Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0038454 (stroke)
 147,016 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurogenesis may contribute to functional recovery after neural injury. Nitric oxide donors such as DETA-NONOate promote functional recovery after stroke. However, the mechanisms underlying functional improvement have not been ascertained. We therefore investigated the effects of DETA-NONOate on neural progenitor/stem cell neurospheres derived from the subventricular zone from young and retired breeder rat brain. Subventricular zone cells were dissociated from normal young adult male Wistar rats (2-3 months old) and retired breeder rats (14 months old), treated with or without DETA-NONOate. Subventricular zone neurosphere formation, proliferation, telomerase activity, and Neurogenin 1 mRNA expression were significantly decreased and glial fibrillary acidic protein expression was significantly increased in subventricular zone neurospheres from retired breeder rats compared with young rats. Treatment of neurospheres with DETA-NONOate significantly decreased neurosphere formation and telomerase activity, and promoted neuronal differentiation and neurite outgrowth concomitantly with increased N-cadherin and beta-catenin mRNA expression in both young and old neurospheres. DETA-NONOate selectively increased Neurogenin 1 and decreased glial fibrillary acidic protein mRNA expression in retired breeder neurospheres. N-cadherin significantly increased Neurogenin 1 mRNA expression in young and old neurospheres. Anti-N-cadherin reversed DETA-NONOate-induced neurosphere adhesion, neuronal differentiation, neurite outgrowth, and beta-catenin mRNA expression. Our data indicate that age has a potent effect on the characteristics of subventricular zone neurospheres; neurospheres from young rats show significantly higher formation, proliferation and telomerase activity than older neurospheres. In contrast, older neurospheres exhibit significantly increased glial differentiation than young neurospheres. DETA-NONOate promotes neuronal differentiation and neurite outgrowth in both young and older neurospheres. The molecular mechanisms associated with the DETA-NONOate modulation of neurospheres from young and older animals as well age dependent effects of neurospheres appear to be controlled by N-cadherin and beta-catenin gene expression, which subsequently regulates the neuronal differentiating factor Neurogenin expression in both young and old neural progenitor cells.
 ...
PMID:N-cadherin mediates nitric oxide-induced neurogenesis in young and retired breeder neurospheres. 1658 Jul 82

Bone marrow stromal cells (BMSCs) facilitate functional recovery in rats after stroke when administered acutely (1 day) or subacutely (7 days). In this study, we postponed the time of cell transplantation to 1 month after stroke. Female retired breeder rats were subjected to 2 h of middle cerebral artery occlusion (MCAo). Male BMSCs (3 x 10(6)) or phosphate-buffered saline were administered intravenously, and the animals were killed 3 months later. An additional population of nontreated rats was killed at 1 month after MCAo. Significant recovery of behavior was found in BMSC-treated rats beginning at 1 month after cell injection in the modified neurologic severity score test and the adhesive-removal test compared with control animals (P<0.05). In situ hybridization showed that BMSCs survived and preferentially localized to the ipsilateral hemisphere. Double staining revealed that approximately 13% and 6% Y-chromosome-positive cells expressed the astrocyte marker, glial fibrillary acidic protein, and the neuronal marker, microtubule-associated protein-2, respectively. In addition, BMSC treatment reduced scar thickness, and increased the number of proliferating cells and oligodendrocyte precursor cells along the subventricular zone in the ipsilateral hemisphere. Expression of the chemokine stromal-cell-derived factor-1 (SDF-1) was significantly increased along the ischemic boundary zone compared with the corresponding areas in the contralateral hemisphere at 1 month and 4 months (P<0.01) after stroke. The SDF-1 receptor, CXC-chemokine receptor-4 (CXCR4), was expressed in BMSCs both in vitro and in vivo. Our data show that the time window of BMSC therapy is at least 1 month after stroke; the interaction of SDF-1/CXCR4 may contribute to the trafficking of transplanted BMSCs.
 ...
PMID:Therapeutic benefit of bone marrow stromal cells administered 1 month after stroke. 1659 21

