Proceedings of the National Academy of Sciences of the United States of America
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Proc. Natl. Acad. Sci. U.S.A. · Apr 2002
Neuroprotection in cerebral ischemia by neutralization of 3-aminopropanal.
Cerebral ischemia stimulates increased activity of polyamine oxidase, a ubiquitous enzyme that catabolizes polyamines to produce 3-aminopropanal. 3-Aminopropanal is a reactive aldehyde that mediates progressive neuronal necrosis and glial apoptosis. Here we report that increased levels of 3-aminopropanal-modified protein levels in humans after aneurysmal subarachnoid hemorrhage correlate with the degree of cerebral injury as measured by admission Hunt/Hess grade. ⋯ Administration of N-2-MPG in clinically relevant doses to rats significantly reduces cerebral 3-aminopropanal-modified protein immunoreactivity and infarct volume in a standardized model of middle cerebral artery occlusion, even when the agent is administered after the onset of ischemia. These results implicate 3-aminopropanal as a therapeutic target for cerebral ischemia.
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Proc. Natl. Acad. Sci. U.S.A. · Dec 2001
Combination bacteriolytic therapy for the treatment of experimental tumors.
Current chemotherapeutic approaches for cancer are in part limited by the inability of drugs to destroy neoplastic cells within poorly vascularized compartments of tumors. We have here systematically assessed anaerobic bacteria for their capacity to grow expansively within avascular compartments of transplanted tumors. ⋯ When C. novyi-NT spores were administered together with conventional chemotherapeutic drugs, extensive hemorrhagic necrosis of tumors often developed within 24 h, resulting in significant and prolonged antitumor effects. This strategy, called combination bacteriolytic therapy (COBALT), has the potential to add a new dimension to the treatment of cancer.
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Proc. Natl. Acad. Sci. U.S.A. · Dec 2001
Delayed-onset ataxia in mice lacking alpha -tocopherol transfer protein: model for neuronal degeneration caused by chronic oxidative stress.
alpha-Tocopherol transfer protein (alpha-TTP) maintains the concentration of serum alpha-tocopherol (vitamin E), one of the most potent fat-soluble antioxidants, by facilitating alpha-tocopherol export from the liver. Mutations of the alpha-TTP gene are linked to ataxia with isolated vitamin E deficiency (AVED). We produced a model mouse of AVED by deleting the alpha-TTP gene, which showed ataxia and retinal degeneration after 1 year of age. ⋯ Lipid peroxidation in alpha-TTP(-/-) mice brains showed a significant increase, especially in degenerating neurons. alpha-Tocopherol supplementation suppressed lipid peroxidation and almost completely prevented the development of neurological symptoms. This therapy almost completely corrects the abnormalities in a mouse model of human neurodegenerative disease. Moreover, alpha-TTP(-/-) mice may prove to be excellent animal models of delayed onset, slowly progressive neuronal degeneration caused by chronic oxidative stress.
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Proc. Natl. Acad. Sci. U.S.A. · Dec 2001
Specific spatial learning deficits become severe with age in beta -amyloid precursor protein transgenic mice that harbor diffuse beta -amyloid deposits but do not form plaques.
Memory impairment progressing to dementia is the main clinical symptom of Alzheimer's disease (AD). AD is characterized histologically by the presence of beta-amyloid (Abeta) plaques and neurofibrillary tangles in specific brain regions. Although Abeta derived from the Abeta precursor protein (beta-APP) is believed to play a central etiological role in AD, it is not clear whether soluble and/or fibrillar forms are responsible for the memory deficit. ⋯ Both pedigrees of the transgenic mice differed from wild-type mice by less expressed increase of escape latencies after the platform position had been changed in the reversal experiment and by failure to prefer the goal quadrant in probe trials. Both pedigrees performed at wild-type level in a number of other tests (open field exploration and passive and active place avoidance). The results suggest that plaque formation is not a necessary condition for the neuronal beta-APP(751) transgene-induced memory impairment, which may be caused by beta-APP overexpression, isoform misexpression, or elevated soluble Abeta.