16 research outputs found
ΠΠ»ΠΈΡΠ½ΠΈΠ΅ ΠΈΠΎΠ½ΠΎΠ² ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² Π½Π° ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠΊΠΈ ΠΊΠ°ΠΊ Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΡΠΉ ΠΌΠ΅Ρ Π°Π½ΠΈΠ·ΠΌ ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π° Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°
The article provides an overview of our own results of comparative study of influence of ions of iron, zinc and aluminium on the structure of microtubules from tubulin and microtubules associated proteins of rat brain with data on the structure of microtubules from tubulin and microtubules associated proteins from the brain of patients with Alzheimerβ²s disease (AD). A significant decrease in the amount of soluble tubulin was found in the postmortem brain of AD patients in comparison with the control group in the hippocampus, frontal cortex and substantia nigra, but not in the inferior olive. In vitro polymerization of tubulin and microtubules associated proteins from the brain of AD patients and electron micrographs of microtubules were obtained. The assembly of microtubules from brains of AD patients is disrupted, resulting in defective structures. On the other hand, the study of the influence of Al3+, Fe3+, Zn2+ on the microtubules from rat brains tubulin and microtubules associated proteins assembly and structure has shown that all studied metals are able to reduce the amount of microtubules and induce the assembly of anomal structures. According to the degree of the destructive effect on the microtubules and, accordingly, the possible significance in the pathogenesis of Alzheimer disease, metal ions can be arranged in the following sequence Al3+ > Zn2+ > Fe3+. Moreover, phosphorylation of tubulin and microtubules associated proteins in the presence of aluminum ions to the greatest extent reflects the phosphorylation of these proteins at AD. Comparison of data on the structure of microtubules after their assembly from brains of AD patients tubulin and microtubules associated proteins from brains of AD patients, and from the brain of rats, but in the presence of metal ions, confirm the conclusion about the possible role of the metals in the AD etiopathogenesis.ΠΠ±ΠΎΠ±ΡΠ΅Π½Ρ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΡΠ΅ ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΡ ΡΡΠ°Π²Π½ΠΈΡΠ΅Π»ΡΠ½ΠΎΠ³ΠΎ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΡΡΠ΅ΠΊΡΠΎΠ² ΠΈΠΎΠ½ΠΎΠ² ΠΆΠ΅Π»Π΅Π·Π°, ΡΠΈΠ½ΠΊΠ° ΠΈ Π°Π»ΡΠΌΠΈΠ½ΠΈΡ Π½Π° ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΈΡ
