Eburnamine derivatives and the brain

Abstract

The Apocynaceae plant family contains a great number of so called eburnamine-vincamine alkaloids. Quite a few of these alkaloids exert varied pharmacological activities on the cell multiplication, cardiovascular system, and brain functions. Many derivatives were also synthesized to find pharmacologically active compounds better characterized and safer to be administered than the natural plant alkaloids themselves. We concentrate on the eburnamine structures with cerebral activities in this review. Vincamine, vinburnine, vindeburnol, apovincaminate, and vinpocetine (cis-ethyl-apovincaminate) all share modulatory effects on brain circulation and neuronal homeostasis, bear antihypoxic and neuroprotective potencies to various degrees. The most eminent compound of this class of alkaloids is vinpocetine. Since its introduction to the market as a neuroprotective agent many non clinical and clinical studies proved vinpocetine's effects on calmodulin dependent phosphodiesterase E1, on sodium, calcium channels, peripheral benzodiazepine receptor, and glutamate receptors as well as its clinical usefulness in the treatment of post-ischaemic stroke disease states and various disorders of cerebrovascular origin. Lately, positron emission tomography studies proved that vinpocetine has a rapid uptake in the primate and human brain with a heterogeneous distribution pattern (preference areas: thalamus, basal ganglia, and visual cortex) both after intravenous and oral administration. Vinpocetine exerts beneficial effects in cerebral glucose metabolism and regional cerebral blood flow in chronic post-stroke patients.

Effects of Vinpocetine on mitochondrial function and neuroprotection in primary cortical neurons

“…A key element of the secondary cell loss is the increased activity of excitatory amino acid regulated receptors, which elevates [Ca 2+ ] i above the physiological levels and leads to disturbed functions and eventually cell death (De Keyser et al, 1999;Nicholls, 2004;Hazell, 2007). Former clinical and experimental studies in vivo and in vitro have shown that Vinpocetine, developed by Richter Ltd., is able to protect the neurons under ischemic condition by a variety of actions (Bonoczk et al, 2000;Vas and Gulyas, 2005). Vinpocetine can block phosphodiesterase I, which can be important for improvement of cerebral circulation (Pelligrino and Wang, 1998) and can act as an antioxidant .…”

“…Importantly, Vinpocetine did not influence the amplitude of the initial glutamate-evoked [Ca 2+ ] i rise indicating that Vinpocetine acts at least partially by influencing mechanisms controlling elevated [Ca 2+ ] i levels. Recent positron emission tomography (PET) studies using radiolabeled PBR ligands and Vinpocetine suggested that mitochondrial peripheral-type benzodiazepine receptors can be therapeutically relevant targets of Vinpocetine Vas and Gulyas, 2005). As mitochondria play an important role in Ca 2+ homeostasis, neuroprotective effects of Vinpocetine can be executed through interfering with PBRs and consequently, via modulating mitochondrial function.…”

“…Its beneficial clinical effects are based on a wide range of action mechanisms including antioxidant, vasodilating and neuroprotective effects, however, the precise nature of the underlying mechanistic processes is not yet clear (Bonoczk et al, 2000;Vas and Gulyas, 2005). Recent studies indicated that Vinpocetine has a relatively high potency towards PBR, raising the possibility that the pharmacological action of Vinpocetine may involve the regulation of PBR function .…”

Cytotoxicity ofVinca minor

“…minor contains eburnamine-type indole alkaloids including vincamine, which has modulatory effects on brain circulation and neuronal homeostasis as well as antihypoxic and neuroprotective potencies (Vas & Gulyas, 2005). However, few studies have been carried out on the cytotoxic activity of the plant extracts (Porska et al, 1988;Sturdikova et al, 1986).…”

Synthesis and antitumor activity of tetrahydrocarbazole hybridized with dithioate derivatives

“…Tetrahydrocarbazole ring can be considered as an isostere to b-carboline ring which is present in many naturally occurring anticancer agents, such as the vinca alkaloids, vincamine (III) and (-)-eburnamonine (IV) (Figure 1) isolated from the Madagascar periwinkle (Catharanthus roseus) [33][34][35] . Although (-)-eburnamonine (IV) was devoid of anticancer activity even at the high dose of 100 M, its synthetic analogue 15-methylene-eburnamonine (V) displayed in vitro micromolar activity against prostate and myeloma cell lines 36 .…”