Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death

Shimazaki, Kuniko; Urabe, Masashi; Monahan, John; Ozawa, Keiya; Kawai, Nobufumi

doi:10.1038/sj.gt.3301211

Cited by 80 publications

(41 citation statements)

References 38 publications

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“…These protective Bcl-2 effects agree with prior reports showing neuroprotection by Bcl-2 against excitotoxins, hypoglycemia and adriamycin in primary cultures derived from a number of brain regions (Jia et al 1996;Lawrence et al 1996;McLaughlin et al 2000;Tamatani et al 2000) and against in vivo models of excitotoxicity, hypoxia-ischemia, ROS generators, or mechanical trauma (Linnik et al 1995;Lawrence et al 1996Lawrence et al , 1997Antonawich et al 1999;Yamada et al 1999;Phillips et al 2000;Shimazaki et al 2000).…”

Section: Glutamate Neurotoxicitysupporting

confidence: 90%

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Howard

Bottino

Brooke

et al. 2002

Journal of Neurochemistry

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Overexpression of bcl-2 protects neurons from numerous necrotic insults, both in vitro and in vivo. While the bulk of such protection is thought to arise from Bcl-2 blocking cytochrome c release from mitochondria, thereby blocking apoptosis, the protein can target other steps in apoptosis, and can protect against necrotic cell death as well. There is evidence that these additional actions may be antioxidant in nature, in that Bcl-2 has been reported to protect against generators of reactive oxygen species (ROS), to increase antioxidant defenses and to decrease levels of ROS and of oxidative damage. Despite this, there are also reports arguing against either the occurrence, or the importance of these antioxidant actions. We have examined these issues in neuron-enriched primary hippocampal cultures, with overexpression of bcl-2 driven by a herpes simplex virus amplicon: (i) Bcl-2 protected strongly against glutamate, whose toxicity is at least partially ROS-dependent. Such protection involved reduction in mitochondrially derived superoxide. Despite that, Bcl-2 had no effect on levels of lipid peroxidation, which is thought to be the primary locus of glutamate-induced oxidative damage; (ii) Bcl-2 was also mildly protective against the pro-oxidant adriamycin. However, it did so without reducing levels of superoxide, hydrogen peroxide or lipid peroxidation; (iii) Bcl-2 protected against permanent anoxia, an insult likely to involve little to no ROS generation. These findings suggest that Bcl-2 can have antioxidant actions that may nonetheless not be central to its protective effects, can protect against an ROS generator without targeting steps specific to oxidative biochemistry, and can protect in the absence of ROS generation. Thus, the antioxidant actions of Bcl-2 are neither necessary nor sufficient to explain its protective actions against these insults in hippocampal neurons.

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Section: Glutamate Neurotoxicitysupporting

confidence: 90%

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Howard

Bottino

Brooke

et al. 2002

Journal of Neurochemistry

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“…However, since a variety of promoters, transgenes, ITRs, and brain regions have been used, a direct comparison between species is not possible. [36][37][38][39][40][41] A comparison of AAV2 and AAV5 injection into the rat striatum indicated that AAV5 transduction was less predictable in the direction of spread and in the volume of transduction than AAV2. 41 There have been no studies examining the ability of AAV1 to transduce the brain in the adult of any species.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus vector-mediated transduction in the cat brain

et al. 2003

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Adeno-associated virus (AAV) vectors are capable of delivering a therapeutic gene to the mouse brain that can result in long-term and widespread protein production. However, the human infant brain is more than 1000 times larger than the mouse brain, which will make the treatment of global neurometabolic disorders in children more difficult. In this study, we evaluated the ability of three AAV serotypes (1,2, and 5) to transduce cells in the cat brain as a model of a large mammalian brain. The human lysosomal enzyme bglucuronidase (GUSB) was used as a reporter gene, because it can be distinguished from feline GUSB by heat stability. The vectors were injected into the cerebral cortex, caudate nucleus, thalamus, corona radiata, internal capsule, and centrum semiovale of 8-week-old cats. The brains were evaluated for gene expression using in situ hybridization and enzyme histochemistry 10 weeks after surgery. The AAV2 vector was capable of transducing cells in the gray matter, while the AAV1 vector resulted in greater transduction of the gray matter than AAV2 as well as transduction of the white matter. AAV5 did not result in detectable transduction in the cat brain.

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“…19,20 These studies, however, used genetically engineered virus vectors such as adenoassociated virus (AAV) 19 or herpes-simplex type I virus Gene Therapy (HSV). 20 Besides the potentially higher biological risk through the transfer of virus genes not necessary for the treatment, with these vectors there is a realistic possibility of permanent integration and expression of transgenic bcl2 in neuronal, glial and endothelial cells in the CNS.…”

Section: Units (Rlu)/mg Protein) Control Nt2 Cells Transfected With mentioning

confidence: 99%

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

Cao

Shibata

2001

Gene Ther

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Expression of anti-apoptotic or neurotrophic transgene proteins in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas. NT2, a human neoplastic cell line which terminally differentiates into postmitotic neuronsIschemia of the brain due to major vessel thrombosis causes hypoxia in the respective vascular territory and subsequently induces neuronal death which is at least in part caused by apoptosis, especially in the penumbra of the lesion. 1,2 Hypoxia-inducible expression of anti-apoptotic or neurotrophic transgenes in hypoxic neurons may provide a novel therapeutic strategy for neuroprotection and alleviation of damage to ischemic brain areas.Hypoxia has been known as a potent inducer of a large number of genes including those encoding erythropoietin, vascular endothelial growth factor (VEGF), and some glycolytic enzymes, eg phosphoglycerate kinase. These genes have specific regulatory sequences in their promoter regions, known as hypoxia responsive elements (HRE). 3 Under hypoxic conditions, the upregulated hypoxia-inducible transcription factor 1 (HIF-1) binds to the HRE and initiates transcription of 3Ј sequences. This physiological mechanism has been utilized for develop- ment of hypoxia-responsive gene transfer vectors with HRE-based promoters. Hypoxia-inducible expression of transgenes has been reported in tumor cells and in cardiac myocytes. [4][5][6][7][8][9] Recently, new hypoxia-responsive vectors for tumor-specific gene therapy were developed. 10

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Adeno-associated virus vector-mediated bcl-2 gene transfer into post-ischemic gerbil brain in vivo: prospects for gene therapy of ischemia-induced neuronal death

Cited by 80 publications

References 38 publications

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Neuroprotective effects of bcl‐2 overexpression in hippocampal cultures: interactions with pathways of oxidative damage

Adeno-associated virus vector-mediated transduction in the cat brain

Hypoxia-inducible transgene expression in differentiated human NT2N neurons – a cell culture model for gene therapy of postischemic neuronal loss

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