Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-02-11
2002-03-19
Weddington, Kevin E. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S617000, C514S619000
Reexamination Certificate
active
06358975
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to the prevention and/or treatment of neural tissue damage resulting from ischemia and reperfusion injury. More particularly, the invention concerns the prevention or treatment of vascular stroke, other neurodegenerative diseases and occlusion of coronary arteries, by administering selective inhibitors of the nucleic enzyme poly(adenosine 5′-diphospho-ribose) polymerase [“poly(ADP-ribose) polymerase” or “PARP”, which is also sometimes called “PARS” for poly(ADP-ribose) synthetase].
2. Description of the Prior Art
Poly(ADP-ribose) polymerase (“PARP”) is an enzyme located in the nuclei of cells of various organs, including muscle, heart and brain cells. PARP plays a physiological role in the repair of strand breaks in DNA. Once activated by damaged DNA fragments, PARP catalyzes the attachment of up to 100 ADP-ribose units to a variety of nuclear proteins, including histones and PARP itself. While the exact range of functions of PARP has not been established, this enzyme is thought to play a role in enhancing DNA repair.
During major cellular stresses, however, the extensive activation of PARP can rapidly lead to cell death through depletion of energy stores. Four molecules of ATP are consumed for every molecule of NAD (the source of ADP-ribose) regenerated. Thus, NAD, the substrate of PARP, is depleted by massive PARP activation and, in the efforts to re-synthesize NAD, ATP may also be depleted.
Neural damage following stroke and other neurodegenerative processes is thought to result from a massive release of the excitatory neurotransmitter glutamate, which acts upon the N-methyl-D-aspartate (NMDA) receptors and other subtype receptors. Evidence includes findings in many animal species, as well as in cerebral cortical cultures treated with glutamate or NMDA, that glutamate receptor antagonists block neural damage following vascular stroke. Dawson et al., “Protection of the Brain from Ischemia”,
Cerebrovascular Disease,
319-325 (ed. Batjer 1997).
The stimulation of NMDA receptors, in turn, activates the enzyme neuronal nitric oxide synthase (nNOS), which causes the formation of nitric oxide (NO), which more directly mediates neurotoxicity. Protection against NMDA neurotoxicity has occurred following treatment with NOS inhibitors. See Dawson et al., “Nitric Oxide Mediates Glutamate neurotoxicity in Primary Cortical Cultures”,
Proc. Natl. Acad. Sci. USA,
88:6368 (1991); and Dawson et al., “Mechanisms of Nitric Oxide-mediated Neurotoxicity in Primary Brain Cultures”,
J. Neurosci.,
13:2651-61 (1993). Protection against NMDA neurotoxicity can also occur in cortical cultures from mice with targeted disruption of nNOS. See Dawson et al., “Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide Synthase Deficient Mice”,
J. Neurosci.,
16:2479-87 (1996). It is known that neural damage following vascular stroke is markedly diminished in animals treated with NOS inhibitors or in mice with nNOS gene disruption. Iadedcola, “Bright and Dark Sides or Nitric Oxide in Ischemic Brain Injury”,
Trends Neurosci.,
20:132-39 (1997); and Huang et al., “Effects of Cerebral Ischemia in Mice Deficient in Neuronal Nitric Oxide Synthase”,
Science,
265:1883-85 (1994).
FIG. 5
provides a simple model of the following sequence of the multitude of cellular events that presumably takes place in the PARP activation associated with ischemia:
(1) Ischemia following blood vessel occlusion reduces the resting membrane potential of glia and neurons in the tissue.
(2) Potassium leaks out of cells and depolarizes the neurons, leading to a massive release of glutamate.
(3) Acting via NMDA receptors, glutamate triggers a release of NO, which combines with superoxide to form peroxynitrite.
(4) Peroxynitrite damages DNA, fragments of which then activate PARP.
(5) Massive activation of PARP depletes NAD via ADP-ribose polymer formation.
