Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0917798 (cerebral ischemia)
 17,036 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Post-ischemia angiogenesis and vascular plasticity help to restore blood flow to ischemic tissue and likely benefit long-term functional recovery. Physical activity has been shown to cause morphologic and functional effects, including promoting angiogenesis in normal or injured animals. A therapeutic effect of peripheral activity on central angiogenesis after cerebral ischemia, however, has not been studied. In the present study of whisker-barrel cortex ischemia in the mouse model, we tested the hypothesis that enhancing whisker activity and sensory input to the ischemic barrel cortex might promote post-ischemia cerebral angiogenesis. Three days after focal ischemia in adult mice, the whiskers corresponding to the ischemic barrel cortex were stimulated by two methods: (1) whiskers on the right side of the mouse face were trimmed away, so the left whiskers were overused by the animals, (2) left whiskers were manually stimulated to enhance input signals to the ischemic barrel cortex. Western blot analysis showed that whisker stimulation increased expression of the angiogenic factors vascular endothelial growth factor, basic fibroblast growth factor, Tie-1, angiopoietin-2 (Ang-2), and possibly Ang-1. Co-immunostaining with markers for proliferation (5-bromo-2'-deoxyuridine (BrdU)) and vascular endothelial cells (Glut-1/CD-31) identified vessel proliferation in the penumbra region. Whisker stimulation increased BrdU-positive endothelial cells and vessels in this region 7 and 14 days after ischemia. Whisker stimulation also attenuated endothelial cell death and increased local cerebral blood flow. Our data suggest that appropriately enhanced peripheral activity and afferent signals to the ischemic cortex can promote post-ischemic angiogenesis, which may imply beneficial effects of specific physical therapy on long-term recovery from ischemic stroke.
 ...
PMID:Whisker stimulation enhances angiogenesis in the barrel cortex following focal ischemia in mice. 1667 Jun 99

Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, not only improves insulin resistance in patients with type II diabetes but also exerts a broad spectrum protective effects in variable animal models of neurologic or cardiovascular diseases. We studied the effect of rosiglitazone on angiogenesis and neurological recovery after focal cerebral ischemia. Rosiglitazone (3 mg/kg or 0.3 mg/kg, p.o.) was administered for 7 days prior to and 3 days after the induction of focal ischemia (total 10 days) in adult rats. The rosiglitazone-treated group showed the enhanced neurologic improvement, the reduced infarction volume compared to the ischemia-vehicle group with dose dependency, and the reduced hemispheric atrophy. Rosiglitazone treatment reduced TUNEL(+)/activated caspase-3(+) cells, MPO(+)/Ox-42(+) inflammatory cell infiltrations, caspase-3 activity, and Bax(+) cells, as compared to the ischemia-vehicle group. The vascular surface area, the vascular branch points, the vascular length, and the number of BrdU(+) endothelial cells were significantly increased in the rosiglitazone group compared with the ischemia-vehicle group. Rosiglitazone increased eNOS expression around the ischemic margin with downregulation of FasL. Here, we show that rosiglitazone treatment enhances angiogenesis and functional recovery with dose-dependent induction of ischemic tolerance.
 ...
PMID:Peroxisome proliferator-activated receptor-gamma-agonist, rosiglitazone, promotes angiogenesis after focal cerebral ischemia. 1669 56

After acute injury of the central nervous system extracellular adenosine 5'-triphosphate (ATP) can reach high concentrations as a result of cell damage and subsequent increase in membrane permeability. Released ATP may act as a toxic agent, which causes cellular degeneration and death, mediated through P2X and P2Y receptors. Mechanisms underlying the various effects of purinoceptor modulators in models of cerebral damage are still uncertain. In the present study the effect of P2 receptor inhibition after permanent middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats was investigated. Rats received either the non-selective P2 receptor antagonist pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS) or artificial cerebrospinal fluid (ACSF) as control by the intracerebroventricular route. First, these treatments were administered 10 min before MCAO and subsequently twice daily for 1 or 7 days after MCAO. The functional recovery of motor and cognitive deficits was tested at an elevated T-labyrinth. The PPADS-treated group showed a significant reduction of paresis-induced sideslips compared with ACSF-treated animals. Infarct volume was reduced in the PPADS group in comparison with the ACSF group. A significant decrease in intermediately and profoundly injured cells in favour of intact cells in the PPADS group was revealed by quantification of celestine blue/acid fuchsin-stained cells in the peri-infarct area. The data provide further evidence for the involvement of P2 receptors in the pathophysiology of cerebral ischaemia in vivo. The inhibition of P2 receptors at least partially reduces functional and morphological deficits after an acute cerebral ischaemic event.
 ...
PMID:Neuroprotective effects of the P2 receptor antagonist PPADS on focal cerebral ischaemia-induced injury in rats. 1681 87

