Mitochondria as a promising target for developing novel agents for treating Alzheimer's disease

Abstract

The mitochondria‐targeting drugs can be conventionally divided into the following groups: those compensating for the energy deficit involved in neurodegeneration, including stimulants of mitochondrial bioenergetics and activators of mitochondrial biogenesis; and neuroprotectors, that are compounds increasing the resistance of mitochondria to opening of mitochondrial permeability transition (MPT) pores. Although compensating for the energy deficit and inhibition of MPT are obvious targets for drugs used in the very early stages of Alzheimer‐like pathology, but their use as the monotherapy for patients with severe symptoms is unlikely to be sufficiently effective. It would be optimal to combine targets that would provide the cognitive‐stimulating, the neuroprotective effects and the ability to affect specific disease‐forming mechanisms. In the design of such drugs, assessment of their potential mitochondrial‐targeted effects is of particular importance. The possibility of targeted drug design for simultaneous action on mitochondrial and neurotransmitter's receptors targets is, in particularly, based on the known interplay of various cellular pathways and the presence of common structural components. Of particular interest is directed search for multitarget drugs that would act simultaneously on mitochondrial calcium‐dependent functions, the targets (receptors, enzymes, etc.) facilitating neurotransmission, and the molecular targets related to the action of so‐called disease‐modifying factors, in particular, the formation and overcoming of the toxicity of β‐amyloid or hyperphosphorylated tau protein. The examples of such approaches realized on the level of preclinical and clinical trials are presented below.

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

“…In the drug design for the treatment of NDs, an important issue is to provide neuroprotective effects against processes causing cell death. A promising target for such activity is the MPT, a key step in the cell death cascade implicated in neurodegeneration [ 75 , 76 ]. According to some authors, the neuroprotective action of dimebon, a prototype of the γ-carboline pharmacophore contained in our conjugates, could be ascribed to its ability to increase the resistance of mitochondria to the induction of the MPT [ 18 , 19 , 20 ].…”

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

“…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 mechanismsgenes which encode antioxidant enzymes and proteins involved in detoxification, repair cellular organelles, inflammation, and mitochondrial bioenergetics.…”

“…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.…”

“…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 …”

Characterisation of the ghrelinergic system in human models of neurodegenerative diseases

“…Indeed, targeting mitochondrial-mediated cell death has been pointed out as a prospective clinical strategy against several age-related neurodegenerative disorders (Wu et al 2019;Dey et al 2020;Shevtsova et al 2021).…”