Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
1999-12-27
2002-04-09
Seidel, Marianne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S550000, C514S562000
Reexamination Certificate
active
06369106
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention relates, in general to the use of antioxidant compounds, also referred herein as antioxidants, for the treatment of ischemic head injuries. More particularly, the present invention relates to novel brain targeted low molecular weight, hydrophobic antioxidants and their use in treatment of ischemic head injuries, such as, but not limited to stroke and head trauma.
Correlation Between Oxidative Stress and Various Neurodegenerative Pathologies
In the last few years evidences have accumulated which connect oxidative stress (OS) with the pathogenesis of Parkinson's, Alzheimer's Creutzfeldt-Jakob's diseases and other human neurodegenerative disorders (Olanow, 1990, 1993; Fahn and Cohen, 1992; Cafe et al., 1996, Brown et al., 1996; Thomas et al., 1996).
These studies were initiated (i) since outo-oxidation of levodopa and dopamine is known to produce oxygen free radicals, H
2
O
2
, quinones and semiquinones, the later two are high molecular weight polymers possessing an aromatic structure and are therefore potentially toxic and (ii) since post-mortem studies in Parkinson's disease patients showed a dramatic decline in the levels of endogenous reduced glutathione (GSH), which is, as is further delineated hereinbelow, essential for maintaining the oxidative state of the cells. The decrease in reduced glutathione levels progresses from the pre symptomatic Parkinson's disease condition to the advanced clinical Parkinson's disease condition.
Two possible explanations may account for the role played by oxidative stress in the pathogenesis of Parkinson's disease.
According to a first hypothesis it is assumed that cells of the substantia nigra (SN), are constantly under oxidative stress due to the oxidation of the catechol ring of dopamine. Dopamine, like other catecholamines, undergoes spontaneous oxidation to form semiquinones, oxygen free-radicals and H
2
O
2
as metabolic by-products. In addition, one of the disposal routs for dopamine is its enzymatic oxidation by MAO (monamine oxidase) type A or B which, like the spontaneous oxidation, creates semiquinones, oxygen free radicals and H
2
O
2
.
These products may cause accumulative oxidation damage within the substantia nigra cells, and eventually lead to cell death. Non-affected cells increase the turnover of dopamine, which in turn, generates more toxic free radicals. Indeed, it was shown that in the presence of H
2
O
2
and copper ions, dopamine as well as L-dopa (levodopa) cause oxidative damage to DNA (Jenner 1994; Spencer et al., 1994).
According to another hypothesis it is assumed that Parkinson's disease is caused by a substance of an unknown composition, similar to the toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which is enzymatically converted to the toxic metabolite 1-methyl-4-phenyl pyridine (MPP
+
) by MAO type B. Since this reaction releases free oxygen radicals, thereby increasing the oxidative stress imposed on the cells, similar mechanisms might affect the nigral cells in Parkinson's disease. If this type of a process indeed occurs in Parkinsonian brains, than again, it would create a high level of oxidative stress in the dopaminergic cells at the substantia nigra.
The following findings demonstrate a strong indication for oxidative stress as a possible cause for the pathogenesis of Parkinson's disease.
First, the iron content in the substentia Nigra of Parkinson's disease patients was found to be significantly higher while ferritin content, the protein which bind free iron ions within tissues, was found to be significantly lower then normal values (Olanow 1990; 1993 and Jenner 1994). These two phenomena indicate a situation where the amount of free iron which acts as a catalyst in oxidation reactions, is abnormally high and thus may contribute to the speed of oxidation reactions at the substantia nigra of Parkinson's disease patients. The above indication was given support when it was shown that injection of free iron directly into the substantia nigra of rodents caused the appearance of Parkinsonian symptoms, which symptoms could be overcome by addition of transferrin, the protein which binds free iron in the blood plasma (Jenner 1994).
Second, one of the protective mechanisms against oxidation processes in the brain is reduced glutathione (GSH), which upon oxidation to oxidized glutathione (GS), acts as a reducing agent. In the substantia nigra of Parkinson's disease patients the level of reduced glutathione is significantly low, whereas the level of oxidized glutathione remains normal. Hence the oxidation potential in the substantia nigra of Parkinson's disease patients is low. This change in the level of reduced glutathione is in all likelihood, specific for Parkinson's disease. The oxidation products which are formed during spontaneous and enzymatic oxidation of dopamine, as described hereinabove, lower the level of reduced glutathione, and thereby increase the ratio of oxidized/reduced glutathione. Since the level of &ggr;-glutamyl-cysteine synthetase, the enzyme which is a rate limiting enzyme in the biochemical pathway of glutathione synthesis, is normal, the ratio stays high and induces a state of oxidative stress in the cells. It is interesting that the level of the enzyme which is responsible for the removal of oxidized glutathione, &ggr;-glutamyl transpeptidase in the cells is higher, as if the cells attempt to overcome the increased oxidative stress by trying to get rid of oxidized glutathione (Sian et al., 1994).
Third, additional evidence for the abnormally high oxidative stress in the Parkinsonian brain comes from a study of lipid oxidation products in the substantia nigra of Parkinson's disease patients. In general, the level of unsaturated fatty acids is low in the substantia nigra, however, the level of lipid hydroperoxides which are the oxidation products of unsaturated fatty acids is high in the substantia nigra of Parkinson's patients. This finding indicates the presence of an abnormally higher frequency of oxidation processes in the Parkinsonian substantia nigra (Jenner, 1994).
And finally, one of the animal models which are currently used for the study of Parkinson's disease is created by the injection of 6-hydroxy-dopamine. Like dopamine, this false neurotransmitter elevates the level of the oxidation products during its degradation, thus leading to cell death. Since the biological half life of 6-hydroxy-dopamine is much longer and since it is readily taken-up by the cells, it increases the rate by which the animal develops the symptoms of the disease.
The different pathological makers of various neurodegenerative diseases e.g., Lewy bodies, plaques, etc., indicate different causal factors in the initiation of these diseases. However, there is growing evidence that once initiated, the progression of a large number of neurodegenerative diseases, is quite similar. Although the characteristic symptoms are descriptive for each neurodegenerative disease, it appears that elevation of the oxidative state of the cells at specific regions in the brain is an important factor in the etiology of Parkinson's disease, basal ganglia degenerative diseases, motoneuron diseases, Alzheimer's and also the Creutzfeldt-Jakob's disease.
An indication for a role played by oxidative stress in the pathogenesis of Alzheimer's disease was found while in a recent study, the relationship between the &bgr;-amyloid protein fragments and oxygen radical formation was tested in a system that is highly sensitive and responds to free oxygen radicals. This system utilizes the vasoactivity of the blood vessel which, in the presence of &bgr;-amyloid, enhances the phenylephrine mediated contraction of the vessels. Pre treatment of the blood vessel with superoxide dismutase (SOD), an enzyme that scavenges free oxygen radicals, eliminated the effect of &bgr;-amyloid, namely, there was no enhancement of vasoconstriction. Whereas, if SOD was added after
Atlas Daphne
Melamed Eldad
Offen Daniel
Jagoe Donna
Seidel Marianne C.
Yissum Research Development Company of the Hebrew University of
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