ΡΠ±ΠΎΡΠΊΠΈ ΠΈΠ· ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ ΠΌΠΈΠΊΡΠΎΡΡΠ±ΡΠ»Π»ΠΎΠ°ΡΡΠΎΡΠΈΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
Π±Π΅Π»ΠΊΠΎΠ² ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡΡ Ρ Π΄Π°Π½Π½ΡΠΌΠΈ ΠΏΠΎ ΠΈΠ·ΠΌΠ΅Π½Π΅Π½ΠΈΡ ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ Π² ΠΏΡΠΎΡΠ΅ΡΡΠ΅ ΠΈΡ
ΡΠ±ΠΎΡΠΊΠΈ ΠΈΠ· ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ Π±Π΅Π»ΠΊΠΎΠ², Π°ΡΡΠΎΡΠΈΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
Ρ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠΊΠ°ΠΌΠΈ (ΠΠΠ ΠΎΡ Π°Π½Π³Π». microtubules associated proteins), ΠΌΠΎΠ·Π³Π° Π±ΠΎΠ»ΡΠ½ΡΡ
Π±ΠΎΠ»Π΅Π·Π½ΡΡ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° (ΠΠ). Π ΠΌΠΎΠ·Π³Π΅ Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΠ Π²ΡΡΠ²Π»Π΅Π½ΠΎ Π·Π½Π°ΡΠΈΡΠ΅Π»ΡΠ½ΠΎΠ΅ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΠ΅ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²Π° ΡΠ°ΡΡΠ²ΠΎΡΠΈΠΌΠΎΠ³ΠΎ ΡΡΠ±ΡΠ»ΠΈΠ½Π°, ΠΏΠΎ ΡΡΠ°Π²Π½Π΅Π½ΠΈΡ Ρ ΠΊΠΎΠ½ΡΡΠΎΠ»ΡΠ½ΠΎΠΉ Π³ΡΡΠΏΠΏΠΎΠΉ, Π² Π³ΠΈΠΏΠΏΠΎΠΊΠ°ΠΌΠΏΠ΅, Π»ΠΎΠ±Π½ΠΎΠΉ ΠΊΠΎΡΠ΅ ΠΈ ΡΡΡΠ½ΠΎΠΉ ΡΡΠ±ΡΡΠ°Π½ΡΠΈΠΈ, Π½ΠΎ Π½Π΅ Π² Π½ΠΈΠΆΠ½Π΅ΠΉ ΠΎΠ»ΠΈΠ²Π΅. ΠΡΡΠ°Π±ΠΎΡΠ°Π½Ρ ΡΡΠ»ΠΎΠ²ΠΈΡ, ΠΏΠΎΠ·Π²ΠΎΠ»ΠΈΠ²ΡΠΈΠ΅ Π²ΠΏΠ΅ΡΠ²ΡΠ΅ ΠΏΡΠΎΠ²Π΅ΡΡΠΈ in vitro ΠΏΠΎΠ»ΠΈΠΌΠ΅ΡΠΈΠ·Π°ΡΠΈΡ ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP ΠΌΠΎΠ·Π³Π° Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΠ ΠΈ ΠΏΠΎΠ»ΡΡΠΈΡΡ ΡΠ»Π΅ΠΊΡΡΠΎΠ½Π½ΡΠ΅ ΠΌΠΈΠΊΡΠΎΡΠΎΡΠΎΠ³ΡΠ°ΡΠΈΠΈ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π²ΡΠΈΡ
ΡΡ ΡΡΡΡΠΊΡΡΡ. ΠΠΎΠΊΠ°Π·Π°Π½ΠΎ, ΡΡΠΎ ΠΏΡΠΈ ΠΠ Π½Π°ΡΡΡΠ΅Π½ ΠΏΡΠΎΡΠ΅ΡΡ ΡΠ±ΠΎΡΠΊΠΈ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ, Π² ΡΠ΅Π·ΡΠ»ΡΡΠ°ΡΠ΅ ΡΠ΅Π³ΠΎ ΠΎΠ±ΡΠ°Π·ΡΡΡΡΡ Π΄Π΅ΡΠ΅ΠΊΡΠ½ΡΠ΅ ΡΡΡΡΠΊΡΡΡΡ. Π‘ Π΄ΡΡΠ³ΠΎΠΉ ΡΡΠΎΡΠΎΠ½Ρ, ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΠ΅ Π²Π»ΠΈΡΠ½ΠΈΡ ΠΈΠΎΠ½ΠΎΠ² Al3+, Fe3+, Zn2+ Π½Π° ΡΠ±ΠΎΡΠΊΡ ΠΈ ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ ΠΈΠ· ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡΡ ΠΏΠΎΠΊΠ°Π·Π°Π»ΠΎ, ΡΡΠΎ Π»ΡΠ±ΠΎΠΉ ΠΈΠ· ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½Π½ΡΡ
Π½Π°ΠΌΠΈ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² ΡΠΏΠΎΡΠΎΠ±Π΅Π½ ΡΠ½ΠΈΠΆΠ°ΡΡ ΠΊΠΎΠ»ΠΈΡΠ΅ΡΡΠ²ΠΎ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ ΠΈ Π²ΡΠ·ΡΠ²Π°ΡΡ ΠΎΠ±ΡΠ°Π·ΠΎΠ²Π°Π½ΠΈΠ΅ Π°Π½ΠΎΠΌΠ°Π»ΡΠ½ΡΡ