The only available treatment for embolic stroke is recombinant tissue plasminogen activator, which must be administered within three hours of stroke onset. We examined the effects of 1,3-di-o-tolyguanidine (DTG), a high affinity sigma receptor agonist, as a potential treatment for decreasing infarct area at delayed time points. Rats were subjected to permanent embolic middle cerebral artery occlusion (MCAO) and allowed to recover before receiving subcutaneous injections of 15 mg/kg of DTG at 24, 48, and 72 hours. At 96 hours the rats were euthanized, and brains harvested and sectioned. Infarct areas were quantified at the level of the cortical/striatal and cortical/hippocampal regions in control (MCAO-only) and DTG treated animals using a marker for neurodegeneration, Fluoro-Jade. DTG treatment significantly reduced infarct area in both cortical/striatal and cortical/hippocampal regions by >80%, relative to control rats. These findings were confirmed by immunohistochemical experiments using the neuronal marker, mouse anti-neuronal nuclei monoclonal antibody (NeuN), which showed that application of DTG significantly increased the number of viable neurons in these regions. Furthermore, DTG blocked the inflammatory response evoked by MCAO, as indicated by decreases in the number of reactive astrocytes and activated microglia/macrophages detected by immunostaining for glial fibrillary acidic protein (GFAP) and binding of isolectin IB4, respectively. Thus, our results demonstrate that the sigma receptor-selective agonist, DTG, can enhance neuronal survival when administered 24 hr after an ischemic stroke. In addition, the efficacy of sigma receptors for stroke treatment at delayed time points is likely the result of combined neuroprotective and anti-inflammatory properties of these receptors.
 ...
PMID:Sigma receptor activation reduces infarct size at 24 hours after permanent middle cerebral artery occlusion in rats. 1671 92

Bone morphogenetic proteins play a key role in astrocytic differentiation. Astrocytes express the gap junctional protein connexin-43, which permits exchange of small molecules in brain and enhances synaptic efficacy. Bone marrow stromal cells produce soluble factors including bone morphogenetic protein 2 and bone morphogenetic protein 4 (bone morphogenetic protein 2/4) in ischemic brain. Here, we tested whether intra-carotid infusion of bone marrow stromal cells promotes synaptophysin expression and neurological functional recovery after stroke in rats. Adult male Wistar rats were subjected to 2 h of right middle cerebral artery occlusion. Rats were treated with or without bone marrow stromal cells at 24 h after middle cerebral artery occlusion via intra-arterial injection (n=8/group). A battery of functional tests was performed. Immunostaining of 5-bromo-2-deoxyuridine, Ki67, bone morphogenetic protein 2/4, connexin-43, synaptophysin, glial fibrillary acidic protein, neuronal nuclear antigen, and double staining of 5-bromo-2-deoxyuridine/glial fibrillary acidic protein, 5-bromo-2-deoxyuridine/neuronal nuclear antigen, glial fibrillary acidic protein/bone morphogenetic protein 2/4 and glial fibrillary acidic protein/connexin-43 were employed. Rats treated with bone marrow stromal cells significantly (P<0.05) improved functional recovery compared with the controls. 5-Bromo-2-deoxyuridine and Ki67 positive cells in the ipsilateral subventricular zone were significantly (P<0.05) increased in bone marrow stromal cell treatment group compared with the controls, respectively. Administration of bone marrow stromal cells significantly (P<0.05) promoted the proliferating cell astrocytic differentiation, and increased bone morphogenetic protein 2/4, connexin-43 and synaptophysin expression in the ischemic boundary zone compared with the controls, respectively. Bone morphogenetic protein 2/4 expression correlated with the expression of connexin-43 (r=0.84, P<0.05) and connexin-43 expression correlated with the expression of synaptophysin (r=0.73, P<0.05) in the ischemic boundary zone, respectively. Administration of bone marrow stromal cells via an intra-carotid route increases endogenous brain bone morphogenetic protein 2/4 and connexin-43 expression in astrocytes and promotes synaptophysin expression, which may benefit functional recovery after stroke in rats.
 ...
PMID:Bone marrow stromal cells upregulate expression of bone morphogenetic proteins 2 and 4, gap junction protein connexin-43 and synaptophysin after stroke in rats. 1673 Sep 12

