Chemical model of a neurodegenerative disease, method for preparation and uses of same

Abstract

The invention concerns the use of pyridinium furosemide or one of the derivatives, analogues, salts, metabolites, or prodrugs thereof in the preparation of a chemical model of a neurodegenerative disease, preferably Parkinson's disease. The invention also concerns the corresponding chemical model and the uses of same, in particular in screening tests for identifying drug candidates.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a divisional of U.S. application Ser. No. 14 / 443,499, filed May 18, 2015, now U.S. Pat. No. 9,744,250, which is the U.S. national stage application of International Patent Application No. PCT / FR2013 / 052784, filed Nov. 19, 2013.FIELD OF THE INVENTION[0002]The invention relates to the development and use of chemical models for the study of a neurodegenerative disease, particularly Parkinson's disease.BACKGROUND[0003]Parkinson's disease is the second most common neurodegenerative disease after Alzheimer's disease. Its prevalence increases with age, and reaches 1% to 2% of subjects over the age of 50. It is characterized by disabling motor symptoms such as akinesia, muscle rigidity, and tremor at rest. These clinical signs can be accompanied by non-motor disorders such as digestive, urinary, or cognitive disorders.[0004]Motor disorders associated with Parkinson's disease are directly related to the degeneration of dopamine...

AI Technical Summary

Benefits of technology

The patent describes a compound called furosemide pyridinium that can be used to create a chemical model of a synucleinopathy, specifically Parkinson's disease. This compound can be placed in contact with a cell system, such as a cell, a cell culture, a tissue, or a non-human animal, to create the model. The cell system can be a nematode, such as C. elegans or a zebrafish, and the marker characteristic of the synucleinopathy can be an increase in intracellular accumulation of synuclein, a decrease in cell survival rate, or a decrease in mitochondrial activity. The invention also provides a kit for using this compound to create the chemical model.

Problems solved by technology

This model has many disadvantages, however; in particular, 6-OHDA must be administered intracranially and has acute toxicity.

Also, administration of 6-OHDA causes neither the appearance of lesions in all areas of the brain involved in Parkinson's disease nor the formation of Lewy bodies.

This model has many limitations, however.

It is generally very difficult to keep animals that have bilateral lesions induced by MPTP alive without administration of L-dopa or dopamine agonists.

Also, this model does not simultaneously reproduce all the motor disorders associated with Parkinson's disease.

Finally, the MPTP / MPP+ model is an “acute” model which does not reproduce the slow progression of Parkinson's disease; this makes it difficult to use it to discover new treatments or to define all the biological mechanisms involved in the onset of Parkinson's disease.

These models have limitations similar to those of MPTP, particularly a lack of specificity towards the dopaminergic system.

Although these are interesting tools for analysis, they do not provide a completely accurate reproduction of the disease, especially the appearance of Lewy bodies (Dawson et al., Neuron, 2010, 66(5): 646-61).

Furthermore, the presence of a genetic mutation in an animal from birth, and even in early embryogenesis, can involve many processes and induce compensation and adaptation phenomena which are not observable in the adult individual, which limits and complicates any transposition of the results to humans.

None of the chemical or genetic models developed so far are capable of reproducing all the symptoms and main markers of Parkinson's disease, especially its progressive development and the appearance of Lewy bodies.

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