ΡΡΡΡΠΊΡΡΡ. ΠΠΎ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ Π΄Π΅ΡΠΎΡΠΌΠΈΡΡΡΡΠ΅Π³ΠΎ Π²ΠΎΠ·Π΄Π΅ΠΉΡΡΠ²ΠΈΡ Π½Π° ΠΌΠΈΠΊΡΠΎΡΡΠ±ΡΠ»ΡΡΠ½ΡΡ ΡΠΈΡΡΠ΅ΠΌΡ ΠΊΠ»Π΅ΡΠΎΠΊ ΠΌΠΎΠ·Π³Π° ΠΈ, ΡΠΎΠΎΡΠ²Π΅ΡΡΡΠ²Π΅Π½Π½ΠΎ, Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΠΉ Π·Π½Π°ΡΠΈΠΌΠΎΡΡΠΈ Π² ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π΅ ΠΠ, ΠΈΠΎΠ½Ρ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² ΠΌΠΎΠΆΠ½ΠΎ ΡΠ°ΡΠΏΠΎΠ»ΠΎΠΆΠΈΡΡ Π² ΡΠ»Π΅Π΄ΡΡΡΠ΅ΠΉ ΠΏΠΎΡΠ»Π΅Π΄ΠΎΠ²Π°ΡΠ΅Π»ΡΠ½ΠΎΡΡΠΈ Al3+ > Zn2+ > Fe3+. ΠΠΎΠ»Π΅Π΅ ΡΠΎΠ³ΠΎ, ΡΠΏΠ΅ΠΊΡΡ ΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP Π² ΠΏΡΠΈΡΡΡΡΡΠ²ΠΈΠΈ ΠΈΠΎΠ½ΠΎΠ² Π°Π»ΡΠΌΠΈΠ½ΠΈΡ Π² Π½Π°ΠΈΠ±ΠΎΠ»ΡΡΠ΅ΠΉ ΡΡΠ΅ΠΏΠ΅Π½ΠΈ ΠΎΡΡΠ°ΠΆΠ°Π΅Ρ ΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΡΡΠΈΡ
Π±Π΅Π»ΠΊΠΎΠ² ΠΏΡΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°. Π‘ΠΎΠΏΠΎΡΡΠ°Π²Π»Π΅Π½ΠΈΠ΅ Π΄Π°Π½Π½ΡΡ
ΠΎ Π½Π°ΡΡΡΠ΅Π½ΠΈΡΡ
ΡΡΡΡΠΊΡΡΡΡ ΠΌΠΈΠΊΡΠΎΡΡΡΠ±ΠΎΡΠ΅ΠΊ, Π½Π°Π±Π»ΡΠ΄Π°Π΅ΠΌΡΡ
ΠΏΡΠΈ ΠΈΡ
ΡΠ±ΠΎΡΠΊΠ΅ ΠΈΠ· ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² ΡΡΠ±ΡΠ»ΠΈΠ½Π° ΠΈ MAP ΠΈΠ· ΠΌΠΎΠ·Π³Π° Π±ΠΎΠ»ΡΠ½ΡΡ
ΠΠ, ΠΈ ΠΈΠ· ΠΌΠΎΠ·Π³Π° ΠΊΡΡΡ, Π½ΠΎ Π² ΠΏΡΠΈΡΡΡΡΡΠ²ΠΈΠΈ ΠΈΠΎΠ½ΠΎΠ² ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ², ΠΏΠΎΠ΄ΡΠ²Π΅ΡΠΆΠ΄Π°ΡΡ Π²ΡΠ²ΠΎΠ΄ ΠΎ Π²ΠΎΠ·ΠΌΠΎΠΆΠ½ΠΎΠΉ ΡΠΎΠ»ΠΈ ΠΌΠ΅ΡΠ°Π»Π»ΠΎΠ² Π² ΡΡΠΈΠΎΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π΅ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°
Π‘ΠΎΠ²ΡΠ΅ΠΌΠ΅Π½Π½ΡΠ΅ ΡΠ΅Π½Π΄Π΅Π½ΡΠΈΠΈ Π² ΡΠΎΠ·Π΄Π°Π½ΠΈΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° ΠΈ ΠΈΡ ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΈΡΠΏΡΡΠ°Π½ΠΈΡ
Intracellular and extracellular accumulation of fibrillary proteins, beta-amyloid and hyperphosphorylated Tau, in patients with Alzheimerβs disease (AD) leads to chronic and progressive neurodegenerative process. Overaccumulation of aggregates results in synaptic dysfunction and inevitable neuronal loss. Although the exact molecular pathways of the AD still require better understanding, it is clear this neuropathology is a multifactorial disorder where the advanced age is the main risk factor. Lately, several dozens of drug candidates have succeeded to phase II clinical trials; however, none has passed phase III. In this review we summarize existing data on anti-AD therapeutic agents currently undergoing clinical trials and included in the public websites www.clinicaltrials.gov and Alzforum.org