Novel Sites of Neuroprotective Action of Dimebon (Latrepirdine)

Abstract

Dimebon (latrepirdine) is an anti-histaminergic agent which belongs to a fast-growing group of "old" medicines suggested to be of therapeutic utility for pathological conditions different from their original design ("repositioning"). Here, we overview the most recent studies on Dimebon directed to pathological processes in the brain-involving in vivo models of proteinopathies. In the latter, neurodegenerative effects are attributed to a group of aggregate-prone proteins such as γ-synuclein, hyperphosphorylated tau, and fused in sarcoma (FUS), which are engaged in numerous neurological diseases. We also focus on in vitro models comprised of cultured SH-SY5Y neuroblastoma cells expressing mutant forms of transactive response DNA binding protein 43 kDa (TDP-43) and showing a reduced number of TDP-43 inclusion-containing cells upon Dimebon treatment along with activation of autophagy markers. Finally, we discuss Dimebon's action in improving cellular energy balance, stabilizing mitochondrial function by increasing the threshold for nonselective mitochondrial pore opening, as well as increasing the calcium retention capacity of mitochondria and reducing lipid peroxidation. Our results, together with data from other laboratories, warrant re-evaluation of the therapeutic potential of Dimebon and its newly designed analogs as promising disease-modifying agents to treat neurodegenerative disorders. Further, emerging data favor a possible anti-aging effect and application of Dimebon for the treatment of depression, anxiety, and ischemia. The most pronounced effect of Dimebon is observed when treatment starts early in disease onset. This is a major factor which needs to be taken into account when planning future clinical trials.

Current Trends in the Development of Drugs for the Treatment of Alzheimer’s Disease and their Clinical Trials

“…Такое "репозиционирование" существующих лекарств представляется крайне привлекательным для инвестиций, поскольку оно сводит к минимуму риск неизвестных побочных эффектов, сокращает общее время клинических исследований, так как характеристики безопасности этих лекарств уже изучены ранее [205]. Интересно, что изучение случаев успешного применения известных препаратов для лечения нейродегенеративных заболеваний часто приводит к открытию новых фармакологических мишеней, как это произошло с препаратами Bexarotene и Dimebon [206].…”

Gamma-Carbolines Derivatives As Promising Agents for the Development of Pathogenic Therapy for Proteinopathy

“…Data from independent studies at several laboratories have demonstrated that compounds belonging to the gamma-carboline class are potential neuroprotective agents leading to reduced levels of pathogenic aggregation and/or activating the intracellular defense mechanisms of controlled degradation of aggregated proteins [7,8]. Initial findings for these gamma-carbolines properties were obtained in Dimebon studies showing a correction of the cognitive function in patients with Alzheimer's disease (AD), which is the most common neurodegenerative disease in the proteinopathy group [9,10].…”

“…However, the exact mechanism of Dimebon action remains unclear. The existing data from biochemical studies, as well as experiments on cell cultures and animals, suggest that Dimebon is a multitarget drug capable of affecting many intracellular processes and various pathogenic pathways in neurons and other cells affected by neurodegenerative changes [7].…”

A review of drugs for treatment of Alzheimer’s disease in clinical trials: main trends

“…В качестве таких подходов можно отметить совмещение в одной структуре ингибиторных свойств холинэстеразы и моноаминоксидазы, антиоксидантных и металлохелатирующих свойств, способности выступать лигандами одновременно нескольких рецепторов, введение дополнительных NO-генерирующих фрагментов в базовую структуру лиганда. Примерами таких мультитаргетных агентов являются препарат лагостиджил [114] и отечественный препарат димебон, успешно прошедший 2-ю фазу клинических испытаний в России [115].…”