Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
1997-06-02
2001-07-24
Criares, Theodore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C562S100000
Reexamination Certificate
active
06265443
ABSTRACT:
BACKGROUND OF THE INVENTION
Glutamate, the main excitatory neurotransmitter in the central nervous system, is necessary for many normal neurological functions, including learning and memory. Overactivation of glutamate receptors, however, and resulting excitotoxic neuronal injury, has been implicated in the pathogenesis of neuronal loss in the central nervous system (CNS) following several acute insults, including hypoxia/ischemia (Simon et al., 1984; Meldrum, 1985; Rothman and Olney, 1986; Sheardown et al., 1990), trauma (Faden and Simon, 1988), epilepsy (Griffiths et al., 1984), and certain neurodegenerative disorders (Greenamayre et al., 1985; Choi, 1988; Meldrum and Garthwaite, 1990; Olanow, 1990; Beal, 1992).
Oxidative stress, caused by reactive oxygen species, represents another injury mechanism implicated in many of the same acute and chronic diseases (Flamm et al., 1978; Chan et al, 1985; Kontos and Wei, 1986; Siesjo et al., 1989; Braughler and Hall, 1989; review Halliwell, 1992). Reactive oxygen species (e.g., superoxide radical) would cause oxidative damage to cellular components, such as peroxidation of cell membrane lipids, inactivation of transport proteins, and inhibition of energy production by mitochondria (Halliwell, 1992).
These two events, glutamate excitotoxicity and oxidative stress, may be interlinked; reactive oxygen species formation may occur as a direct consequence of glutamate receptor overstimulation (Dugan et al., 1992; Lafon-Cazal et al., 1993) and thus mediate a component of glutamate neurotoxicity (Choi, 1988; Coyle and Puttfarcken, 1993). Excitotoxicity, in turn, can be reduced by free radical scavengers, including C, Zn-superoxide dismutase and catalase (Dykens et al., 1987; Chan et al., 1990), the 21-aminosteroid “lazaroids” (Monyer et al., 1990), the vitamin E analog, trolox (Chow et al, 1994), spin-trapping agents such as phenylbutyl-N-nitrone (Yue et al., 1992), and the ubiquinone analog, idebenone (Bruno et al., 1994) which reduce the amount of reactive oxygen species.
Free radical scavengers are neuroprotective in in vitro as well as in vivo models of traumatic or hypoxic/ischemic CNS injury. N-methyl-D-aspartate and AMPA/kainate receptor antagonists are neuroprotective in oxygen-glucose deprivation injury in vitro (Choi, 1988; Goldberg and Choi, 1993), and reduce loss of brain tissue in animal models of ischemia (Simon et al., 1984; Sheardown et al., 1990). Free radical scavengers also protect against excitotoxic neuronal death in vitro (Dykens et al., 1987; Monyer et al., 1990), and reduce ischemic injury in vivo (Liu et al., 1989; Imaizumi et al., 1990; Lesiuk et al., 1991; Rosenthal et al., 1992). Transgenic animals which overexpress the free radical scavenger enzyme, CuZn superoxide dismutase (SOD), are resistant to glutamate toxicity (Chan et al., 1990), and ischemic brain injury (Chan et al., 1991; Kinouchi et al., 1991).
Programmed cell death, or apoptosis, also contributes to cell death in certain neurologic disease states. For example, apoptosis would mediate delayed neuronal degeneration days after ischemia-reperfusion (Dessi et al., 1994; McManus et al., 1994), and would be a factor in neuronal cell death in certain neurodegenerative diseases (Mochizuki et al., 1994). Oxidative stress due to free radical oxygen species would be one of the insults that can trigger apoptosis (Raff, 1992; Verity, 1994; Stewart, 1994), so that free radical scavengers would also be able to limit programmed cell death (Ratan et al., 1994; Franklin et al., 1994). Bcl-2 appears to act on a free radical scavenging pathway to mediate its cytoprotective effects against apoptosis (Hockenbery et al., 1993).
SUMMARY OF THE INVENTION
We have discovered that carboxylated derivatives of C
60
(C(COOH)
2
)
n
, wherein C
60
is buckminsterfullerene and n is an integer from 1 to 4 are biological free radical scavengers and neuroprotective agents, and so inhibit glutamate receptor-mediated neuronal injury and serum-deprivation-induced apoptotic neuronal death.
REFERENCES:
patent: 5648523 (1997-07-01), Chiang
patent: 96/36631 (1996-11-01), None
Hersch et al., “Fullerene Chemistry in three Dimensions: Isolation of Seven Regioisometric Bisadducts and Chiral Trisadducts of C60 and DI(Ethoxycarbonyl) Methylene”, Angewandte Chemie Int. Ed. Engl., vol. 33, No. 4 pp. 437-438 (1994).