as well as the Thomson Reuters Β«IntegrityΒ» database. We revealed three major trends in AD drug discovery. First, developing of βdisease-modifying agentsβ could potentially slow the progression of structural and functional abnormalities in the central nervous system providing sustainable improvements of cognitive functions, which persist even after drug withdrawal. Secondly, the focused design of multitargeted drugs acting on multiple key molecular pathways. Finally, the repositioning of drugs that are already available on the market for the novel (anti-AD) application provides a promising strategy for finishing clinical trials and re-marketing.ΠΡΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° (ΠΠ) ΠΏΡΠΎΠΈΡΡ
ΠΎΠ΄ΠΈΡ Π²Π½ΡΡΡΠΈΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ΅ ΠΈ Π²Π½Π΅ΠΊΠ»Π΅ΡΠΎΡΠ½ΠΎΠ΅ Π½Π°ΠΊΠΎΠΏΠ»Π΅Π½ΠΈΠ΅ ΡΠΈΠ±ΡΠΈΠ»Π»ΡΡΠ½ΡΡ
Π±Π΅Π»ΠΊΠΎΠ²: Π±Π΅ΡΠ°-Π°ΠΌΠΈΠ»ΠΎΠΈΠ΄Π° ΠΈ Π³ΠΈΠΏΠ΅ΡΡΠΎΡΡΠΎΡΠΈΠ»ΠΈΡΠΎΠ²Π°Π½Π½ΠΎΠ³ΠΎ ΡΠ°Ρ, ΠΊΠΎΡΠΎΡΡΠ΅ ΠΏΡΠΈΠ²ΠΎΠ΄ΡΡ ΠΊ Ρ
ΡΠΎΠ½ΠΈΡΠ΅ΡΠΊΠΎΠΌΡ ΠΈ ΠΏΡΠΎΠ³ΡΠ΅ΡΡΠΈΡΡΡΡΠ΅ΠΌΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΠΎΠΌΡ ΠΏΡΠΎΡΠ΅ΡΡΡ Π² ΠΌΠΎΠ·Π³Π΅. ΠΠ°ΠΊΠΎΠΏΠ»Π΅Π½ΠΈΠ΅ ΠΎΡΠ»ΠΎΠΆΠ΅Π½ΠΈΠΉ Π²ΡΠ·ΡΠ²Π°Π΅Ρ ΡΠΈΠ½Π°ΠΏΡΠΈΡΠ΅ΡΠΊΡΡ Π΄ΠΈΡΡΡΠ½ΠΊΡΠΈΡ ΠΈ Π½Π΅ΠΈΠ·Π±Π΅ΠΆΠ½ΡΡ Π³ΠΈΠ±Π΅Π»Ρ Π½Π΅ΠΉΡΠΎΠ½ΠΎΠ². ΠΠΎ ΡΠΈΡ
ΠΏΠΎΡ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΡΠ΅ ΠΌΠ΅Ρ
Π°Π½ΠΈΠ·ΠΌΡ ΠΠ ΠΈΠ·ΡΡΠ΅Π½Ρ Π½Π΅ ΠΏΠΎΠ»Π½ΠΎΡΡΡΡ, ΠΎΠ΄Π½Π°ΠΊΠΎ ΡΡΡΠ°Π½ΠΎΠ²Π»Π΅Π½ΠΎ, ΡΡΠΎ ΠΠ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΌΠ½ΠΎΠ³ΠΎΡΠ°ΠΊΡΠΎΡΠ½ΡΠΌ ΡΠ°ΡΡΡΡΠΎΠΉΡΡΠ²ΠΎΠΌ, ΠΏΡΠΈ ΡΡΠΎΠΌ ΠΏΡΠ΅ΠΊΠ»ΠΎΠ½Π½ΡΠΉ Π²ΠΎΠ·ΡΠ°ΡΡ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΎΡΠ½ΠΎΠ²Π½ΡΠΌ ΡΠ°ΠΊΡΠΎΡΠΎΠΌ ΡΠΈΡΠΊΠ°. ΠΠ° ΠΏΠΎΡΠ»Π΅Π΄Π½Π΅Π΅ Π΄Π΅ΡΡΡΠΈΠ»Π΅ΡΠΈΠ΅ Π±ΠΎΠ»Π΅Π΅ 50 Π»Π΅ΠΊΠ°ΡΡΡΠ²Π΅Π½Π½ΡΡ
ΠΊΠ°Π½Π΄ΠΈΠ΄Π°ΡΠΎΠ² ΡΡΠΏΠ΅ΡΠ½ΠΎ ΠΏΡΠΎΡΠ»ΠΈ ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΈΠ΅ ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ II ΡΠ°Π·Ρ, ΠΏΡΠΈ ΡΡΠΎΠΌ Π½ΠΈ ΠΎΠ΄ΠΈΠ½ ΠΈΠ· Π½ΠΈΡ
Π½Π΅ ΠΏΡΠΎΡΠ΅Π» ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡ ΡΠ°Π·Ρ III. Π‘ ΠΈΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ΠΌ ΠΎΠ±ΡΠ΅Π΄ΠΎΡΡΡΠΏΠ½ΠΎΠ³ΠΎ ΠΈΠ½ΡΠ΅ΡΠ½Π΅Ρ-ΡΠ΅ΡΡΡΡΠ° www.clinicaltrials.gov ΠΈ Alzforum.org, Π° ΡΠ°ΠΊΠΆΠ΅ Π±Π°Π·Ρ Thomson Reuters βIntegrityβ Π² ΠΎΠ±Π·ΠΎΡΠ΅ ΡΡΠΌΠΌΠΈΡΠΎΠ²Π°Π½Ρ Π΄Π°Π½Π½ΡΠ΅ ΠΏΠΎ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ΅ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ°, Π½Π°Ρ
