Exploration of the Antiplatelet Activity Profile of Betulinic Acid on Human Platelets

Abstract

Betulinic acid, a natural pentacyclic triterpene acid, presents a diverse mode of biological actions including anti-retroviral, antibacterial, antimalarial and anti-inflammatory activities. The potency of betulinic acid as an inhibitor of human platelet activation was evaluated and its antiplatelet profile against in vitro platelet aggregation, induced by several platelet agonists (Adenosine Diphosphate, Thrombin Receptor Activator Peptide-14 and Arachidonic Acid), was explored. Flow cytometric analysis was performed to examine the effect of betulinic acid on P-selectin membrane expression and PAC-1 binding to activated platelets. Betulinic acid potently inhibits platelet aggregation and also reduced PAC-1 binding and the membrane expression of P-selectin. Principal component analysis was used to screen, on the chemical property space, for potential common pharmacophores of betulinic acid with approved antithrombotic drugs. A common pharmacophore was defined between the NMR derived structure of betulinic acid and prostacyclin agonists (PGI2) and the importance of its carboxylate group in its antiplatelet activity was determined. The present results indicate that betulinic acid has potential use as an antithrombotic compound and suggest that the mechanism underlying the antiplatelet effects of betulinic acid is similar to that of the PGI2 receptor agonists, a hypothesis that reserves further investigation.

Ameliorative effect of betulinic acid on oxidative damage and apoptosis in the splenocytes of dexamethasone treated mice

“…Plants produce a variety of antioxidant compounds such as phenolics, alkaloids, terpenoids and polysaccharides which could attenuate oxidative damage of a tissue directly by scavenging the free radical species and/or indirectly by enhancing natural defenses of cell [5]. Furthermore, natural products have evolved through natural selection to interact with multiple targets and to modulate multiple signal transduction pathways [9]. In the past decade, a number of studies have suggested that certain bioactive chemicals present in plants may protect against immunosuppression and oxidative stress induced by Dex [9][10][11].…”

“…Furthermore, natural products have evolved through natural selection to interact with multiple targets and to modulate multiple signal transduction pathways [9]. In the past decade, a number of studies have suggested that certain bioactive chemicals present in plants may protect against immunosuppression and oxidative stress induced by Dex [9][10][11]. Quercetin, rutin and okra (Abelmoschus esculentus Linn.)…”

“…Pharmacological relevance has increased during the past two decades, demonstrating multitarget properties combined with low toxicity [9]. BA exhibits a wide variety of biological and pharmacological activities including anti-tumor, anti-HIV, anti-inflammatory, antioxidant, immunomodulation, anti-neoplastic, antiobese, antiangiogenesis and anti-plasmodial properties [12][13][14].…”

Anti-platelet aggregation of mixtures of betulinic oleanolic and maslinic acids and derivatives from medicinal plants

“…The present study revealed that the plant-derived triterpenes and derivatives possess anti-platelet aggregation activities regardless of the agonists. Anti-platelet aggregation activities of some triterpenes have previously been reported [17,18]. The anti-platelet aggregation activity of BA/OA mixture isolated from the leaves of Callisteum viminalis has also been reported, and further separation of BA/OA mixture using open column silica gel chromatography has been unsuccessful [13].…”

Plant and Marine Sources

“…In vivo preclinical studies showed some remarkable anticancer effects and a complete absence of systemic toxicity in rodents [236,237]. Regarding anti-inflammatory activities, betulinic acid potently inhibits platelet aggregation and also reduced PAC-1 binding and the membrane expression of P-selectin [238], so it has potential use as an antithrombotic compound as well.…”