Treatment of ischemic brain injuries with brain targeted antioxidant compounds

Abstract

A method of reducing oxidative stress in the brain of an organism having a blood brain barrier and suffering an ischemic brain injury, the method comprising the step of administering a compound to the organism, the compound having (a) a combination of molecular weight and membrane miscibility properties for permitting the compound to cross the blood brain barrier of the organism; (b) a readily oxidizable chemical group for exerting antioxidation properties; and (c) a chemical make-up for permitting the compound or its intracellular derivative to accumulate within the cytoplasm of cells.

Description

FIELD AND BACKGROUND OF THE INVENTION[0001] 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.[0002] Correlation Between Oxidative Stress and Various Neurodegenerative Pathologies:[0003] 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).[0004] These studies were initiated (i) since outo-oxidation of levodopa and dopamine is known to produce oxygen free radicals, H.sub.2O.sub.2, quinones and semiq...

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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.

PCT / US97 / 23997, however, fails to teach the use of such antioxidants for treatment in cases of ischemic brain injuries.

Ischemic brain injury, due to, for example, stroke or head trauma, is a major cause of morbidity and mortality in adults but also of neurodevelopmental impairment and disability.

These ionic imbalances, together with a breakdown in cellular defense systems following ischemia, can contribute to enhanced local oxidative stress with a net increase in potentially harmful reactive oxygen species (ROS).

Subsequent damage to lipids, proteins, DNA and inactivation of key cellular enzymes ultimately lead to cell death.

However, such an approach is impractical and may be too late for most patients with ischemic stroke.

Most, if not all, of the currently available antioxidants cannot penetrate the blood brain barrier (BBB) from the systemic circulation and therefore fail to decrease the ischemic damage in brains.

Furthermore, overexpression of thioredoxin, a redox-active disulfide / dithiol in transgenic mice, attenuates focal ischemic brain damage (Takagi et al., 1999).

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