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

Nogo-A is a myelin-associated protein that has been shown to inhibit axonal sprouting after lesions to the CNS. Several studies have demonstrated that blocking the activity or expression of this inhibitor can induce structural and functional recovery after CNS lesions. However, there are limited and contradictory data on the expression of Nogo-A after CNS lesions. In the present study, marmoset monkeys received permanent occlusion of the middle cerebral artery (MCAo). Two, 3, or 4 months after the onset of injury brain sections were stained for Nogo-A protein. Two sham operated marmosets were included as a control. Nogo-A protein expression was quantified in white matter and grey matter in the areas adjacent to the lesion (or the equivalent areas in the intact side). At 2 months after injury, but not at 3 or 4 months, there was a significant increase in the number of oligodendrocytes that were Nogo-A immunopositive. This increase was observed in white matter structures that were adjacent to the lesion (e.g. corona radiate (CR)); but not in: white matter structures distal to the lesion (e.g. corpus callosum (CC)); cortical regions adjacent to the lesion; contralateral regions or in sham operated marmosets. These data suggest that Nogo-A levels are significantly increased within oligodendrocytes in areas adjacent to the lesion up to 2 months following cerebral ischaemia. Future studies will determine whether this offers the opportunity to promote plasticity by targeting Nogo-A weeks or months following stroke.
 ...
PMID:Time-dependent increase in Nogo-A expression after focal cerebral ischemia in marmoset monkeys. 1698 44

Intravenous administration of human mesenchymal stem cells (hMSCs) prepared from adult bone marrow has been reported to ameliorate functional deficits after cerebral artery occlusion in rats. Several hypotheses to account for these therapeutic effects have been suggested, and current thinking is that neuroprotection rather than neurogenesis is responsible. To enhance the therapeutic benefits of hMSCs potentially, we transfected hMSCs with the glial cell line-derived neurotrophic factor (GDNF) gene using a fiber-mutant F/RGD adenovirus vector and investigated whether GDNF gene-modified hMSCs (GDNF-hMSCs) could contribute to functional recovery in a rat permanent middle cerebral artery occlusion (MCAO) model. We induced MCAO by using intraluminal vascular occlusion, and GDNF-hMSCs were intravenously infused into the rats 3 hr later. MRI and behavioral analyses revealed that rats receiving GDNF-hMSCs or hMSCs exhibited increased recovery from ischemia compared with the control group, but the effect was greater in the GDNF-hMSC group. Thus, these results suggest that intravenous administration of hMSCs transfected with the GDNF gene using a fiber-mutant adenovirus vector may be useful in the cerebral ischemia and may represent a new strategy for the treatment of stroke.
 ...
PMID:Intravenous administration of glial cell line-derived neurotrophic factor gene-modified human mesenchymal stem cells protects against injury in a cerebral ischemia model in the adult rat. 1699 18

Application of adult bone marrow stromal cells (BMSC) improves functional outcome in animal models of cerebral ischemia, traumatic brain injury, and spinal cord injury. Accumulating evidence suggests that such functional recovery after BMSC treatment is mediated by enhanced trophic support of the injured neurons and improved neuronal plasticity rather than tissue replacement by bone marrow-derived stem cells. Therefore, the aim of the present study was to explore the potential of non-hematopoietic BMSC to stimulate signaling pathways in neurons that mediate trophic effects and neuroprotection. In primary embryonic rat neurons, BMSC conditioned medium (CM) attenuated staurosporine (STS) or amyloid-beta peptide-induced apoptosis in a concentration-dependent manner. The neuroprotective effect of CM required several hours of pretreatment and was abolished by heating over 90 degrees C. Immunoblot analyses revealed that CM enhanced Erk1/2 and Akt phosphorylation in neurons, and the specific MEK1 inhibitor PD98059 or the phosphoinositide-3 kinase (PI3-K) inhibitor Ly294002 abolished the neuroprotective effect of CM. Further, double-conditioned medium (DCM) obtained from BMSC previously stimulated by medium from STS-challenged neurons showed a more potent anti-apoptotic effect compared to the single-conditioned medium. Overall, these findings demonstrate that BMSC trigger endogenous survival signaling pathways in neurons that mediate protection against apoptotic insults. Moreover, the interaction between stressed neurons and BMSC further amplifies the observed neuroprotective effect.
 ...
PMID:Bone marrow stromal cells mediate protection through stimulation of PI3-K/Akt and MAPK signaling in neurons. 1705 38

