exemplify a source of "individually tailored" donor cells that completely match the transplant recipient, at least in women. The present neurostructural and behavioral benefits afforded by transplanted menstrual blood-derived cells support their use as a stem cell source for cell therapy in stroke.
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http://dx.doi.org/10.1089/scd.2009.0340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3158424PMC
April 2010

Amnion: a potent graft source for cell therapy in stroke.

Cell Transplant 2009 ;18(2):111-8

Department of Neurology, Medical College of Georgia, Augusta, GA, USA.

Regenerative medicine is a new field primarily based on the concept of transplanting exogenous or stimulating endogenous stem cells to generate biological substitutes and improve tissue functions. Recently, amnion-derived cells have been reported to have multipotent differentiation ability, and these cells have attracted attention as a novel cell source for cell transplantation therapy. Cells isolated from amniotic membrane can differentiate into all three germ layers, have low immunogenicity and anti-inflammatory function, and do not require the destruction of human embryos for their isolation, thus circumventing the ethical debate commonly associated with the use of human embryonic stem cells. Accumulating evidence now suggests that the amnion, which had been discarded after parturition, is a highly potent transplant material in the field of regenerative medicine. In this report, we review the current progress on the characterization of MSCs derived from the amnion as a remarkable transplantable cell population with therapeutic potential for multiple CNS disorders, especially stroke.
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http://dx.doi.org/10.3727/096368909788341243DOI Listing
August 2009