The Natural Flavonoid Pinocembrin: Molecular Targets and Potential Therapeutic Applications

Abstract

Pinocembrin is a natural flavonoid compound extracted from honey, propolis, ginger roots, wild marjoram, and other plants. In preclinical studies, it has shown anti-inflammatory and neuroprotective effects as well as the ability to reduce reactive oxygen species, protect the blood-brain barrier, modulate mitochondrial function, and regulate apoptosis. Considering these pharmaceutical characteristics, pinocembrin has potential as a drug to treat ischemic stroke and other clinical conditions. In this review, we summarize its pharmacologic characteristics and discuss its mechanisms of action and potential therapeutic applications.

Keywords: Neuroinflammation; Neuroprotection; Pinocembrin; Stroke.

Figure 1

Chemical structure of pinocembrin.

Figure 2

Potential therapeutic applications of pinocembrin. In the central nervous system (CNS), pinocembrin is a drug candidate for ischemic stroke, but it also exerts protection against Alzheimer’s disease (AD) and Parkinson’s disease (PD). Pinocembrin has been shown to exert anti-inflammatory and anti-infectious effects (including against bacterial and fungal infections), indicating that it might be useful for treating post-stroke infections. In addition, pinocembrin might have potential application in the treatment of hemorrhagic stroke. In the circulatory system, pinocembrin reduces atherosclerosis (AS) symptoms in animals when combined with simvastatin.

Figure 3

Main mechanisms of pinocembrin. Clockwise from top: Based on their multiple protective properties, high levels of epoxyeicosatrienoic acids (EETs) released from astrocytes could modulate microglial, neuronal, and oligodendrocyte activity to benefit the injured brain. However, EETs can be metabolized by sEH into less-active dihydroxyeicosatrienoic acids (DHETs). Pinocembrin might inhibit sEH expression/activity and thereby increase EET level in the brain. The effects of pinocembrin on the activity/function of different cell types (neurons, astrocytes, microglia, or oligodendrocytes) and the role of sEH in these cells or cell-cell interactions needs further study. To modulate mitochondrial function, pinocembrin reduces endoplasmic reticulum stress via C/EBP homologous protein (CHOP) and caspase-12, and decreases apoptosis of neurons by suppressing caspase-3 expression/activity. Pinocembrin decreases oxidation, as evidenced by the inhibition of superoxide dismutase (SOD), malondialdehyde (MDA), myeloperoxidase (MPO), and reactive oxygen species (ROS). Pinocembrin decreases expression of the receptor for advanced glycation end products (RAGE) and regulates its downstream targets, including NF-κB and MAPK pathways, to exert an anti-inflammatory effect in macrophages. In the circulatory system, pinocembrin inhibits vasoconstriction via extracellular-signal-related kinase (ERK), Rho-activated kinases (ROCK), and PI3K pathways.