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.

Microglia-mediated neuroinflammation is one of the key mechanisms involved in acute brain injury and chronic neurodegeneration. This study investigated the inhibitory effects of 2-hydroxy-4-methylbenzoic anhydride (HMA), a novel synthetic derivative of HTB (3-hydroxy-4-trifluoromethylbenzoic acid) on neuroinflammation and underlying mechanisms in activated microglia in vitro and an in vivo mouse model of Parkinson’s disease (PD). In vitro studies revealed that HMA significantly inhibited lipopolysaccharide (LPS)-stimulated excessive release of nitric oxide (NO) in a concentration dependent manner. In addition, HMA significantly suppressed both inducible NO synthase and cyclooxygenase-2 (COX-2) at the mRNA and protein levels in LPS-stimulated BV-2 microglia cells. Moreover, HMA significantly inhibited the proinflammatory cytokines such as interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha in LPS-stimulated BV-2 microglial cells. Furthermore, mechanistic studies ensured that the potent anti-neuroinflammatory effects of HMA (0.1, 1.0, and 10 μM) were mediated by phosphorylation of nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor, alpha (IκBα) in LPS-stimulated BV-2 cells. In vivo evaluations revealed that intraperitoneal administration of potent neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg, four times a 1 day) in mice resulted in activation of microglia in the brain in association with severe behavioral deficits as assessed using a pole test. However, prevention of microglial activation and attenuation of Parkinson’s disease (PD)-like behavioral changes was obtained by oral administration of HMA (30 mg/kg) for 14 days. Considering the overall results, our study showed that HMA exhibited strong anti-neuroinflammatory effects at lower concentrations than its parent compound. Further work is warranted in other animal and genetic models of PD for evaluating the efficacy of HMA to develop a potential therapeutic agent in the treatment of microglia-mediated neuroinflammatory disorders, including PD.

Inflammation-induced placental dysfunction is a major contributor to pregnancy complications. Activation of NF-κB and NLRP3 inflammasome pathways in the placenta is a key driver of this pathology. Decursinol, a natural coumarin derivative from Angelica gigas, possesses anti-inflammatory properties; however, its effect on placental inflammation remains unclear. Therefore, in this study, we investigated the protective effects of decursinol against lipopolysaccharide (LPS)-induced placental inflammation and trophoblast dysfunction and explored the underlying molecular mechanisms. Decursinol significantly inhibited LPS-induced NLRP3 inflammasome activation and NF-κB/p65 signaling in Sw.71 human trophoblast cells, reducing interleukin-1β secretion and pro-inflammatory gene expression. It restored the trophoblast invasive capacity and preserved mesenchymal marker expression suppressed by LPS. It also improved the fetal and placental weights, restored the placental architecture, and attenuated placental NLRP3 inflammasome activation and cytokine expression in vivo. Mechanistically, decursinol preserved the mitochondrial homeostasis, reduced mitochondrial reactive oxygen species levels, and upregulated antioxidants and mitochondrial biogenesis-related gene levels, exerting effects comparable to those of mitochondria-targeted antioxidant Mito-TEMPO. These findings suggest that decursinol protects against LPS-induced trophoblast dysfunction and adverse pregnancy outcomes by preserving mitochondrial functions and suppressing NLRP3/NF-κB-mediated inflammation. Overall, our results highlight decursinol as a promising therapeutic candidate for inflammation-associated pregnancy complications.