Potent anti-inflammatory activity of betulinic acid treatment in a model of lethal endotoxemia

Abstract

Betulinic acid (BA) is a lupane-type triterpene with a number of biological activities already reported. While potent anti-HIV and antitumoral activities were attributed to BA, it is considered to have a moderate anti-inflammatory activity. Here we evaluated the effects of BA in a mouse model of endotoxic shock. Endotoxemia was induced through intraperitoneally LPS administration, nitric oxide (NO) and cytokines were assessed by Griess method and ELISA, respectively. Treatment of BALB/c mice with BA at 67 mg/kg caused a 100% survival against a lethal dose of lipopolysaccharide (LPS). BA treatment caused a reduction in TNF-α production induced by LPS but did not alter IL-6 production. Moreover, BA treatment increased significantly the serum levels of IL-10 compared to vehicle-treated, LPS-challenged mice. To investigate the role of IL-10 in BA-induced protection, wild-type and IL-10(-/-) mice were studied. In contrast to the observations in IL-10(+/+) mice, BA did not protect IL-10(-/-) mice against a lethal LPS challenge. Addition of BA inhibited the production of pro-inflammatory mediators by macrophages stimulated with LPS, while promoting a significant increase in IL-10 production. BA-treated peritoneal exudate macrophages produced lower concentrations of TNF-α and NO and higher concentrations of IL-10 upon LPS stimulation. Similarly, macrophages obtained from BA-treated mice produced less pro-inflammatory mediators and increased IL-10 when compared to non-stimulated macrophages obtained from vehicle-treated mice. In conclusion, we have shown that BA has a potent anti-inflammatory activity in vivo, protecting mice against LPS by modulating TNF-α production by macrophages in vivo through a mechanism dependent on IL-10.

The protective effect of betulinic acid on microvascular responsivity and protein expression in alzheimer disease induced by cerebral micro‐injection of beta‐amyloid and streptozotocin

“…For more explanation, in the context of dementia, the bypassing of Aβ oligomers possibly allows this triterpenoid to limit cell death susceptibility via inhibition of glial cell activation or ROS generation . The potent anti‐inflammatory function of BA (or its derivatives) also specifies its importance on immune‐dependent diseases such as lethal endotoxemia (or Autoimmune Encephalomyelitis) that trigger the levels of TNF‐alpha (increased trend) or IL‐10 (decreased trend) . Many papers are in accordance with the current data and clearly describe a significant increase in TNF‐alpha in the serum or hippocampi in dementia, while quantified IL‐10 levels only represent inconclusive data; although a high expression of hippocampal IL‐10 in AD transgenic mice could demonstrate a potent compensatory mechanism in the immune feedback .…”

Protective Action of Betulinic Acid on Cerebral Ischemia/Reperfusion Injury through Inflammation and Energy Metabolic Homeostasis

“…BA inhibits the activation of inflammation and regulates the expression of TNF-α and other inflammatory factors from myocardial and renal ischemia/reperfusion injury [10,11]. In addition, BA exhibits mild anti-inflammatory effects, thereby inhibiting the inflammation of mice induced with carrageenan, phorbol, and bryostatin-1, but showing no inhibitory effect toward arachidonic acid-induced inflammation and neurogenic inflammation models [38,39]. Isoflurane-induced brain neuron injuries in rats were shown to be improved by BA in that oxygen electrodes and ultraviolet spectrophotometer demonstrated that mitochondrial respiratory levels and intracellular ATP contents improved after treatment [40].…”

Ursolic Acid and Its Derivatives as Bioactive Agents

“…The inflammatory response is initiated after harm and/or microbial invasion to recover homeostatic tissue balance between composition and physiological function. Persistent inflammation may lead to damage of tissues, resulting in non-functioning organs [93]. Inflammation is a complicated occurrence linked to the development of different diseases, such as cardiovascular and neurodegenerative diseases, and cancer [55].…”