Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo

Lawrence, Matthew S.; Ho, Dora Y.; Sun, Guo Hua; Steinberg, Gary K.; Sapolsky, R. M.

doi:10.1523/jneurosci.16-02-00486.1996

Cited by 300 publications

(178 citation statements)

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“…In agreement with a prior report (Lawrence et al 1996), overexpression of bcl-2 decreased the neurotoxicity of glutamate, causing an approximate doubling of the LD 50 (Fig. 1).…”

Section: Resultssupporting

confidence: 93%

“…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%

“…Both plasmids also contained the oriS and a sequences required for replication and packaging. Construction of plasmids was described previously (Lawrence et al 1996).…”

Section: Hippocampal Cell Culturesmentioning

confidence: 99%

“…Bcl-2 can decrease the toxicity of a number of insults that are heavily or entirely oxidative in nature, such as adriamycin, paraquat, hydrogen peroxide, or 6-OHDA (Oh et al 1995;Lawrence et al 1996;Lezoualc'h et al l996;Marin et al 1996;Bruce-Keller et al 1998;;Hochman et al 1998;Yang et al 1998Yamada et al 1999Luc Cadet et al 2000). We examined whether Bcl-2 could protect against an insult that is overwhelmingly oxidative in nature, and if any such protection arose as a result of reducing ROS accumulation or oxidative damage.…”

Section: Adriamycin Neurotoxicitymentioning

confidence: 99%

“…Overexpression of bcl-2 attenuates the cell death caused by numerous insults whose toxicities depend heavily upon ROS generation (such as adriamycin, paraquat, hydrogen peroxide, 6-OHDA, MPTP; see below). Moreover, many of these instances of protection are accompanied by a reduction in ROS accumulation (Kane et al 1993, insult of glutathione depletion in neural cell lines; Lawrence et al 1996, adriamycin in primary hippocampal cultures; Papadopoulos et al 1998, aglycemia in cortical astrocyte cultures). In addition, Bcl-2 decreases oxidative damage (Kane et al 1993, glutathione depletion in neural cell lines; Myers et al 1995, cyanide/aglycemia in hypothalamic tumor lines; Bruce-Keller et al 1998, hydrogen peroxide and amyloid b-peptide in PC12 cells; Giardino et al 1996, hyperglycemia in peripheral tissue; Lee et al 2001, hydrogen peroxide in teratocarcinoma and neuroblastoma cell lines).…”

mentioning

confidence: 99%

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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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“…In agreement with a prior report (Lawrence et al 1996), overexpression of bcl-2 decreased the neurotoxicity of glutamate, causing an approximate doubling of the LD 50 (Fig. 1).…”

Section: Resultssupporting

confidence: 93%

Section: Glutamate Neurotoxicitysupporting

confidence: 90%

“…Both plasmids also contained the oriS and a sequences required for replication and packaging. Construction of plasmids was described previously (Lawrence et al 1996).…”

Section: Hippocampal Cell Culturesmentioning

confidence: 99%

Section: Adriamycin Neurotoxicitymentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

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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DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats

et al. 1999

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Spinal cord injury in adult mammals causes atrophy or death of some axotomized neurons. The product of the antiapoptotic gene Bcl‐2 prevents neuron death in vivo. We delivered Bcl‐2 by intraspinal injection of a DNA plasmid encoding this gene to determine if axotomized neurons destined to undergo retrograde death could be rescued. Axons of the right side Clarke's Nucleus (CN) were cut unilaterally in adult Sprague‐Dawley rats by T8 hemisection, leaving the contralateral (left) CN as an intact control. Two months postoperatively, there was ∼35% loss of total CN neurons in the right L1 segment. Only 15% of large CN neurons (>400 μm2), whose axons project to the cerebellum, survived—indicating atrophy and/or death of 85% of these cells. We injected a DNA plasmid encoding the human Bcl‐2 gene and the bacterial reporter gene LacZ, which was complexed with cationic lipids, into the right side of segment T8 of the normal spinal cord, or just caudal to the hemisection site. The reporter gene was expressed in the perikarya of right CN neurons at L1 for up to 7 days, but not 14 days. Two months following T8 hemisection and Bcl‐2/LacZ DNA injection, there was no significant loss of CN neurons ipsilateral to the lesion. Surprisingly, 61% of large neurons survived, indicating partial protection from atrophy. In contrast, a DNA plasmid that codes for the LacZ reporter gene, but not Bcl‐2, did not prevent CN neuron death or atrophy. Administration of the Bcl‐2 gene in adult rats and its expression in these CNS neurons prevents retrograde cell death, and also minimizes atrophy. These results may serve as the basis for developing novel gene therapy strategies for patients with spinal cord injury. J. Comp. Neurol. 404:159–171, 1999. © 1999 Wiley‐Liss, Inc.

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Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice

et al. 1999

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The cell death regulatory protein, Bcl‐2, has been suggested to participate in the pathophysiology of various neurological disorders, including traumatic brain injury (TBI). The cognitive function and histopathologic sequelae after controlled cortical impact brain injury were evaluated in transgenic (TG) mice that overexpress human Bcl‐2 protein (n = 13) and their wild type (WT) controls (n = 9). Although brain‐injured Bcl‐2 TG mice exhibited similar posttraumatic deficits in a Morris water maze (MWM) test of spatial memory as their WT counterparts at 1 week postinjury, the preinjury learning ability of Bcl‐2 TG mice was impaired significantly compared with their WT littermates (P < 0.05). In contrast, histopathologic analysis revealed significantly attenuated tissue loss in the ipsilateral hemisphere (p < 0.01) and decreased tissue loss in ipsilateral hippocampal area CA3 (P < 0.001) and the dentate gyrus (P < 0.01) in brain‐injured Bcl‐2 TG mice compared with brain‐injured WT mice. Immunohistochemical evaluation of glial fibrillary acidic protein also revealed a significant decrease in reactive astrocytosis in the ipsilateral dorsal thalamus (P < 0.05) and the ventral thalamus (P < 0.01) in brain‐injured Bcl‐2 TG mice. These results suggest that overexpression of Bcl‐2 protein may play a protective role in neuropathologic sequelae after TBI. J. Comp. Neurol. 412:681–692, 1999. © 1999 Wiley‐Liss, Inc.

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Overexpression of Bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo

Cited by 300 publications

References 0 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

DNA plasmid that codes for human Bcl-2 gene preserves axotomized Clarke's nucleus neurons and reduces atrophy after spinal cord hemisection in adult rats

Overexpression of Bcl-2 is neuroprotective after experimental brain injury in transgenic mice

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