Neurodegenerative disorders—Searching for targets and new ways of diseases treatment

Abstract

Research and development of efficient therapeutic strategies for the treatment of neurodegenerative diseases is one of the most risky and challenging problems of modern neuromedicine. At the same time, the social and economic importance of the solution, at least in part, of these problems outweighs any possible risks and development costs. Such common neurodegenerative diseases as Alzheimer's or Parkinson's diseases were described more than 100 years ago, but they are still uncurable. Notwithstanding the substantial progress in our understanding of the pathogenesis of these diseases, the triggers and detailed mechanisms of neurodegeneration remain unclear.1, 2 It hampers focused search of novel efficient neuroprotectors and therapeutic strategies that could prevent the development of such neurodegenerative diseases. In the last two decades, numerous mutations that mediate familial forms of major neurodegenerative disorders have been found in a number of genes,3 which initiated a new wave of study for investigation of the mechanism of pathology of neurodegeneration and finding the ways for neuronal protection.4 Based on the toxicological and transgenic models of diseases, a number of possible mechanisms of neurodegeneration have been suggested. They share common features and mechanisms – such as an accumulation of intrinsically disordered proteins in the form of aggregates, involvement of mitochondrial dysfunction and oxidative stress, and neuroinflammation5, 6 were taken for development of the therapeutic strategies designed to halt or at least slow disease progression, rather than therapy used for treatment of symptoms of disease.7, 8 From these standpoints the analysis of contemporary approaches for study molecular mechanisms of neurodegenerative diseases progress and potential perspective ways for neuronal protection seems very important for further development of efficient therapeutic CNS disease modifying strategies. This Special Issue of Medical Research Reviews, “Novel approaches for neurodegenerative diseases treatment,” provides the reader with various views on the development of neurodegeneration in different pathology and a modern view on the potential perspective ways for neuronal protection. The present series of reviews not only provide a critical view of authors about current and future approaches for the treatment of specific neurodegenerative disorders, but also explore new views on the mechanism of neurodegeneration and disease-associated processes. It is well known that most neurodegenerative diseases have a multifactorial nature. From this standpoint the development of original multitarget drugs that interact simultaneously with the whole group of biotargets and process involved in pathogenesis of neurodegenerative diseases looks highly promising. The review of Albertini et al9 attract attention of the readers to polypharmacological approaches in the development of drugs for complex neurodegenerative disorders such as Alzheimer's disease. Various pharmacological opportunities, from drug combinations to multitarget-directed ligands (both codrugs and hybrids) and the development of successful Alzheimer's disease's multitarget drug-discovery are discussed with examples taken from the recent literature. Mitochondrial dysfunction and oxidative stress are the common features in the mechanism of neurodegeneration. Mitochondria itself represents the multitarget organelle being the major reactive oxygen species producers but also the vulnerable target of oxidative stress. One of the features of oxidative stress, lipid peroxidation, is a hallmark of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and other neurological conditions. The role of mitochondria and lipid peroxidation in the mechanism of neuronal loss and analysis of novel therapeutic directions to prevent it were reviewed by Angelova et al.10 From the other side mitochondria is an organelle that plays a key role in energy metabolism and involvement in the cell death mechanism, particularly involved in the pathogenesis of a number of neurodegenerative disorders including Parkinson's and Alzheimer's diseases and even ecotoxic lesions.10-12 It gives rise to quite new approaches connected with focused design of novel group of mitoprotective agents that interact with different molecular targets in mitochondria, in particular, so-called mitochondrial permeability pores. Shevtsova with colleagues described broad number of such approaches and their perspectives in Alzheimer's disease treatment.12 Claudia Bento-Pereira and Albena Dinkova-Kostova provide an in depth look of the protective role of activation of nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) and simulation of mitochondrial function in pathogenesis of Parkinson's disease.13 This transcriptional target orchestrates networks of cellular defence mechanisms - genes which encode antioxidant enzymes and proteins involved in detoxification, repair cellular organelles, inflammation, and mitochondrial bioenergetics. The authors discuss how development of small molecules which act as Nrf2 activators can become one of the most promising therapeutic targets for mitochondrial dysfunction in PD, a therapeutic option in treatment of currently incurable neurodegenerative diseases. Recent years the important role of broad group cell growth factors as potential targets for new group of neuroprotectors have been actively discussed. Low molecular weight of mimetics of neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) were developed for therapy of various diseases including neurological disorders. Gudasheva et al reviews the relationship between the structure of the mimetics, mechanism of action and pharmacological properties.14 Another group of short peptides, in particular, glyproline peptides, their effect on fat and carbohydrate metabolism and perspectives for their use as protective therapeutic agents critically analysed by N. Mysoedov et. al.15 The retrospective analysis of variable signalling pathways involved in Alzheimer's disease pathogenesis was made in Gadhave et al review.16 The authors highlighted the importance of finding a correlation and crosstalk between these signalling pathways and establishing different therapeutic targets within and between those pathways for development of drugs for treatment of Alzheimer's disease. Among different strategies in developing efficient agents for neurodegenerative diseases treatment the repositioning (or re-evaluation) of known drugs for new application attracts strong interest. This strategy was actively developed by pharmaceutical companies for complex neurological diseases, where it is very difficult to identify one (or even limited number of) target due to the multifactorial nature of the pathology. Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative neuromuscular disease with no cure for this disorder or treatment that targeted at improving the symptoms. Recent progress in understanding the mechanism of neurodegeneration suggests new drug targets. Kukharsky et al discuss the potential use of known drugs used for treatment of other diseases for ALS therapy and describes current approaches to the repurposing of such "old" drugs for treatment of patients with ALS.17 Gene therapy is a modern and perspective direction of research, which could be used for treatment of currently uncurable diseases including neurodegenerative disorders. Maria Zakharova discusses modern approaches in gene therapy of motor neuron diseases, its current stage, and the potential for development of innovative therapeutic strategies, including viral vector therapy and RNA modulating approaches.18 Potential application of antisense oligonucleotide (ASO) therapies, which based on the use of short synthetic single-stranded ASOs that bind to disease-related target RNAs and pleiotropically modulate their function is analysed by Epaminondas Doxakis.19 The effectiveness of ASO therapies for treatment of movement disorders including Parkinson's disease, Huntington's disease, and ataxias 1, 2, 3, and 7 and possible ways for chemical modifications aimed at improving ASO effectiveness were analysed. One more genetically based modern direction in drug development – pharmacotranscriptomics aims to reach more accurate drug dosing based on interindividual transcriptome variations. Dergunova et al reviews of studies on the effects of peptides with neuroprotective properties on gene transcription in nerve cells.20 We believe that very broad analysis of contemporary strategies and specific approaches for treatment neurodegenerative disease presented in this issue could be helpful and stimulating for further successful research in this area. We thank the authors for their excellent contributions, as well as the support of grant № 075-15-2020-777 (of the RMSHE).

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