In Vivo Profiling of a Natural Alkaloid, Anatabine, in Rodents: Pharmacokinetics and Anti-Inflammatory Efficacy

Abstract

Natural alkaloids, a large class of plant-derived substances, have attracted considerable interest because of their pharmacological activities. In this study, the in vivo pharmacokinetics and anti-inflammatory profile of anatabine, a naturally occurring alkaloid, were characterized in rodents. Anatabine was found to be bioavailable and brain-penetrant following systemic administration. Following intraperitoneal (i.p.) administration (1, 2, and 5 mg/kg), anatabine caused a dosedependent reduction in carrageenan-induced paw edema in rats; in mice, it inhibited the production of pro-inflammatory cytokines and simultaneously elevated the levels of an anti-inflammatory cytokine in a dose-dependent manner 2 h after lipopolysaccharide challenge. Furthermore, anatabine (∼10 and ∼20 mg/kg/day for 4 weeks; inhalation exposure) had effects in a murine model of multiple sclerosis, reducing neurological deficits and bodyweight loss. Comparative studies of the pharmacokinetics and anti-inflammatory activity of anatabine demonstrated its bioequivalence in rats following i.p. administration and inhalation exposure. This study not only provides the first detailed profile of anatabine pharmacokinetics in rodents but also comprehensively characterizes the anti-inflammatory activities of anatabine in acute and chronic inflammatory models. These findings provide a basis for further characterizing and optimizing the anti-inflammatory properties of anatabine.

Systems biology reveals anatabine to be an NRF2 activator

“…Over the last decade, anatabine has been shown to alleviate inflammation in multiple disease models ( Paris et al, 2013b ; Ruiz Castro et al, 2020 ; Xia et al, 2021 ). However, the molecular mechanisms triggered by anatabine in a non-inflammatory state are yet to be explored.…”

“…During this period, an open-label case series showed that a facial cream containing anatabine could improve the appearance of skin in patients with mild to moderate rosacea ( Lanier et al, 2013a ), while an internet-based survey study provided evidence that anatabine supplementation could improve chronic joint pain disorders ( Lanier et al, 2013b ). More recently, anatabine has been shown to ameliorate intestinal inflammation in mice ( Ruiz Castro et al, 2020 ), inhibit acute and chronic inflammation in mice in a dose-dependent manner ( Xia et al, 2021 ), and improve the outcomes of repetitive mild traumatic brain injury in mice upon a 3-month delayed treatment ( Morin et al, 2021 ).…”

“…At the molecular level, anatabine inhibits the activity of two transcription factors that are involved in cellular inflammatory response—NF-κB (nuclear factor-kappa B) and STAT3 (signal transducer and activator of transcription 3)—both in vivo ( Paris et al, 2013a ; Paris et al, 2013b ) and in vitro ( Paris et al, 2011 ; Paris et al, 2013a ). In addition, it decreases lipopolysaccharide (LPS)-induced TNFα (tumor necrosis factor α) and IL-6 (interleukin 6) levels in a dose-dependent manner while increasing the levels of the anti-inflammatory cytokine IL-10 in vivo ( Xia et al, 2021 ).…”

Tobacco Alkaloid Assessment in a DSS-Induced Colitis Mouse Model with a Fully Humanized Immune System

“…The biological activity of anatabine has been poorly characterized compared with nicotine, but recent publications have shown anatabine-dependent inhibition of pro-inflammatory gene expression induced by lipopolysaccharide in SY-SY5Y, HEK293, human microglia, and human blood mononuclear cells, as well as in the brain and spleen of mouse models of autoimmune encephalomyelitis and Alzheimer’s disease [ 29 , 30 ]. Finally, we have demonstrated potential anatabine-dependent, anti-inflammatory properties in both in vitro and in vivo models of intestinal inflammation [ 15 , 31 , 32 , 33 ].…”