A promising candidate for drugs against neurodegenerative diseases
The first signs of Parkinson's disease can be deceptively harmless and, for several years, manifest themselves, for example, by shaking the little finger of one of the hands. However, the disease inevitably progresses. German researchers from the Maximilian Ludwig University in Munich and the Institute of Biophysical Chemistry in Göttingen have synthesized a chemical compound called Anle138b that can slow down the appearance of the first symptoms and progression of Parkinson's disease in mice. They hope that it will form the basis of an effective method of treating this disease in humans.
Parkinson's disease usually manifests at the age of 50-60 years as a result of the death of dopamine–producing neurons of the substantia nigra - the region of the midbrain. When examining the brain tissue of patients under a microscope, insoluble aggregates of a protein known as alpha-synuclein are detected in the affected neurons. In the early stages of the pathological cascade, this protein forms so–called oligomers - tiny aggregates consisting of a small number of alpha-synuclein molecules, apparently having high neurotoxicity. By the time the first obvious symptoms of the disease appear, as a rule, more than half of the susceptible cells have already died. A large number of specialists are developing methods for early diagnosis of Parkinson's disease, but existing treatment methods can only slightly weaken the manifestation of symptoms.
In search of a solution to the problem, the authors systematically tested 20,000 compounds for the ability to block the formation of protein deposits characteristic of Parkinson's disease using an exceptionally sensitive approach developed by them. Of the several compounds identified as a result of screening, the most active was selected, based on the structure of which a pharmacologically promising derivative was synthesized. The experimental drug, called Anle138b, is suitable for oral use, penetrates the blood-brain barrier and accumulates in significant concentrations in brain tissue, while being well tolerated in doses that provide a pronounced therapeutic effect.
The promising results of the experiments conducted by the authors, devoted not only to the study of the biochemical and structural features of Anle138b, but also its effect on several animal models of Parkinson's disease, indicate that the experimental compound may well find its application in clinical practice.
The use of Anle138b not only reduced the number of alpha-synuclein aggregates in the brain of animals, but also improved the coordination of movements compared to the control group. The authors claim that the earlier animals with a predisposition to Parkinson's disease started receiving experimental therapy, the later they showed the first signs of the disease.
In experiments on a mouse model of Parkinson's disease, significantly fewer alpha-synuclein aggregates (colored brown) were formed in the brain tissue of animals treated with the experimental drug Anle138b compared to the brain tissue of control mice treated with placebo.
Moreover, it turned out that Anle138b is also effective in cases caused by the accumulation of toxic prion aggregates – the cause of Creutzfeld-Jakob disease, which was manifested by a decrease in the amount of protein deposits in brain tissue and a significant increase in the life expectancy of animal models. In the near future, the developers plan to study the effect of Anle138b on the state of the brain and the severity of symptoms of other neurodegenerative diseases caused by the formation of toxic protein aggregates in the brain tissue, primarily Alzheimer's disease.
In addition to clinical potential applications, Anle138b can be used in experiments devoted to the study of the formation of protein oligomers and the search for methods to inhibit this process. Thus, the researchers hope to understand the primary mechanisms of the development of neurodegenerative diseases.
Article by Jens Wagner et al. Anle138b: a novel oligomer modulator for disease-modifying therapy of neurodegenerative diseases such as prion and Parkinson's disease is published in the journal Acta Neuropathologica.
Evgeniya Ryabtseva
Portal "Eternal youth" http://vechnayamolodost.ru based on the materials of Max Planck Society: Putting the brakes on Parkinson's.
24.04.2013