ΠΎΠ΄ΡΡΠΈΡ
ΡΡ Π² Π½Π°ΡΡΠΎΡΡΠ΅Π΅ Π²ΡΠ΅ΠΌΡ Π½Π° ΠΊΠ»ΠΈΠ½ΠΈΡΠ΅ΡΠΊΠΈΡ
ΠΈΡΡΠ»Π΅Π΄ΠΎΠ²Π°Π½ΠΈΡΡ
. ΠΡΠ΄Π΅Π»Π΅Π½Ρ Π½Π΅ΠΊΠΎΡΠΎΡΡΠ΅ ΠΎΡΠ½ΠΎΠ²Π½ΡΠ΅ ΡΠ΅Π½Π΄Π΅Π½ΡΠΈΠΈ: (1) ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ, Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΡ
Π½Π° ΠΎΡΠ½ΠΎΠ²Π½ΡΠ΅ ΡΡΠ°Π΄ΠΈΠΈ ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π·Π° Π±ΠΎΠ»Π΅Π·Π½ΠΈ (ΡΠ°ΠΊ Π½Π°Π·ΡΠ²Π°Π΅ΠΌΡΠ΅ βΠ±ΠΎΠ»Π΅Π·Π½Ρ-ΠΌΠΎΠ΄ΠΈΡΠΈΡΠΈΡΡΡΡΠΈΠ΅β ΡΡΠ΅Π΄ΡΡΠ²Π°) β ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ, ΠΊΠΎΡΠΎΡΡΠ΅ ΠΌΠΎΠ³ΡΡ Π·Π°ΠΌΠ΅Π΄Π»ΠΈΡΡ ΡΠ°Π·Π²ΠΈΡΠΈΠ΅ ΡΡΡΡΠΊΡΡΡΠ½ΡΡ
ΠΈ ΡΡΠ½ΠΊΡΠΈΠΎΠ½Π°Π»ΡΠ½ΡΡ
Π°Π½ΠΎΠΌΠ°Π»ΠΈΠΉ Π² ΡΠ΅Π½ΡΡΠ°Π»ΡΠ½ΠΎΠΉ Π½Π΅ΡΠ²Π½ΠΎΠΉ ΡΠΈΡΡΠ΅ΠΌΠ΅, ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠΈΠ²Π°Ρ ΡΡΡΠΎΠΉΡΠΈΠ²ΠΎΠ΅ ΡΠ»ΡΡΡΠ΅Π½ΠΈΠ΅ ΠΊΠΎΠ³Π½ΠΈΡΠΈΠ²Π½ΡΡ
ΡΡΠ½ΠΊΡΠΈΠΉ, ΡΠΎΡ
ΡΠ°Π½ΡΡΡΠΈΡ
ΡΡ Π΄Π°ΠΆΠ΅ ΠΏΠΎΡΠ»Π΅ ΠΎΡΠΌΠ΅Π½Ρ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠ°; (2) ΡΠ΅Π»Π΅Π½Π°ΠΏΡΠ°Π²Π»Π΅Π½Π½Π°Ρ ΡΠ°Π·ΡΠ°Π±ΠΎΡΠΊΠ° ΠΌΡΠ»ΡΡΠΈΡΠ°ΡΠ³Π΅ΡΠ½ΡΡ
Π»Π΅ΠΊΠ°ΡΡΡΠ², Π΄Π΅ΠΉΡΡΠ²ΡΡΡΠΈΡ
Π½Π° Π½Π΅ΡΠΊΠΎΠ»ΡΠΊΠΎ ΠΌΠΎΠ»Π΅ΠΊΡΠ»ΡΡΠ½ΡΡ
ΠΌΠΈΡΠ΅Π½Π΅ΠΉ, Π²ΠΎΠ²Π»Π΅ΡΠ΅Π½Π½ΡΡ
Π² ΠΏΠ°ΡΠΎΠ³Π΅Π½Π΅Π· Π±ΠΎΠ»Π΅Π·Π½ΠΈ; (3) ΡΠ΅ΠΏΠΎΠ·ΠΈΡΠΈΠΎΠ½ΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΠΈΠ·Π²Π΅ΡΡΠ½ΡΡ
ΡΠ°Π½Π΅Π΅ Π»Π΅ΠΊΠ°ΡΡΡΠ² Π½Π° Π½ΠΎΠ²ΠΎΠ΅ (Π°Π½ΡΠΈ-Π°Π»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠΎΠ²ΡΠΊΠΎΠ΅) ΠΏΡΠΈΠΌΠ΅Π½Π΅Π½ΠΈΠ΅, ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΡΡΠ΅Π΅ ΡΠΎΠ±ΠΎΠΉ ΠΎΡΠ΅Π½Ρ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄
ΠΠΈΡΠΎΡ ΠΎΠ½Π΄ΡΠΈΠΈ ΠΊΠ°ΠΊ Π²Π°ΠΆΠ½Π°Ρ ΠΌΠΈΡΠ΅Π½Ρ ΠΏΡΠΈ ΠΏΠΎΠΈΡΠΊΠ΅ Π½ΠΎΠ²ΡΡ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° ΠΈ ΡΡΠ°ΡΡΠ΅ΡΠΊΠΈΡ Π΄Π΅ΠΌΠ΅Π½ΡΠΈΠΉ
The review and summarizes own and literature data about the role of mitochondria as the important target in the search for drugs for the treatment of neurodegenerative diseases. Aging is a major risk factor for sporadic forms of various neurodegenerative diseases, including Alzheimerβ²s disease. One of the most argued and currently accepted theories is the Mitochondrial Free Radical Theory of Aging. Mitochondrial hypotheses of the development of sporadic forms of neurodegenerative diseases particularly Alzheimerβ²s disease, are closely connected with it. Impairments of mitochondrial functions lead to a decrease in their ability to regulate calcium homeostasis in the cell and to a decrease in the threshold for the induction of mitochondrial