Neuroprotective effects of the securinine-analogues: identification of Allomargaritarine as a lead compound

Neganova, Margarita E.; Klochkov, Sergey G.; Afanasieva, Svetlana V.; Serkova, T. P.; Chudinova, E. S.; Бачурин, С. О.; Reddy, Padmalatha S.; Aliev, Gjumrakch; Shevtsova, Elena F.

doi:10.2174/1871527314666150821111812

Cited by 20 publications

(23 citation statements)

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“…Алломаргаритарин проявляет выраженные нейропротекторные свойства, защищая нейроны первичной культуры коры мозга от гибели, вызванной эксайтотоксичностью, окислительным стрессом и Аb. Очевидно, этот эффект связан с его антиоксидантной и митопротекторной активностью [54,55]. Кроме того, алломаргаритарин снижает агрегацию Аb [56].…”

Section: ингибиторы мрт как перспективная группа лекарственных препарunclassified

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Shevtsova

Vinogradova

Neganova

et al. 2018

BMCRM

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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 Alzheimer′s 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 Alzheimer′s 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 – 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.

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Section: ингибиторы мрт как перспективная группа лекарственных препарunclassified

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Shevtsova

Vinogradova

Neganova

et al. 2018

BMCRM

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“…A study of the neuroprotective properties of this conjugate in various neurotoxicity models using a primary culture of the rat cortex showed that allomargaritarine has a pronounced cytoprotective effect that contributes to an increased cell survival rate after glutamate, Fe3+ and Aβ exposure. The ability of allomargaritarine to protect neurons from death correlated with its antioxidant potential: namely, there was a concentration-depended inhibition of lipid peroxidation caused by ferric iron ions and tert-butylhydroxyperoxide [ 41 , 42 ]. Allomargaritarine also has an anticonvulsant activity [ 43 ], which may be due to its antioxidant potential, since oxidative stress is known to be involved in the pathogenesis of epilepsy [ 44 , 45 ].…”

Section: Problems and Targets In The Treatment Of Neurodegeneative DImentioning

confidence: 99%

“…Preincubation of rat mitochondria with allomargaritarine, the conjugate of securinine and tryptamine, inhibits Ca 2+ -induced mitochondrial permeability transition in a dose-dependent manner. It also effectively suppresses it when Aβ35-25 is used as an inducer and, as a result, displays cyto(neuro)protector activity in models of excitotoxicity and toxicity mediated by trivalent iron ions and amyloid [ 41 , 42 , 168 ]. Moreover, allomargaritarine has the ability to reduce Aβ [ 169 ].…”

Section: Problems and Targets In The Treatment Of Neurodegeneative DImentioning

confidence: 99%

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

et al. 2020

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Drug development for the treatment of neurodegenerative diseases has to confront numerous problems occurring, in particular, because of attempts to address only one of the causes of the pathogenesis of neurological disorders. Recent advances in multitarget therapy research are gaining momentum by utilizing pharmacophores that simultaneously affect different pathological pathways in the neurodegeneration process. The application of such a therapeutic strategy not only involves the treatment of symptoms, but also mainly addresses prevention of the fundamental pathological processes of neurodegenerative diseases and the reduction of cognitive abilities. Neuroinflammation and oxidative stress, mitochondrial dysfunction, dysregulation of the expression of histone deacetylases, and aggregation of pathogenic forms of proteins are among the most common and significant pathological features of neurodegenerative diseases. In this review, we focus on the molecular mechanisms and highlight the main aspects, including reactive oxygen species, the cell endogenous antioxidant system, neuroinflammation triggers, metalloproteinases, -synuclein, tau proteins, neuromelanin, histone deacetylases, presenilins, etc. The processes and molecular targets discussed in this review could serve as a starting point for screening leader compounds that could help prevent or slow down the development of neurodegenerative diseases.

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“…Процесс "набухания" митохондрий регистрировали спектрофотометрически в 96-луночных планшетах с прозрачным дном при 540 нм на планшетном анализаторе Victor 3 . В качестве индуктора "набухания" (скачка митохондриальной проницаемости) митохондрий использовали СаCl 2 [10]. Скорость "набухания" определяли в программе Excel как dA540/dt.…”

Section: исследование влияния соединений на митохондриальные характерunclassified

Bioisosteric Analogues of Cinnamic Acid as Effective Neuroprotectors

Neganova

Семенов

Semenova

et al. 2018

BMCRM

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Compounds that act on mitochondrial functions are considered as promising drugs for the treatment of neurodegenerative diseases and age-related dementias. As a basis for the creation of such potential drugs, bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives were selected. Derivatives of cinnamic acid have a wide range of biological activities, which can be important for drugs aimed at the treatment of neurodegenerative diseases, in particular Alzheimer′s disease. In this work, the neuroprotective activity of bioisosteric cinnamic acid analogs and polymethoxybenzene derivatives was studied. Among the compounds studied, lead substances 3, 4, and 7 have been identified. These compounds show no intrinsic toxicity and have a neuroprotective effect on the cellular model of neurodegeneration associated with calcium stress. The mechanism of their cytoprotective activity is probably due to the influence on mitochondrial functions, because these compounds effectively suppress the calcium-induced process of mitochondrial permeability jump. In addition, one of the substances investigated (7) has antioxidant properties, showing the ability to inhibit lipid peroxidation (LPO) of rat brain homogenate, which may be an additional mechanism of neuroprotective effect. The data obtained make it possible to recommend the investigated substances as a basis for the creation of effective neuroprotective drugs capable of influencing early stages of the development of neurodegenerative diseases.

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Neuroprotective effects of the securinine-analogues: identification of Allomargaritarine as a lead compound

Cited by 20 publications

References 0 publications

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Mitochondria are an Important Target in the Search for new Drugs for the Treatment of Alzheimer′s Disease and Senile Dementia

Promising molecular targets for pharmacological therapy of neurodegenerative pathologies

Bioisosteric Analogues of Cinnamic Acid as Effective Neuroprotectors

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