3-n-Butylphthalide: a promising therapeutic drug for inflammatory disease

Introduction

3-n-Butylphthalide (NBP), a pure component extracted from Apium graveolens Linn, was approved by the China Food and Drug Administration in 2002 for treating ischemic stroke because of its protective effects against cerebral ischemia. The mechanism might be that NBP inhibits neuronal apoptosis by modulating the Akt/mTOR and GDNF/GFRAK1/Ret signalling pathways[1-2].

Notably, a recent randomized multicenter clinical trial has shown that NBP exerts a protective effect on vascular cognitive impairment. The underlying mechanism may be related to the multitargeted protective effects of NBP, such as the reduction of oxidative damage and inflammatory response, improvement of mitochondrial function, and inhibition of apoptosis. Moreover, another clinical trial has shown that NBP exerts beneficial effects on cognitive impairment induced by brain microcirculatory disorders and mitochondrial dysfunction in Alzheimer's disease (AD).

Metabolism

NBP is composed of optical isomers l-3-N-butylphthalide (l-NBP) isolated from seeds of Apium graveolens (Chinese celery), d-3-N-butylphthalide (d-NBP), and a synthesized compound, dl-3-N-butylphthalide (dl-NBP). NBP is oxidized by cytochrome P450 (P450) after oral administration. Moreover, hydroxylation of the n-butyl side chain and C-3 are involved in the primary metabolism process. Then, dl-NBP converts to four principal metabolites, including 10-keto-NBP (M2), 3-hydroxy-NBP (M3-1), 10-hydroxy-NBP (M3-2), and NBP-11-oic acid (M5-2), and finally is discharged mainly by the kidneys.

Mode of action

The utility of NBP, targeting the signal molecules concerning the response to immune and inflammation, can be a promising therapeutic drug for inflammatory and immune-mediated diseases[3].

The ways subsequently regulating immune cells are the following:

a. upregulating proinflammatory factors (TNF-α, lL-1β, IL-6, etc.); promoting macrophages/microglia to express a proinflammatory phenotype (M1) and prohibiting the expression of the anti-inflammatory phenotype (M2); regulating DC development, survival, and cytokine production; modulating B lymphocyte survival during their differentiation and in their activation; prohibiting induction of Treg and Th2; b. increasing proinflammatory mediators (TNF-α, PGE2, IL-1β, IL-1, IL-2, IL-3, IL-6 IL-8, IL-12, COX-2, etc.); regulating macrophage/microglia polarization; increasing apoptosis of immune cells; c. shifting macrophages/microglia toward M1 phenotype; modulating DC mature and immigration; regulating neutrophil extracellular trap formation and survival; differentiating and activating various T cells; reducing apoptosis of immune cells; d. downregulating proinflammatory molecules (COX-2, IL-1, etc.); accommodating T cell differentiation towards the anti-inflammatory phenotype; determining macrophage/microglia polarization; decreasing the production of ROS/NO; reducing autophagy, e. reducing apoptosis and prolonging immune cell survival time; promoting phagocytosis and macrophage/microglia polarization via inducing related regulators (TGF-β, IL-10, and BMP-7); f. driving macrophage/microglia shift to M2 phenotype; prohibiting activation of Th and TC; regulating the function of Treg.

References:

You may like