permeability transition (MPT) pores. MPT inhibitors can be considered as a promising approach to the treatment of neurodegenerative diseases, since these drugs can not only exhibit the properties of neuroprotectors, but also can provide normalization of synaptic activity due to increased calcium capacity of mitochondria. The review presents data on the number of MPT inhibitors, including endogenous compounds melatonin and N-acetylserotonin, their bioisosteric analogue Dimebon and a number of other compounds. The use of mitochondria as a basis for the formation of screening strategy for the search for compounds for the treatment of neurodegenerative diseases is of particular interest β both as a test of their potential toxicity, and as a basis for the creation of metabolic stimulants and drugs with neuroprotective and cognitive-stimulating effect.ΠΠ±ΠΎΠ±ΡΠ΅Π½Ρ ΡΠΎΠ±ΡΡΠ²Π΅Π½Π½ΡΠ΅ ΠΈ Π»ΠΈΡΠ΅ΡΠ°ΡΡΡΠ½ΡΠ΅ Π΄Π°Π½Π½ΡΠ΅, ΠΎΠ±ΠΎΡΠ½ΠΎΠ²ΡΠ²Π°ΡΡΠΈΠ΅ ΡΠΎΠ»Ρ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ ΠΊΠ°ΠΊ Π²Π°ΠΆΠ½Π΅ΠΉΡΠ΅ΠΉ ΠΌΠΈΡΠ΅Π½ΠΈ ΠΏΡΠΈ ΠΏΠΎΠΈΡΠΊΠ΅ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ² Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ. Π‘ΡΠ°ΡΠ΅Π½ΠΈΠ΅ ΡΠ²Π»ΡΠ΅ΡΡΡ ΠΎΡΠ½ΠΎΠ²Π½ΡΠΌ ΡΠ°ΠΊΡΠΎΡΠΎΠΌ ΡΠΈΡΠΊΠ° ΡΠΏΠΎΡΠ°Π΄ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΎΡΠΌ ΡΠ°Π·Π»ΠΈΡΠ½ΡΡ
Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, Π² ΡΠΎΠΌ ΡΠΈΡΠ»Π΅ ΠΈ Π±ΠΎΠ»Π΅Π·Π½ΠΈ ΠΠ»ΡΡΠ³Π΅ΠΉΠΌΠ΅ΡΠ° (ΠΠ). ΠΠ΄Π½ΠΎΠΉ ΠΈΠ· Π½Π°ΠΈΠ±ΠΎΠ»Π΅Π΅ Π°ΡΠ³ΡΠΌΠ΅Π½ΡΠΈΡΠΎΠ²Π°Π½Π½ΡΡ
ΠΈ ΠΏΡΠΈΠ½ΡΡΡΡ
Π² Π½Π°ΡΡΠΎΡΡΠ΅Π΅ Π²ΡΠ΅ΠΌΡ ΡΠ²Π»ΡΠ΅ΡΡΡ ΡΠ²ΠΎΠ±ΠΎΠ΄Π½ΠΎΡΠ°Π΄ΠΈΠΊΠ°Π»ΡΠ½Π°Ρ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½Π°Ρ ΡΠ΅ΠΎΡΠΈΡ ΡΡΠ°ΡΠ΅Π½ΠΈΡ. ΠΠΌΠ΅Π½Π½ΠΎ Ρ Π½Π΅ΠΉ ΡΠ΅ΡΠ½ΠΎ ΡΠ²ΡΠ·Π°Π½Ρ ΠΈ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΡΠ΅ Π³ΠΈΠΏΠΎΡΠ΅Π·Ρ ΡΠ°Π·Π²ΠΈΡΠΈΡ ΡΠΏΠΎΡΠ°Π΄ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΠΎΡΠΌ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΈ, Π² ΡΠ°ΡΡΠ½ΠΎΡΡΠΈ, ΠΠ. ΠΠ°ΡΡΡΠ΅Π½ΠΈΠ΅ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΡΡ
ΡΡΠ½ΠΊΡΠΈΠΉ ΠΏΡΠΈΠ²ΠΎΠ΄ΠΈΡ ΠΊ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΡ ΠΈΡ
ΡΠΏΠΎΡΠΎΠ±Π½ΠΎΡΡΠΈ ΡΠ΅Π³ΡΠ»ΠΈΡΠΎΠ²Π°ΡΡ Π³ΠΎΠΌΠ΅ΠΎΡΡΠ°Π· ΠΊΠ°Π»ΡΡΠΈΡ Π² ΠΊΠ»Π΅ΡΠΊΠ΅ ΠΈ ΡΠ½ΠΈΠΆΠ΅Π½ΠΈΡ ΠΏΠΎΡΠΎΠ³Π° Π΄Π»Ρ ΠΈΠ½Π΄ΡΠΊΡΠΈΠΈ ΠΏΠΎΡΡ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠ°Π»ΡΠ½ΠΎΠΉ ΠΏΡΠΎΠ½ΠΈΡΠ°Π΅ΠΌΠΎΡΡΠΈ (ΠΠ Π’). ΠΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΡ ΠΠ Π’ ΠΌΠΎΠΆΠ½ΠΎ ΡΠ°ΡΡΠΌΠ°ΡΡΠΈΠ²Π°ΡΡ ΠΊΠ°ΠΊ ΠΏΠ΅ΡΡΠΏΠ΅ΠΊΡΠΈΠ²Π½ΡΠΉ ΠΏΠΎΠ΄Ρ