(6) ATP is depleted in an effort to re-synthesize NAD, leading to cell death by energy depletion.
NO is a free radical that reacts chemically with multiple cellular targets to elicit a range of activities from cellular signalling to cell death. Most of the toxic effects of NO appear to be a result of the reaction of NO with superoxide to form the extremely toxic peroxynitrite. See Beckman et al., “Pathological Implications of Nitric Oxide, Superoxide and Peroxynitrite Formation”,
Biochem. Soc. Trans.,
21:330-34 (1993). Either NO or peroxynitrite can cause DNA damage, which activates PARP. PARP activation plays a key role in both NMDA- and NO-induced neurotoxicity, as shown by the use of PARP inhibitors to prevent such toxicity in cortical cultures in proportion to their potencies as inhibitors of this enzyme (Zhang et al., “Nitric Oxide Activation of Poly(ADP-ribose) Synthetase in Neurotoxicity”,
Science,
263:786-89 (1994)) and in hippocampal slices (Wallis et al., “Neuroprotection Against Nitric Oxide Injury with Inhibitors of ADP-ribosylation,
Neuroreport,
5:313, 245-48 (1993)). Zhang et al., U.S. Pat. No. 5,587,384 issued Dec. 24, 1996 also discusses the use of PARP inhibitors, such as benzamide and 1,5-dihydroxyisoquinoline, to prevent NMDA-mediated neurotoxicity and, thus, treat stroke, Alzheimer's disease, Parkinson's disease and Huntingtin's disease.
Using this model, the conventional thought that neurotoxicity came from glutamate acting through NO has suggested that the modest protective effects of non-selective PARP inhibitors, which are comparable to the protective effects of inhibitors of NO formation or drugs that block glutamate receptors, were the best one could reasonably expect.
The NMDA-NO model, however, provided only one potential mechanism for neural injury such as stroke. There has been substantial evidence that other mechanisms, such as the production of oxygen-free radicals, independently of nitric oxide, also play a role. For example, PARP activation has been shown to provide an index of damage following neurotoxic insults, not only by glutamate (via NMDA receptor stimulation) and reactive oxygen intermediates, but also by amyloid &bgr;-protein, n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP*), which participate in such pathological conditions as stroke, Alzheimer's disease and Parkinson's disease. Zhang et al., “Poly(ADP-Ribose) Synthetase Activation: An Early Indicator of Neurotoxic DNA Damage”,
J. of Neurochem.,
65:3, 1411-14 (1995). See also, Choi, “Glutamate Neurotoxicity and Diseases of the Nervous system,
Neuron,
1:623-34 (1988); and Meldrum et al., “Excitatory Amino Acid Neurotoxicity and Neurodegenerative Disease”,
Trends in Pharmacological Sciences,
11:379-87 (1990); Choi et al., “The Role of Glutamate Neurotoxicity in Hypoxic ischemic Neuronal Death”,
Ann. Rev. of Neurosci.,
13:171-78 (1990). Thus, the relative contribution of oxygen-free radicals versus the NO system has been somewhat unclear.
It has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of the non-selective PARP 3-aminobenzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%). Another PARP inhibitor, 1,5-dihydroxyisoquinoline (1 mg/kg), reduced infarct size by a comparable degree (38-48%). Thiemermann et al., “Inhibition of the Activity of Poly(ADP Ribose) Synthetase Reduces Ischemia-Reperfusion Injury in the Heart and Skeletal Muscle”,
Proc. Natl. Acad. Sci. USA,
94:679-83 (1997). This finding has suggested that PARP inhibitors might be able to salvage previously ischemic heart or skeletal muscle tissue.
However, the approach of using PARP inhibitors generally to reduce NMDA-receptor stimulation or to treat or prevent tissue damage caused by NO is limited in effect. Accordingly, there remains a need for a procedure that pro
Bao Jun
Dawson Ted M.
Dawson Valina L.
Eliasson Mikael J.
Hurn Patricia D.
Johns Hopkins University
Weddington Kevin E.
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