Recent studies have revealed that the adult mammalian brain has the capacity to regenerate some neurons after various insults. However, the precise mechanism of insult-induced neurogenesis has not been demonstrated. In the normal brain, GFAP-expressing cells in the subventricular zone (SVZ) of the lateral ventricles include a neurogenic cell population that gives rise to olfactory bulb neurons only. Herein, we report evidence that, after a stroke, these cells are capable of producing new neurons outside the olfactory bulbs. SVZ GFAP-expressing cells labeled by a cell-type-specific viral infection method were found to generate neuroblasts that migrated toward the injured striatum after middle cerebral artery occlusion. These neuroblasts in the striatum formed elongated chain-like cell aggregates similar to those in the normal SVZ, and these chains were observed to be closely associated with thin astrocytic processes and blood vessels. Finally, long-term tracing of the green fluorescent-labeled cells with a Cre-loxP system revealed that the SVZ-derived neuroblasts differentiated into mature neurons in the striatum, in which they expressed neuronal-specific nuclear protein and formed synapses with neighboring striatal cells. These results highlight the role of the SVZ in neuronal regeneration after a stroke and its potential as an important therapeutic target for various neurological disorders.
 ...
PMID:Subventricular zone-derived neuroblasts migrate and differentiate into mature neurons in the post-stroke adult striatum. 1677 51

Carbamylerythropoietin (CEPO) does not bind to the classical erythropoietin (EPO) receptor. Nevertheless, similarly to EPO, CEPO promotes neuroprotection on the histologic level in short-term stroke models. In the present study, we investigated whether CEPO and other nonerythropoietic EPO analogs could enhance functional recovery and promote long-term histologic protection after experimental focal cerebral ischemia. Rats were treated with the compounds after focal cerebral ischemia. Animals survived 1, 7, or 60 days and underwent behavioral testing (sensorimotor and foot-fault tests). Brain sections were stained and analyzed for Iba-1, myeloperoxidase, Tau-1, CD68 (ED1), glial fibrillary acidic protein (GFAP), Fluoro-Jade B staining, and overall infarct volumes. Treatment with CEPO reduced perifocal microglial activation (P<0.05), polymorphomonuclear cell infiltration (P<0.05), and white matter damage (P<0.01) at 1 day after occlusion. Carbamylerythropoietin-treated rats showed better functional recovery relative to vehicle-treated animals as assessed 1, 7, 14, 28, and 50 days after stroke. Both GFAP and CD68 were decreased within the ipsilateral thalamus of CEPO-treated animals 60 days postoperatively (P<0.01 and P<0.05, respectively). Furthermore, behavioral analysis showed efficacy of CEPO treatment even if administered 24 h after the stroke. Other nonerythropoietic derivatives such as carbamylated darbepoetin alfa and the mutant EPO-S100E were also found to protect against ischemic damage and to improve postischemic neurologic function. In conclusion, these results show that postischemic intravenous treatment with nonerythropoietic EPO derivatives leads to improved functional recovery, which may be linked to their long-term effects against neuroinflammation and secondary tissue damage.
 ...
PMID:Reduced functional deficits, neuroinflammation, and secondary tissue damage after treatment of stroke by nonerythropoietic erythropoietin derivatives. 1683 29

Impaired peripheral wound healing is a hallmark of diabetics pathology and has been attributed to compromised macrophage activation. Stroke is another component of diabetic pathology, with increased tissue infarction and worsened recovery although the mechanisms remain unresolved. In this study, we investigated whether a compromised glial/macrophage response might contribute to cerebral hypoxic-ischemic (H/I) brain damage in diabetic (db/db), relative to their normoglycemic db/+ mice. Hypoxia-ischemia was induced in 8-week-old male db/db and db/+ mice by the ligation of right common carotid artery followed by systemic hypoxia (8% O2: 92% N2) for 17 mins. Mice were killed at specific intervals of reperfusion/recovery and the brains analyzed by in situ hybridization or total RNA isolation. In situ hybridization using bfl-1 (microglia) and glial fibrillary acidic protein (GFAP) (astrocytes) revealed expression of both bfl-1 and GFAP in the ipsilateral hemisphere at 4 h in the db/+ mice, which was delayed and minimal in the db/db mice. RNase protection assays showed a robust increase in expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNFalpha), interleukin-1 IL-1alpha, and IL-1beta mRNA in the db/+ mice at 6 to 8 h of reperfusion peaking at 8 to 12 h; in db/db mice expression was markedly delayed and diminished. Real-time-polymerase chain reaction (RT-PCR) confirmed the reduced and delayed expression TNFalpha, IL-1alpha, IL-1beta, and the growth factors insulin-like growth factor-1 and ciliary neurotrophic factor in the db/db mice; enzyme-linked immunosorbent assays confirmed the reduced and delayed translation of IL-1beta protein. These findings suggest that a compromised inflammatory response may underlie the greater infarct associated with diabetic db/db mice compared with their nondiabetic littermates following a hypoxic/ischemic insult.
 ...
PMID:Impaired wound healing after cerebral hypoxia-ischemia in the diabetic mouse. 1692 46