ΠΎΠ΄ ΠΊ ΡΠ΅ΡΠ°ΠΏΠΈΠΈ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ, ΡΠ°ΠΊ ΠΊΠ°ΠΊ ΡΡΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΡ ΠΌΠΎΠ³ΡΡ Π½Π΅ ΡΠΎΠ»ΡΠΊΠΎ ΠΏΡΠΎΡΠ²Π»ΡΡΡ ΡΠ²ΠΎΠΉΡΡΠ²Π° Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠΎΠ², Π½ΠΎ ΠΈ ΠΎΠ±Π΅ΡΠΏΠ΅ΡΠΈΠ²Π°ΡΡ Π½ΠΎΡΠΌΠ°Π»ΠΈΠ·Π°ΡΠΈΡ ΡΠΈΠ½Π°ΠΏΡΠΈΡΠ΅ΡΠΊΠΎΠΉ Π°ΠΊΡΠΈΠ²Π½ΠΎΡΡΠΈ Π±Π»Π°Π³ΠΎΠ΄Π°ΡΡ ΡΠ²Π΅Π»ΠΈΡΠ΅Π½Π½ΠΎΠΉ ΠΊΠ°Π»ΡΡΠΈΠ΅Π²ΠΎΠΉ ΡΠΌΠΊΠΎΡΡΠΈ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ. Π ΠΎΠ±Π·ΠΎΡΠ΅ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»Π΅Π½Ρ Π΄Π°Π½Π½ΡΠ΅ ΠΎ ΡΡΠ΄Π΅ ΠΈΠ½Π³ΠΈΠ±ΠΈΡΠΎΡΠΎΠ² ΠΠ Π’, Π²ΠΊΠ»ΡΡΠ°Ρ ΡΠ½Π΄ΠΎΠ³Π΅Π½Π½ΡΠ΅ ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΡ β ΠΌΠ΅Π»Π°ΡΠΎΠ½ΠΈΠ½, N-Π°ΡΠ΅ΡΠΈΠ»ΡΠ΅ΡΠΎΡΠΎΠ½ΠΈΠ½, ΠΈΡ
Π±ΠΈΠΎΠΈΠ·ΠΎΡΡΠ΅ΡΠ½ΡΠΉ Π°Π½Π°Π»ΠΎΠ³ Π΄ΠΈΠΌΠ΅Π±ΠΎΠ½ ΠΈ ΡΡΠ΄ Π΄ΡΡΠ³ΠΈΡ
ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ. ΠΡΠΏΠΎΠ»ΡΠ·ΠΎΠ²Π°Π½ΠΈΠ΅ ΠΌΠΈΡΠΎΡ
ΠΎΠ½Π΄ΡΠΈΠΉ ΠΊΠ°ΠΊ ΠΎΡΠ½ΠΎΠ²Ρ Π΄Π»Ρ ΡΠΎΡΠΌΠΈΡΠΎΠ²Π°Π½ΠΈΡ ΡΠΊΡΠΈΠ½ΠΈΠ½Π³ΠΎΠ²ΠΎΠΉ ΡΡΡΠ°ΡΠ΅Π³ΠΈΠΈ ΠΏΠΎΠΈΡΠΊΠ° ΡΠΎΠ΅Π΄ΠΈΠ½Π΅Π½ΠΈΠΉ Π΄Π»Ρ Π»Π΅ΡΠ΅Π½ΠΈΡ Π½Π΅ΠΉΡΠΎΠ΄Π΅Π³Π΅Π½Π΅ΡΠ°ΡΠΈΠ²Π½ΡΡ
Π·Π°Π±ΠΎΠ»Π΅Π²Π°Π½ΠΈΠΉ ΠΏΡΠ΅Π΄ΡΡΠ°Π²Π»ΡΠ΅Ρ ΠΎΡΠΎΠ±ΡΠΉ ΠΈΠ½ΡΠ΅ΡΠ΅Ρ ΠΈ ΠΊΠ°ΠΊ ΡΠ΅ΡΡΠΈΡΠΎΠ²Π°Π½ΠΈΠ΅ ΠΈΡ
ΠΏΠΎΡΠ΅Π½ΡΠΈΠ°Π»ΡΠ½ΠΎΠΉ ΡΠΎΠΊΡΠΈΡΠ½ΠΎΡΡΠΈ, ΠΈ ΠΊΠ°ΠΊ ΠΎΡΠ½ΠΎΠ²Π° Π΄Π»Ρ ΡΠΎΠ·Π΄Π°Π½ΠΈΡ ΠΌΠ΅ΡΠ°Π±ΠΎΠ»ΠΈΡΠ΅ΡΠΊΠΈΡ
ΡΡΠΈΠΌΡΠ»ΡΡΠΎΡΠΎΠ² ΠΈ ΠΏΡΠ΅ΠΏΠ°ΡΠ°ΡΠΎΠ², ΠΎΠ±Π»Π°Π΄Π°ΡΡΠΈΡ
Π½Π΅ΠΉΡΠΎΠΏΡΠΎΡΠ΅ΠΊΡΠΎΡΠ½ΡΠΌ ΠΈ ΠΊΠΎΠ³Π½ΠΈΡΠΈΠ²Π½ΠΎ-ΡΡΠΈΠΌΡΠ»ΠΈΡΡΡΡΠΈΠΌ Π΄Π΅ΠΉΡΡΠ²ΠΈΠ΅ΠΌ
Gamma-carbolines derivatives as promising agents for the development of pathogenic therapy for proteinopathy
Uncontrolled protein aggregation, accompanied by the formation of specific inclusions, is a major
component of the pathogenesis of many common neurodegenerative diseases known as proteinopathies. The
intermediate products of this aggregation are toxic to neurons and may be lethal. The development strategy of
pathogenic therapy for proteinopathy is based on the design of drugs capable of both inhibiting proteinopathy
progression and increasing the survival of affected neurons. The results of a decade-long research effort at
leading Russian and international laboratories have demonstrated that Dimebon (Latrepirdine), as well as a
number of its derivatives from a gamma-carboline group, show a strong neuroprotective effect and can modulate