Restoration of local blood supply in the post-ischemic brain plays a critical role in tissue repair and functional recovery. The present investigation explored beneficial effects of recombinant human erythropoietin (rhEPO) on vascular endothelial cell survival, angiogenesis, and restoration of local cerebral blood flow (LCBF) after permanent focal cerebral ischemia in adult mice. Saline or rhEPO (5,000 U/kg, intraperitoneal) was administered 30 mins before ischemia and once daily after ischemic stroke. Immunohistochemistry showed an enhancing effect of rhEPO on expression of EPO receptor (EPOR) of endothelial cells in the penumbra region 3 to 21 days after the ischemic insult. The treatment with rhEPO decreased ischemia-induced cell death and infarct volume 3 days after stroke. Specifically, rhEPO reduced the number of terminal deoxynucleotidyl transferase biotin-dUPT nick end labeling- and caspase-3-positive endothelial cells in the penumbra region. Colocalization of the vessel marker glucose transporter-1 (Glut-1) and cell proliferation marker 5-bromo-2'-deoxyuridine indicated enhanced angiogenic activity in rhEPO-treated mice 7 to 21 days after stroke. Western blot showed upregulation of the expression of angiogenic factors Tie-2, Angiopoietin-2, and vascular endothelial growth factor in rhEPO-treated animals. Local cerebral blood flow was measured by laser scanning imaging 3 to 21 days after stroke. At 14 days, LCBF in the penumbra was recovered to preischemia levels in rhEPO-treated mice but not in control mice. Our data suggest that rhEPO treatment upregulates the EPOR level in vascular endothelial cells, confers neurovascular protection, and enhances angiogenesis. We further show a promoting effect of rhEPO on LCBF recovery in the ischemic brain. These rhEPO-induced effects may contribute to therapeutic benefits in the treatment of ischemic stroke.
 ...
PMID:Erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice. 1707 15

Old age is associated with a deficient recovery from stroke, but the cellular mechanisms underlying such phenomena are poorly understood. To address this issue, focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. Aged rats showed a delayed and suboptimal functional recovery in the post-stroke period. Using BrdU-labeling, quantitative immunohistochemistry and 3-D reconstruction of confocal images, we found that aged rats are predisposed to rapidly develop an infarct within the first few days after ischemia. The emergence of the necrotic zone is associated with a high rate of cellular degeneration, premature accumulation of proliferating BrdU-positive cells that appear to emanate from capillaries in the infarcted area, and a large number of apoptotic cells. With double labeling techniques, we were able to identify, for the first time, over 60% of BrdU-positive cells either as reactive microglia (45%), oligodendrocyte progenitors (17%), astrocytes (23%), CD8+ lymphocytes (4%), or apoptotic cells (<1%). Paradoxically, despite a robust reactive phenotype of microglia and astrocytes in aged rats, at 1-week post-stroke, the number of proliferating microglia and astrocytes was lower in aged rats than in young rats. Our data indicate that aging is associated with rapid infarct development and a poor prognosis for full recovery from stroke that is correlated with premature cellular proliferation and increased cellular degeneration and apoptosis in the infarcted area.
 ...
PMID:Accelerated infarct development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats. 1713 Nov 30

To evaluate the hypothesis that platelet activating factor (PAF) antagonism may affect the functional recovery following the nerve injuries and also to evaluate the effect of PAF receptor antagonism on the neuroprotective effect of tacrolimus and sodium valproate, effect of PAF receptor antagonist, WEB2086 was evaluated in animal models of sciatic nerve crush and endothelin-1 induced focal cerebral ischemia. WEB2086, per se, while attenuating spontaneous sensory motor recovery after sciatic nerve crush, enhanced functional recovery after focal cerebral ischemia. WEB2086 also attenuated the neuroprotective effect of tacrolimus and sodium valproate subsequent to peripheral nerve injury, while it significantly improved the neuroprotective action of tacrolimus and sodium valproate following cerebral ischemia reperfusion injury. These results suggest that PAF receptor antagonists alone and in combination with tacrolimus/sodium valproate could be used in the treatment of cerebral ischemia reperfusion injuries however, their use following peripheral nerve injuries could be detrimental.
 ...
PMID:PAF antagonism modifies neuroprotective action of histone deacetylase and calcineurin phosphatase inhibitors in mice. 1720 8


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