Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice

Wiessner, Christoph; Allegrini, Peter R.; Rupalla, Katrin; Sauer, Dirk; Oltersdorf, Tilman; McGregor, Ailsa L.; Bischoff, Serge; Böttiger, Bernd W.; Putten, Herman van der

doi:10.1016/s0304-3940(99)00392-4

Cited by 89 publications

(52 citation statements)

References 17 publications

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“…The resulting histological and functional improvement was comparable in magnitude to that observed after overexpression of other Bcl-2-family proteins. 15,16 It is reasonable to ask whether these findings have any implications for clinical disease, since animal models of stroke have predicted the clinical usefulness of some (eg thrombolytic) but not other (eg anti-excitotoxic) therapies. 17 However, the administration of anti-excitotoxic drugs in clinical studies of stroke has generally been delayed beyond the therapeutic window predicted from animal studies, and the failure of clinical trials involving such drugs has often resulted from adverse effects or marketing considerations, and not always from lack of efficacy.…”

Section: Discussionmentioning

confidence: 99%

Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia

et al. 2003

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A recombinant adeno-associated virus (rAAV) vector was used to overexpress the anti-apoptotic Bcl-2-family protein, BCL-w, in rat brain. Three weeks after injecting the vector into cerebral cortex and striatum on one side, temporary focal ischemia was induced by occlusion of the ipsilateral middle cerebral artery for 90 min, followed by reperfusion for 24 h. BCL-w expression was increased in cerebral cortex and striatum -and in neurons, astroglia and endothelial cells -in the brains of rats that received the rAAV-BCL-w vector, compared to rats given phosphate-buffered saline or a control vector containing the gene for green fluorescent protein. Recipients of the rAAV-BCL-w vector also showed a 30% reduction in infarct size and a 33-40% improvement in neurological function, compared to the control groups. These results provide evidence for a role of BCL-w in regulating histological and functional outcome after focal cerebral ischemia.

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Section: Discussionmentioning

confidence: 99%

Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia

et al. 2003

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“…Briefly, the CRF transgene was composed of the complete coding sequence of rat CRF cDNA (0.6 kb fragment; Thompson et al, 1987), which was inserted into a 8.2 kb genomic DNA fragment encompassing the murine Thy-1.2 gene, including regulatory regions and polyadenylation signal sequence (Aigner et al, 1995). The Thy-1 regulatory sequences drive constitutive transgene expression in postnatal and adult neurons (Morris and Grosveld, 1989;Vidal et al, 1990;Moechars et al, 1996;Lüthi et al, 1997;Wiessner et al, 1999). Subsequent breeding at the local breeding facilities (Central Laboratory Animal Institute, Utrecht, The Netherlands) consisted of matings between heterozygous transgenic males (C57BL/6J background) and C57BL/6JIco females (obtained from Charles River, The Netherlands).…”

Section: Animalsmentioning

confidence: 99%

“…To gain more insight into the relationship between chronically elevated levels of CRF and associated neuroendocrine, autonomic, physiological, and behavioral changes, we have developed a transgenic mouse model of life-long CRF overproduction (CRF-OE) (Dirks et al, 2002b;Groenink et al, 2002), under control of the Thy-1 promoter which drives constitutive transgene expression in neurons in postnatal and adult brain (eg Morris and Grosveld, 1989;Vidal et al, 1990;Moechars et al, 1996;Lüthi et al, 1997;Wiessner et al, 1999). Chronic CRF overproduction in the transgenic mice appears to be associated with chronic stress-like alterations, including increased CRF expression and CRF-immunoreactivity in the hypothalamus, increased heart rate and body temperature, decreased heart rate variability, and altered hypothalamus-pituitary-adrenal (HPA) axis activity and regulation, reflected in increased basal plasma corticosterone concentrations, adrenal gland hypertrophy, and nonsuppression of corticosterone secretion in response to dexamethasone (Dirks et al, 2002b;Groenink et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Reversal of Startle Gating Deficits in Transgenic Mice Overexpressing Corticotropin-Releasing Factor by Antipsychotic Drugs

Dirks

Groenink

Westphal

et al. 2003

Neuropsychopharmacol

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Chronically elevated levels of corticotropin-releasing factor (CRF) in transgenic mice overexpressing CRF in the brain (CRF-OE) appear to be associated with alterations commonly associated with major depressive disorder, as well as with sensorimotor gating deficits commonly associated with schizophrenia. In the present study, we tested the hypothesis that antipsychotics may be effective in normalizing prepulse inhibition (PPI) of acoustic startle in CRF-OE mice, which display impaired sensorimotor gating compared to wildtype (WT) mice. The typical antipsychotic haloperidol and atypical antipsychotic risperidone improved PPI in the CRF-OE mice, but were ineffective in WT mice. The atypical antipsychotic clozapine did not influence PPI in CRF-OE mice, but reduced gating in WT mice. This effect of clozapine in the CRF-OE mice may thus be regarded as a relative improvement, consistent with the observed effect of haloperidol and risperidone. As expected, the anxiolytic, nonantipsychotic chlordiazepoxide was devoid of any effect. All four compounds dose-dependently reduced the acoustic startle response irrespective of genotype. These results indicate that antipsychotic drugs are effective in improving startle gating deficits in the CRF-OE mice. Hence, the CRF-OE mouse model may represent an animal model for certain aspects of psychotic depression, and could be a valuable tool for research addressing the impact of chronically elevated levels of CRF on information processing.

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“…In Bcl-2 transgenic mice, Bcl-2 overexpression blocks naturally occurring neuronal death (26,27) and reduces axotomyinduced (27)(28)(29)(30), ischemia-induced (26), and chemically induced (31) neuronal death. Similarly, Bcl-XL overexpression inhibits axotomy-induced (32) and ischemia-induced apoptosis (32,33) in transgenic mice.…”

mentioning

confidence: 99%

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

Liu¹,

Collier²,

Youle³

2001

Journal of Biological Chemistry

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Bcl-2 and Bcl-XL prevent neuronal apoptosis during development, neurodegenerative disease, and trauma. To test a new anti-apoptosis strategy for neuroprotection, we engineered nontoxic components of anthrax toxin into a Bcl-XL delivery system. Delivery of Bcl-XL by this system prevented apoptosis of cultured rat cerebellar granule cells and macrophages, and the prevention depended on both the Bcl-XL and the anthrax toxin receptor binding/translocation moieties. Furthermore, neuronal death in vivo in a retinal ganglion cell model of axotomy-induced apoptosis was inhibited by administration of this fusion protein. Thus, Bcl-XL protein can be delivered into cells from the medium or interstitial space, offering a new way to block apoptosis upstream of many caspases and the mitochondria dysfunction phase of apoptosis.

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Neuron-specific transgene expression of Bcl-XL but not Bcl-2 genes reduced lesion size after permanent middle cerebral artery occlusion in mice

Cited by 89 publications

References 17 publications

Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia

Adeno-associated virus-mediated delivery of BCL-w gene improves outcome after transient focal cerebral ischemia

Reversal of Startle Gating Deficits in Transgenic Mice Overexpressing Corticotropin-Releasing Factor by Antipsychotic Drugs

Inhibition of Axotomy-induced Neuronal Apoptosis by Extracellular Delivery of a Bcl-XL Fusion Protein

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