This study aimed at an analysis of glial fibrillary acidic protein (GFAP) in acute ischemic stroke, its association with the neurovascular status and its potential value as monitoring parameter. In 53 consecutive patients, serial venous blood samples were taken on admission, 6, 12, 18, 24, 48, 72, 96, and 120 h after stroke onset. The neurovascular status was assessed by repetitive extracranial and transcranial duplex sonography. Neurologic deficits were quantified by the National Institutes of Health stroke scale, and functional outcome was assessed with the modified Rankin Scale. Mean GFAP values were elevated from admission on with highest levels 48 h after stroke onset. GFAP release was highly correlated with severity of neurologic deficits and infarct volume. In patients with persistent middle cerebral artery occlusion, GFAP increased significantly compared with patients with normal sonographic findings (P = 0.019) and recanalization after thrombolysis resulted in a significant reduced increase (P = 0.038). GFAP concentrations were associated with the functional outcome after 3 months. Release kinetics of GFAP are associated with patients clinical deficits and infarct volume, depend on the neurovascular status on admission and on early recanalization after thrombolysis, and may be used as an additional predictor of the early course and functional outcome.
 ...
PMID:Release of glial fibrillary acidic protein is related to the neurovascular status in acute ischemic stroke. 1698 65

Reactive astrocytes in neurotrauma, stroke, or neurodegeneration are thought to undergo cellular hypertrophy, based on their morphological appearance revealed by immunohistochemical detection of glial fibrillary acidic protein, vimentin, or nestin, all of them forming intermediate filaments, a part of the cytoskeleton. Here, we used a recently established dye-filling method to reveal the full three-dimensional shape of astrocytes assessing the morphology of reactive astrocytes in two neurotrauma models. Both in the denervated hippocampal region and the lesioned cerebral cortex, reactive astrocytes increased the thickness of their main cellular processes but did not extend to occupy a greater volume of tissue than nonreactive astrocytes. Despite this hypertrophy of glial fibrillary acidic protein-containing cellular processes, interdigitation between adjacent hippocampal astrocytes remained minimal. This work helps to redefine the century-old concept of hypertrophy of reactive astrocytes.
 ...
PMID:Redefining the concept of reactive astrocytes as cells that remain within their unique domains upon reaction to injury. 1709 Jun 84

Stroke causes cell death but also birth and migration of new neurons within sites of ischemic damage. The cellular environment that induces neuronal regeneration and migration after stroke has not been defined. We have used a model of long-distance migration of newly born neurons from the subventricular zone to cortex after stroke to define the cellular cues that induce neuronal regeneration after CNS injury. Mitotic, genetic, and viral labeling and chemokine/growth factor gain- and loss-of-function studies show that stroke induces neurogenesis from a GFAP-expressing progenitor cell in the subventricular zone and migration of newly born neurons into a unique neurovascular niche in peri-infarct cortex. Within this neurovascular niche, newly born, immature neurons closely associate with the remodeling vasculature. Neurogenesis and angiogenesis are causally linked through vascular production of stromal-derived factor 1 (SDF1) and angiopoietin 1 (Ang1). Furthermore, SDF1 and Ang1 promote post-stroke neuroblast migration and behavioral recovery. These experiments define a novel brain environment for neuronal regeneration after stroke and identify molecular mechanisms that are shared between angiogenesis and neurogenesis during functional recovery from brain injury.
 ...
PMID:A neurovascular niche for neurogenesis after stroke. 1716 90


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>