the course of a neurodegenerative process in both in vitro and in vivo model systems. The accumulated
data indicate that gamma-carbolines are promising compounds for the development of pathogenic therapy for
proteinopathies
Gamma-carbolines derivatives as promising agents for the development of pathogenic therapy for proteinopathy
Uncontrolled protein aggregation, accompanied by the formation of specific inclusions, is a major
component of the pathogenesis of many common neurodegenerative diseases known as proteinopathies. The
intermediate products of this aggregation are toxic to neurons and may be lethal. The development strategy of
pathogenic therapy for proteinopathy is based on the design of drugs capable of both inhibiting proteinopathy
progression and increasing the survival of affected neurons. The results of a decade-long research effort at
leading Russian and international laboratories have demonstrated that Dimebon (Latrepirdine), as well as a
number of its derivatives from a gamma-carboline group, show a strong neuroprotective effect and can modulate
the course of a neurodegenerative process in both in vitro and in vivo model systems. The accumulated
data indicate that gamma-carbolines are promising compounds for the development of pathogenic therapy for
proteinopathies
Structural basis for understanding structure-activity relationships for the glutamate binding site of the NMDA receptor
Novel conjugates of tacrine with 1,2,4,-thiadiazole as highly effective cholinesterase inhibitors, blockers of NMDA receptors, and antioxidants
[Proteinopathies--forms of neurodegenerative disorders with protein aggregation-based pathology]
A number of neurodegenerative disorders have recently been coalesced into a group of proteinopathies because of the similarity of molecular mechanisms underlying their pathogenesis. A key step in the development of proteinopathies is a structural change that triggers aggregation of proteins, which are intrinsically prone to form aggregates due to their physical and chemical properties. Present review is devoted to the recent progress in the field of proteinopathies with specific focus on properties of aggregate-prone proteins, main stages of the development of molecular pathology and the role of cellular clearance systems in progression of neurodegeneration. Recent modifications in the nomenclature of neurodegenerative diseases will also be addressed