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

Topical application of GDNF protein greatly reduced the infarct size and brain edema at 24 hr of continuous MCAO in rats. The reduction of the infarct size was not related to a change of cerebral blood flow (CBF), but was accompanied by marked reduction of positive cells for TUNEL and caspases in the affected area. GDNF protein showed a direct protective effect against ischemic brain damage, but not secondary by improving CBF. Pretreatment of animals with Ad-GDNF 24 hr before the subsequent 90 min of transient MCAO effectively reduced infract volume and area without affecting regional CBF compared to the vehicle or Ad-LacZ animal groups. Free radical scavenger edaravone effectively reduced brain edema, infarct size, and peroxidative markers of protein, lipid and DNA. Thus, gene therapy and neuroprotective strategy have a great potential for reducing ischemic brain damage of human stroke patients in the near future.
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PMID:[Gene therapy and neuroprotection for cerebral infarction]. 1515 96

Mesenchymal stem cells (MSC) were reported to ameliorate functional deficits after stroke in rats, with some of this improvement possibly resulting from the action of cytokines secreted by these cells. To enhance such cytokine effects, we previously transfected the telomerized human MSC with the BDNF gene using a fiber-mutant adenovirus vector and reported that such treatment contributed to improved ischemic recovery in a rat transient middle cerebral artery occlusion (MCAO) model. In the present study, we investigated whether other cytokines in addition to BDNF, i.e., GDNF, CNTF, or NT3, might have a similar or greater effect in this model. Rats that received MSC-BDNF (P < 0.05) or MSC-GDNF (P < 0.05) showed significantly more functional recovery as demonstrated by improved behavioral test results and reduced ischemic damage on MRI than did control rats 7 and 14 days following MCAO. On the other hand, rats that received MSC-CNTF or MSC-NT3 showed neither functional recovery nor ischemic damage reduction compared to control rats. Thus, MSC transfected with the BDNF or GDNF gene resulted in improved function and reduced ischemic damage in a rat model of MCAO. These data suggest that gene-modified cell therapy may be a useful approach for the treatment of stroke.
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PMID:Mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model. 1558 10

The delivery of proteins across the blood-brain barrier is severely limited by the proteins' size and biochemical properties. Thus, a large number of peptides have been characterized in recent years that efficaciously prevent neuronal death in vitro, but which may not be applied in vivo, since they are unable to cross cell membrane barriers. In the 1990ies, it had been shown that the HIV TAT protein is able to cross cell membranes even when coupled with larger peptides. Subsequent studies with fusion proteins of the 11-amino acid protein transduction domain of HIV-TAT revealed that TAT fusion proteins may successfully be used for therapeutic purposes in vivo, even when systemically applied. Indeed, intravenous delivery of TAT proteins linked with anti-apoptotic (Bcl-XL) and neurotrophic (GDNF) factors resulted in a rapid and highly efficacious transduction of the brain tissue. When administered after focal cerebral ischemia, intravenous TAT-Bcl-XL and TAT-GDNF significantly reduced brain injury, both when applied after severe and mild ischemic insults. These data provided the first in vivo evidence of the efficacy of fusion proteins in the ischemic brain, thus raising new hopes that neuroprotection is feasible after stroke. Yet, molecular biological studies have pointed out more recently that there are also limitations of the TAT protein strategy, which still need to be addressed. The development of clinically-applicable treatments for ischemic stroke based on fusion protein technologies deserves concerted efforts in the future.
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PMID:TAT fusion proteins against ischemic stroke: current status and future perspectives. 1636 50

This review presents our experience and results concerning cerebral stroke gene therapy with a rat model subjected to rAAV-vector delivered IL-1ra and GDNF. The methodology involving the production of high-titer recombinant adeno-associated virus vectors in the absence of helper adenovirus and the creation of a tri-vessel ligation model of focal ischemic cerebral stroke in rats are described in detail. Furthermore, a literature review of other viral vectors, murine models of focal cerebral ischemia and candidates for therapeutic transgenes used for cerebral stroke gene therapy are presented. Lastly, the potentials and limitations of stroke gene therapy are discussed adding an analysis of possibilities of future experiment designs.
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PMID:Gene therapy of focal cerebral ischemia using defective recombinant adeno-associated virus vectors. 1672 Feb 92

