Piperine and Its Metabolite's Pharmacology in Neurodegenerative and Neurological Diseases

Abstract

Piperine (PIP) is an active alkaloid of black and long peppers. An increasing amount of evidence is suggesting that PIP and its metabolite's could be a potential therapeutic to intervene different disease conditions including chronic inflammation, cardiac and hepatic diseases, neurodegenerative diseases, and cancer. In addition, the omnipresence of PIP in food and beverages made this compound an important investigational material. It has now become essential to understand PIP pharmacology and toxicology to determine its merits and demerits, especially its effect on the central nervous system (CNS). Although several earlier reports documented that PIP has poor pharmacokinetic properties, such as absorption, bioavailability, and blood-brain barrier permeability. However, its interaction with metabolic enzyme cytochrome P450 superfamily and competitive hydrophobic interaction at Monoamine oxide B (MAO-B) active site have made PIP both a xenobiotics bioenhancer and a potential MAO-B inhibitor. Moreover, recent advancements in pharmaceutical technology have overcome several of PIP's limitations, including bioavailability and blood-brain barrier permeability, even at low doses. Contrarily, the structure activity relationship (SAR) study of PIP suggesting that its several metabolites are reactive and plausibly responsible for acute toxicity or have pharmacological potentiality. Considering the importance of PIP and its metabolites as an emerging drug target, this study aims to combine the current knowledge of PIP pharmacology and biochemistry with neurodegenerative and neurological disease therapy.

Keywords: Alzheimer’s disease; Parkinson’s disease; biosynthesis; metabolites; piperine.

Figure 1

Possible biosynthesis pathway of PIP.

Figure 2

Possible biotransformation of PIP metabolites in hepatocyte. Based on Li Y et al. [28], 20 metabolites could be detected from PIP in the liver. Li and colleagues used hepatocytes of four different species (human, rat, mouse, and dog) and found that a few of these 20 metabolites could be detected in all species (C6, C9, C11, C12, C13, C14, C15, C19, and C20), but not all. C1–5, C7, and C17 were found to be present in both mouse and rat species, while C10, C16, and C18 were exclusively present in mouse. Metabolite C8 was observed only in rat hepatocyte. Other than common metabolites for all species, C7 in human and C2–5 in dog hepatocytes were observed.

Figure 3

The structure–activity relationship of PIP in MAO selectivity.

Figure 4

Prospective machinery of PIP in oxidative stress-induced neurodegenerative events. Oxidative stress arises from a decrease in endogenous antioxidant defense including HO-1, GSH, CAT, and Nrf2. This leads to a cascade of events including protein oxidation/glycation/mitochondrial damage, protein aggregation, and impaired autophagy/lysosome vacuoles. PIP is a potential antioxidant that could induce oxidative stress via promoting antioxidant defense, reducing ROS, and preserving mitochondrial integrity. On the other hand, Keap1 degradation and Nrf2 activation by PIP could counteract oxidative stress, reduce mitochondrial damage, promote autophagy by degrading/ubiquitination of p62/sequesterosome, promote autophagic flux by converting microtubule-associated protein 1A/1B-light chain 3 (LC3), promote mitophagy and mitobiogenesis via distinct pathway, and rescue from cellular apoptosis and degeneration [74].