Mitochondria protecting agents for treating mitochondria associated diseases

Abstract

The present invention relates generally to mitochondria protecting agents for treating diseases in which mitochondrial dysfunction leads to tissue degeneration and, more specifically, to compounds, compositions and methods related to the same. The methods of this invention involve administration of a pharmaceutically effective amount of a mitochondria protecting agent to a warm-blooded animal in need thereof, and composition of this invention contain a mitochondria protecting agent in combination with a pharmaceutically acceptable carrier or diluent. Mitochondrial associated diseases which may be treated by the present invention include (but are not limited to) Alzheimer's Disease, diabetes mellitus. Parkinson's Disease, neuronal and cardiac ischemia. Huntington's disease and stroke.

Description

[0001] This application claims the benefit of U.S. Provisional Application Nos. 60 / 072,484, 60 / 072,487, 60 / 072,483 and 60 / 072,482, all filed Jan. 26, 1998.THE TECHNICAL FIELD[0002] The present invention relates generally to mitochondria protecting agents for treating diseases in which mitochondrial dysfunction leads to tissue degeneration and, more specifically, to compounds, compositions and methods for treating such diseases.[0003] Mitochondria are the subcellular organelles that manufacture essential adenosine triphosphate (ATP) by oxidative phosphorylation. A number of degenerative diseases may be caused by or associated with either direct or indirect alterations in mitochondrial function. These include Alzheimer's Disease, diabetes mellitus, Parkinson's Disease, neuronal and cardiac ischemia, Huntington's disease and other related polyglutamine diseases (spinalbulbar muscular atrophy, Machado-Joseph disease (SCA-3), dentatorubro-pallidoluysian atrophy (DRPLA) and spinocerebella...

AI Technical Summary

Benefits of technology

[0131] According to this assay, the ability of a mitochondria protecting agent of the invention to inhibit production of ROS intracellularly may be compared to its antioxidant activity in a cell-free environment. Production of ROS may be monitored using, for example by way of illustration and not limitation, 2',7'-dichlorodihydroflurescein diacetate ("dichlorofluorescin diacetate" or DCFC). a sensitive indicator of the presence of oxidizing species. Non-fluorescent DCFC is converted upon oxidation to a fluorophore that can be quantified fluorimetrically. Cell membranes are also permeable to DCFC, but the charged acetate groups of DCFC are removed by intracellular esterase activity, rendering the indicator less able to diffuse back out of the cell.

Problems solved by technology

For example, altered mitochondrial activity may lead to undesirable elevated levels of intracellular reactive oxygen species (ROS) and subsequent intracellular damage or cell death.

Although L-Dopa treatment reduces tremors in most patients for a while, ultimately the tremors become more and more uncontrollable, making it difficult or impossible for patients to even feed themselves or meet their own basic hygiene needs.

Since parkinsonism may be induced by exposure to mitochondrial toxins that affect Complex I activity, it appears likely that defects in Complex I proteins may contribute to the pathogenesis of PD by causing a similar biochemical deficiency in Complex I activity.

Many individuals who have lived normal, productive lives are slowly stricken with AD as they grow older, and the disease gradually robs them of their memory and other mental faculties.

Eventually, they cease to recognize family and loved ones, and they often require continuous care until their eventual death.

This suggests that the COX in AD patients is defective, leading to decreased catalytic activity that in some fashion causes or contributes to the symptoms that are characteristic of AD.

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