Nurr1 has been implicated as a transcription factor mediating the endogenous neuroprotective mechanism against stroke. We examined the in vivo and in vitro properties of a new human embryonic carcinoma Ntera-2 cell line carrying the human Nurr1 gene (NT2N.Nurr1). Adult Sprague-Dawley rats underwent experimental stroke initially and 14 days later were assigned randomly to receive stereotaxic transplantation of NT2N.Nurr1 cells or infusion of vehicle into their ischemic striatum. Transplantation of NT2N.Nurr1 cells promoted significant attenuation of behavioral impairments over a 56-day period after stroke, characterized by decreased hyperactivity, biased swing activity, and neurologic deficits, as well as significant reduction in ischemic striatal cell loss compared to vehicle-infused stroke animals. Transplanted NT2N.Nurr1 cells survived and expressed neuronal phenotypic markers in the ischemic striatum. In vitro results showed that cultured NT2.Nurr1 cells were already negative for nestin even before retinoic acid treatment, despite strong nestin immunoreactivity in NT2 cells. This indicates Nurr1 triggered a rapid commitment of NT2 cells into a neuronal lineage. Indeed, NT2.Nurr1 cells, at 4 weeks into RA treatment, displayed more abundant tyrosine hydroxylase positive cells than NT2 cells. Parallel ELISA studies showed further that cultured NT2N.Nurr1, but not NT2N cells, secreted glial cell derived neurotrophic factor. The present study shows efficacy of NT2N.Nurr1 cell grafts in ischemic stroke, with in vitro evidence suggesting the cells' excellent neuronal differentiation capability and ability to secrete GDNF as likely mechanisms mediating the observed therapeutic benefits.
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PMID:Transplantation of post-mitotic human neuroteratocarcinoma-overexpressing Nurr1 cells provides therapeutic benefits in experimental stroke: in vitro evidence of expedited neuronal differentiation and GDNF secretion. 1733 85

Aquaporin 4 (AQP4) is a predominant water channel protein in mammalian brains, which is localized in the astrocyte plasma membrane. AQP4 has gained much attraction due to its involvement in the physiopathology of cerebral disorders including stroke, tumor, infection, hydrocephalus, epilepsy, and traumatic brain injury. But there is almost no evidence whether abnormal AQP4 levels are associated with degenerative diseases, such as Parkinson's disease (PD). In our studies, we established PD animal models by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to test the hypothesis that abnormal AQP4 expression is involved in the pathophysiology of this disease. We show that mutant mice lacking AQP4 were significantly more prone to MPTP-induced neurotoxicity than their wild-type littermates. Furthermore, after administration of MPTP, astroglial proliferation and GDNF protein synthesis were inhibited by AQP4 deficiency. This study demonstrates that AQP4 is important in the MPTP neurotoxic process and indicates that the therapeutic strategy targeted to astrocytic modulation with AQP4 may offer a great potential for the development of new treatment for PD.
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PMID:Hypersensitivity of aquaporin 4-deficient mice to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyrindine and astrocytic modulation. 1735 68

A new generation of multifunctional fusion proteins presents a potential solution to overcome the challenges associated with brain drug delivery and development of treatments for neurological disorders, including stroke, Alzheimer's disease, Parkinson's disease and inherited mucopolysaccharidosis. These biotherapeutics are engineered i) to cross the blood-brain barrier (BBB) following i.v. administration and ii) to produce a brain therapeutic effect. These fusion proteins are comprised of both a transport and a therapeutic domain. The transport domain is a monoclonal antibody (MAb) directed to an exofacial epitope of the BBB human insulin receptor (HIR), which uses the BBB endogenous insulin transport system to gain access to the brain via receptor-mediated transcytosis without interfering with the normal transport of insulin. Both human-chimeric and fully humanized versions of the anti-human HIRMAb have already been produced. The therapeutic domain of these fusion proteins consists of the peptide or protein of interest fused to the carboxyl terminus of the C(H)3 region of the heavy chain of the anti-human HIRMAb. A variety of HIRMAb fusion proteins were engineered aiming at the development of therapeutics for the central nervous system (CNS), i.e., stroke and Parkinson's disease, as in the case of HIRMAb-BDNF and HIRMAb-GDNF, respectively, HIRMAb-IDUA for the treatment of Hurler's disease, HIRMAb-A beta single chain antibody for passive immunotherapy of Alzheimer's disease, and HIRMAb-avidin as delivery system for biotinylated drugs, like siRNAs. The multifunctionality of these fusion proteins has been validated in preclinical work, including brain update in primates. Pending further development into pharmacological and toxicological studies, and clinical trials, members of the biotherapeutic family discussed in the present review, designed to overcome the brain drug delivery hurdle, are positioned to become a new generation of neuropharmaceutical drugs for the treatment of human CNS disorders.
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PMID:A new generation of neurobiological drugs engineered to overcome the challenges of brain drug delivery. 1918 Feb 67

