Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-04-01
2001-01-16
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06174875
ABSTRACT:
BACKGROUND OF INVENTION
Oxidative stress is considered to be an important causative factor in the onset or progression of neurodegenerative diseases and may contribute to neuronal damage that results from cerebral ischemia (Coyle et al. (1993)
Science
262:689). Reactive oxygen species (ROS), which are generated as by-products of many metabolic process including monoamine metabolism and arachidonic acid oxidation, may be the principal intracellular mediators of cell death in oxidatively stressed neuronal cells. The damage to various macromolecules by chemical reactions with ROS can initiate an apoptotic program of cell death or lead to cell death by necrosis. Despite the molecular and biochemical details of cellular responses to ROS, it is unclear why neuronal toxicity in response to oxidative stress is often delayed and in some conditions limited to discrete populations of vulnerable neurons.
The neuroprotective effects of a pre-conditioned thermal stress are known and are presumably attributable to the induced synthesis of heat shock proteins (Maihos et al. (1993)
Neuroscience
55:621). Various members of the heat shock protein family, such as the 70 kDa protein hsp70, play a role in cellular recovery from various forms of stress due to their capacity to act as molecular chaperones (Hartl (1996)
Nature
381:571). While some studies have detailed the induction of hsp70 mRNA and protein expression in the brain in response to various ischemic insults, the mechanisms responsible for any neuroprotective effects of hsp70 remain enigmatic (Fink et al. (1997)
J. Neurochem.
68:961). Although thermal stress is clearly an effective means of inducing hsp70 expression, it is not a pharmacologically acceptable approach to the manipulation of heat shock protein expression.
A number of cell culture systems have been exploited to analyze the mechanisms of oxidative stress-induced neuronal death. For example, a mouse hippocampal cell line, HT22, has been developed that is particularly sensitive to glutamate-induced oxidative toxicity (Maher et al. (1997)
J. Neurosci.
16:6394). The cytotoxic effect of glutamate in HT22 cells is not due to excitotoxic effects of this stimulatory amino acid, as this cell line is devoid of ionotropic glutamate receptors. Rather, glutamate-induced oxidative toxicity of HT22 cells is associated with an inhibition of cysteine transport which subsequently leads to depletion of intracellular glutathione levels and activation of neuronal 12-lipoxygenase. The resulting ROS that are generated by arachidonic acid oxidation in these cells likely activate an apoptotic program of cell death by a number of different mechanisms (Lief al. (1997)
Neuron
19:453).
Cell culture models, such as HT22 cells, are well suited for studies designed to assess the effectiveness of pharmacological agents in preventing oxidative toxicity. The list of agents that protect cultured neurons from this form of toxicity is quite extensive and includes growth factors, vitamin E, antioxidants, non-steroidal anti-inflammatory agents such as aspirin, and protein kinase inhibitors. The different mechanisms of action of these neuroprotective compounds probably reflects the multitude of cellular processes that contribute to oxidative toxicity. However, since many compounds that provide protection against oxidative toxicity are only effective when given prior to the onset of oxidative stress, their clinical applicability is limited. A need exists for neuroprotective agents that are effective when administered after the onset of oxidative stress, for example after cardiac arrest or stroke.
Geldanamycin, herbimycin A and macbecin are naturally occurring antitumor antibiotics of the benzoquinoid ansamycin class. (DeBoer et al. (1970)
J. Antibiot.
(Tokyo) 23:442, Omura et al. (1979)
J. Antibiot.
32:255; Ono et al. (1982)
I. Gann.
73:938.) The main intracellular target of geldanamycin and herbimycin A is the 90 kDa heat shock protein, hsp90. The binding of geldanamycin to hsp90 alters the chaperoning activity of hsp90 and, among other effects, leads to induction of the 70 kDa heat shock protein, hsp70. (Whitesell et al. (1996)
Mol. Endocrinol.
10:705; Morimoto et al.
J. Biol. Chem.
267:21987; Wu (1995) Rev. Cell
Dev. Biol.
11:441.)
In particular, herbimycin A and geldanamycin have been found to induce hsp70 expression in fibroblasts (Murakami et al. (1991)
Exp. Cell Res.
195:338; Hedge et al. (1995)
J. Cell. Physiol.
165:186), a myogenic cell line, and rat cardiomyocytes in culture (Conde et al. (1997)
J. Mol. Cell. Cardiol.
26:1927). Conde et al. disclose that pretreatment of myogenic H9c2 cells and cardiomyocytes with herbimycin or geldanamycin resulted in overexpression of heat shock proteins and conferred protection against simulated ischemia.
A requirement for pretreatment limits the practical therapeutic utility of agents for the treatment of cardiac arrest or stroke. The present invention, by providing a method of preventing damage resulting from cardiac arrest or stroke in which the agent is administered following the onset of the damaging insult, has significant clinical applicability.
SUMMARY OF THE INVENTION
The present invention provides a method of inhibiting cell death induced by oxidative stress in a cell comprising contacting the cell with an cell-death-inhibiting effective amount of a composition comprising a benzoquinoid ansamycin. In a preferred embodiment the cell is a neuronal cell and the benzoquinoid ansamycin is geldanamycin or herbimycin A.
The present invention further provides a method of reducing neurological injury resulting from cardiac arrest or stroke comprising administering to a patient suffering from cardiac arrest or stroke a composition comprising an effective amount of a benzoquinoid ansamycin. In a preferred embodiment the benzoquinoid ansamycin is geldanamycin or herbimycin A.
In another embodiment, the present invention provides an article of manufacture comprising a packaging material and a pharmaceutical composition contained within the packaging material, wherein the pharmaceutical composition comprises a benzoquinoid ansamycin, and wherein the packaging material comprises a label that indicates that the composition can be used to reduce neurological injury resulting from cardiac arrest or stroke.
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Czar et al., “Geldanamycin, a Heat Shock Protein 90-Binding Benzoquinone Ansamycin, Inhibits Steroid-Dependent Translocation of the Glucocorticoid Receptor from the Cytoplasm to the Nucleus”,Biochemistry, vol. 36, No. 25, 1997, pp. 7776-7785.
Segnitz et al., “The Function of Steriod Hormone R
Callaway Clifton W.
DeFranco Donald B.
Lipinski Christopher
Xiao Nianqing
Baker & Botts LLP
Reamer James H.
University of Pittsburgh
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