Brain targeted low molecular weight hydrophobic anti oxidant compounds

Abstract

Novel brain targeted low molecular weight, hydrophobic antioxidants and use of antioxidants in treatment of central nervous system neurodegenerative disorders such as Parkinson's, Alzheimer's and Creutzfeldt-Jakob's diseases and in treatment of conditions of peripheral tissues, such as acute respiratory distress syndrome, amyotrophic lateral sclerosis, atheroscierotic cardiovascular disease and multiple organ dysfunction, in which oxidants are overproduced.

Description

[0001] This is a Continuation of U.S. patent application Ser. No. 09 / 322,980, filed Jun. 1, 1999, which is a Continuation-In-Part of PCT / US97 / 23997, filed Dec. 23, 1997, now expired, which claims priority from U.S. patent application Ser. No. 08 / 773,153, filed Dec. 26, 1996, now U.S. Pat. No. 5,874,468, issued Feb. 23, 1999.FIELD AND BACKGROUND OF THE INVENTION[0002] The present invention relates to composition and use of novel antioxidant compounds, also referred herein as antioxidants. More particularly, the present invention relates to novel brain targeted low molecular weight, hydrophobic antioxidants and their use in treatment of central nervous system neurodegenerative disorders such as Parkinson's, Alzheimer's and Creutzfeldt-Jakob's diseases. The compounds according to the present invention can also be used as antioxidants in treating conditions of peripheral tissues, such as acute respiratory distress syndrome, amyotrophic lateral sclerosis, atheroscierotic cardiovascular d...

AI Technical Summary

Benefits of technology

[0013] 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.

[0016] 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 .beta.-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 .beta.-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 .beta.-amyloid, namely, there was no enhancement of vasoconstriction. Whereas, if SOD was added after treatment with .beta.-amyloid protein, the protective effect of the radical scavenger was abolished (Thomas et al., 1996). Recently, other studies have shown that oxidative stress and free radicals production are linked to .beta.-amyloid fragment which includes amino acids 25-35 and may contribute to neurodegenerative events associated with Alzheimer's disease (Cafe et al., 1996).

[0026] There is thus a widely recognized need for, and it would be highly advantageous to have novel antioxidant compounds and methods for use of antioxidants in treatment of central nervous system neurodegenerative disorders such as Parkinson's, Alzheimer's and Creutzfeldt-Jakob's diseases and in treating conditions of peripheral tissues, such as acute respiratory distress syndrome, amyotrophic lateral sclerosis, atheroscierotic cardiovascular disease and multiple organ dysfunction, which compounds act as oxygen scavengers to lower the oxidative stress within and in the vicinity of affected cells and eventually to stop cell death which is associated with oxidative stress in the brain and / or peripheral tissues.

Problems solved by technology

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.

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.

Like dopamine, this false neurotransmitter elevates the level of the oxidation products during its degradation, thus leading to cell death.

However, like any other protein, GDNF cannot cross the blood brain barrier.

Therefore, it can not be taken orally or be injected systemically.

The only possible mode of administration would thus be via an intracerebral injection which would constitute a main drawback for such a treatment.

Similarly, in other neurodegenerative diseases such as Alzheimer's and Creutzfeldt-Jakob's, where the theory of free oxygen radicals appears to play a major role, there is no major breakthrough in therapy.

The most common are vitamin E and vitamin C. However, vitamin E was found to be ineffective at decreasing the oxidative stress at the substantia nigra (The Parkinson Study Group, 1993, Offen et al., 1996) since this compound, although capable of crossing the blood brain barrier, is trapped in the cell membrane and therefore does not reach the cytoplasm where its antioxidant properties are needed.

Vitamin C does not cross the blood brain barrier and therefore, cannot be used effectively for neurodegenerative diseases of central origin.

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