M. Beal, “Does Impairment of Energy Metabolism Result in Excitotoxic Neuronal Death in Neurodegenerative Illnesses?”, Ann. Neurol. 31: 119-130 (1992).
Braughler et al., “Central Nervous System Trauma and Stroke”, Free. Radic. Biol. Med. 6:289-301 (1989).
Chan et al., “Cellular and molecular effects of polyunsaturated fatty acids in brain ischemia and injury”, Prog. Brain Res. 63:227-235 (1985).
Chan et al., “Attenuation of Glutamate-induced Neuronal Swelling and Toxicity in Transgenic Mice Overexpressing Human CuZn-Superoxide Dismutase”, Acta Neurochirurgica. 51:245-247 (1990).
Chan et al., “Cold-induced Brain Edema and Infarction are Reduced in Transgenic Mice Overexpressing CuZn-Superoxide Dismutase”, Ann. Neurol. 29:482-486 (1991).
Choi et al., “Glutamate Neurotoxicity and Diseases of the Nervous System”, Neuron 1:623-634 (1988).
Chow et al., “Trolox attenuates cortical neuronal injury induced by iron, ultraviolet light, glucose deprivation, or AMPA”, Brain Res. 639:102-108 (1994).
Coyle et al., “Oxidative Stress, Glutamate, and Neurodegenerative Disorders”, Science 262:689-694 (1993).
Dessi et al., “Regional variability in DNA fragmentation after global ischemia evidenced by combined histological and gel electrophoresis observations in the rat brain”, J. Neurochem. 61:1973-1976 (1993).
Dugan et al., “NMA Receptor-induced membrane Fluidity Changes may Modulate Calcium influx in Cortical Neurons”, Soc. Neurosci. Abs. 18:756, No. 321.5 (1992).
Dykens et al., “Mechanism of Kainate Toxicity to Cerebellar Neurons In vitro is Analagous to Reperfusion Tissue Injury”, J. Neurochem. 49:1222-1228 (1987).*
Faden et al., “A potential role for excitotoxins in the pathophysiology of spinal cord injury”, Ann. Nuerol. 23:623-626 (1988).*
Flamm et al., “Free Radicals in Cerebral Ischemia”, Stroke 9:445-447 (1978).*
Franklin et al., Inhibition of Programmed Neuronal Death by Spin Traps: Evidence of a Role for Reactive Oxygen in Neuronal Apoptosis, Soc. Neurosci. Abs. 20:432 No. 188.7 (1994).*
Goldberg et al., “Combined oxygen and glucose deprivation in cortical culture: calcium-dependent and calcium-independent mechanisms of neuronal injury”, J. Neurosci. 13:3510-3524 (1993).*
Greenamyre et al., “Alterations in L-Glutamate Binding in Alzeimer's and Huntington's Diseases”, Science 227:1496-1498 (1985).*
Griffiths et al., “Status Epilepticus: The Reversibility of Calcium Loading and Acute Neuronal Pathological Changes in the Rat Hippocampus”, Neurosci. 12:557-567 (1984).*
B. Halliwell, “Reactive Oxygen Species and the Central Nervous System”, J. Neurochem. 59:1609-1623 (1992).*
Hirsch et al., “Fullerene Chemisty in Three Dimensions: Isolation of Seven Regioisomeric Bisadducts and Chiral Trisadducts of C60and Di)ethoxycarbonyl)methylene”, Angew. Chem . Int. Ed. Engl. 33:437-438 (1994).*
Hockenbery et al., Bci-2 Functions in an Antioxidant Pathway to Prevent Apoptosis Cell 75:241-251 (1993).*
Imaizumi et al., Liposome-Entrapped Superoxide dismutase Reduces Cerebral Infarction in Cerebral Ischemia in Rats, Stroke 21:1312-1317 (1990).*
Kinouchi et al., “Attenuation of focal cerebral ischemic injury in transgenic mice overexpressing CuZn superoxide dismutase”, Proc. Natl. Acad. Sci. USA 88:11158-11162 (1991).*
Kontos et al., “Superoxide production in experimental brain injury”, J. Neurosurg. 64:803-807 (1986).*
Lafon-Cazal et al., “NMDA-dependent superoxide production and neurotoxicity”, Nature 364:535-537 (1993).*
Lesiuk et al., “Effect of U74006F on Forebrain Ischemia in Rats”, Stroke 22:896-901 (1991).*
Liu et al., “Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury”, Amer. J. Physiol. 256:H589-593 (1989).*
MacManus et al., “DNA damage consistent with
Choi Dennis Wonkyu
Dugan Laura
Lin Tien-Sung Tom
Luh Tien-Yau
Criares Theodore J.
Johnston George W.
Kirk, Jr. Joseph P.
Tramaloni Dennis P.
Washington University
LandOfFree
Method for treating neuronal injury with carboxyfullerene does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for treating neuronal injury with carboxyfullerene, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for treating neuronal injury with carboxyfullerene will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2449713