Recent studies have reported that glial cell line-derived growth factor (GDNF) has neurotrophic effects on the central nervous system, and the neural stem cells (NSCs) engrafted in animal models of stroke survive and ameliorate the neurological deficits. In this study, a stable human NSC line overexpressing GDNF (F3.GDNF) was transplanted next to the intracerebral hemorrhage (ICH) lesion site and a possible therapeutic effect was investigated. F3.GDNF human NSC line was transplanted into the cortex overlying the striatal ICH lesion. ICH was induced in adult mice by the unilateral injection of bacterial collagenase into the striatum. The animals were evaluated for 8 weeks with rotarod and limb placement tests. Transplanted NSCs were detected by beta-gal immunostaining with double labeling of neurofilament, microtubule associated protein-2, glial fibrillary acidic protein or human nuclear matrix antigen (HuNuMA). F3.GDNF human NSCs produced a four times higher amount of GDNF over parental F3 cells in vitro, induced behavioral improvement in ICH mice after brain transplantation and two- to threefold increase in cell survival of transplanted NSCs at 2 and 8 weeks post-transplantation. In F3.GDNF-grafted ICH brain, a significant increase in the antiapoptotic protein and cell survival signal molecules, and a marked reduction in proapoptotic proteins were found as compared with control group. Brain transplantation of human NSCs overexpressing GDNF in ICH animals provided functional recovery in ICH animals, and survival and differentiation of grafted human NSCs. These results indicate that the F3.GDNF human NSCs should be of a great value as a cellular source for the cellular therapy in animal models of human neurological disorders including ICH.
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PMID:Human neural stem cells overexpressing glial cell line-derived neurotrophic factor in experimental cerebral hemorrhage. 1955 35

We recently demonstrated that blood-brain barrier permeabilization using mannitol enhances the therapeutic efficacy of systemically administered human umbilical cord blood (HUCB) by facilitating the entry of neurotrophic factors from the periphery into the adult stroke brain. Here, we examined whether the same blood-brain barrier manipulation approach increases the therapeutic effects of intravenously delivered HUCB in a neonatal hypoxic-ischaemic (HI) injury model. Seven-day-old Sprague-Dawley rats were subjected to unilateral HI injury and then at day 7 after the insult, animals intravenously received vehicle alone, mannitol alone, HUCB cells (15k mononuclear fraction) alone or a combination of mannitol and HUCB cells. Behavioural tests at post-transplantation days 7 and 14 showed that HI animals that received HUCB cells alone or when combined with mannitol were significantly less impaired in motor asymmetry and motor coordination compared with those that received vehicle alone or mannitol alone. Brain tissues from a separate animal cohort from the four treatment conditions were processed for enzyme-linked immunosorbent assay at day 3 post-transplantation, and revealed elevated levels of GDNF, NGF and BDNF in those that received HUCB cells alone or when combined with mannitol compared with those that received vehicle or mannitol alone, with the combined HUCB cells and mannitol exhibiting the most robust neurotropic factor up-regulation. Histological assays revealed only sporadic detection of HUCB cells, suggesting that the trophic factor-mediated mechanism, rather than cell replacement per se, principally contributed to the behavioural improvement. These findings extend the utility of blood-brain barrier permeabilization in facilitating cell therapy for treating neonatal HI injury.
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PMID:Mannitol facilitates neurotrophic factor up-regulation and behavioural recovery in neonatal hypoxic-ischaemic rats with human umbilical cord blood grafts. 2056 76

Deep brain stimulation (DBS) is used to treat a variety of neurological disorders including Parkinson's disease. In this study, we explored the effects of striatal stimulation (SS) in a rat model of chronic-phase ischemic stroke. The stimulation electrode was implanted into the ischemic penumbra at 1 month after middle cerebral artery occlusion (MCAO) and thereafter continuously delivered SS over a period of 1 week. Rats were evaluated behaviorally coupled with neuroradiological assessment of the infarct volumes using magnetic resonance imaging (MRI) at pre- and post-SS. The rats with SS showed significant behavioral recovery in the spontaneous activity and limb placement test compared to those without SS. MRI visualized that SS also significantly reduced the infarct volumes compared to that at pre-SS or without SS. Immunohistochemical analyses revealed a robust neurogenic response in rats that received SS characterized by a stream of proliferating cells from the subventricular zone migrating to and subsequently differentiating into neurons in the ischemic penumbra, which exhibited a significant GDNF upregulation. In tandem with this SS-mediated neurogenesis, enhanced angiogenesis was also recognized as revealed by a significant increase in VEGF levels in the penumbra. These results provide evidence that SS affords neurorestoration at the chronic phase of stroke by stimulating endogenous neurogenesis and angiogenesis.
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PMID:Striatal stimulation nurtures endogenous neurogenesis and angiogenesis in chronic-phase ischemic stroke rats. 2109 9


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