Morphine-3-glucuronide

This study investigates the effects of traumatic brain injury (TBI) on the pharmacokinetics of morphine and its metabolite, morphine-3-glucuronide (M3G), and their influence on neuroinflammation and systemic inflammation. We hypothesized that disruptions in the blood-brain barrier (BBB) due to TBI would enhance M3G exposure to the brain, which could potentially trigger inflammatory responses. We implemented a rat model of controlled cortical impact (CCI) injury to assess systemic pharmacokinetics of morphine and M3G over 24 hours postintravenous bolus administration. To gain an understanding of relative levels in the brain, we measured the drug and metabolite concentrations in both brain tissue and plasma at the systemic maximum concentration, which occurred at 1 hour post-CCI. While this study was designed to conduct a thorough acute pharmacokinetic analysis, the design also afforded an early examination of potential pharmacodynamic effects. Markers of neuroinflammation and systemic inflammation were measured in plasma and cerebrospinal fluid at 24 hours post-CCI. Results showed a 2-fold increase in systemic M3G exposure and doubled concentrations of both morphine and M3G in the brain. Notably, only M3G demonstrated a significant increase in the brain/plasma ratio at 1 hour. Despite these pharmacokinetic changes following a single bolus, there were limited morphine-induced or M3G-induced increases in markers of neuroinflammation or systemic inflammation at 24 hour post-CCI. This study highlights that TBI significantly alters the pharmacokinetics of morphine and M3G, increasing their brain penetration without worsening acute inflammation. Future research will need to explore the implications of extended and repeated dosing on these pharmacokinetic and inflammatory outcomes after TBI. SIGNIFICANCE STATEMENT: To our knowledge, this is the first pharmacokinetic analysis of morphine and its metabolite morphine-3-glucuronide (M3G) following traumatic brain injury (TBI). This research provides the first evidence that morphine and M3G show increased systemic and brain concentrations following experimental TBI, with an acute rise in M3G's brain/plasma ratio. Although no exacerbation of acute TBI-induced inflammation was observed with either morphine or M3G, the impact of longer, more frequent dosing needs evaluation because its longer administration could exacerbate TBI's neuroinflammatory response.

Mitochondriogenesis refers to the process of creating and maintaining mitochondria, which plays an essential role in cellular metabolism. Mitochondrial processes such as energy generation, the response to oxidative stress, and cell death are all tightly regulated by enzymes. The flavonoid molecule malvidin-3-glucoside (M3G), which may be found in a wide variety of fruits and vegetables, has been shown to improve mitochondrial activity. However, the precise enzymes that mediate M3G’s effect on mitochondriogenesis are yet unknown.

Here, we used in silico molecular modeling tools to look at how enzymes contribute to mitochondriogenesis after M3G administration. We used computational methods to discover candidate target enzymes known to interact with M3G and play important roles in mitochondrial physiology. Molecular docking was conducted to measure the binding affinity and stability of the M3G-enzyme complexes. The found enzymes’ structural and functional features were analyzed using bioinformatics techniques, and the predicted functional implications of their interaction with M3G were formulated.

Our goal in doing these studies was to understand better how M3G regulates mitochondriogenesis by the action of altering SIRT-1, AMPK, and PGC-1α via M3G.

In sum, our findings provide light on the molecular pathways by which M3G influences mitochondriogenesis. Furthermore, experimental validation of the discovered enzymes and their interactions with M3G may aid in the development of therapeutic approaches to improve mitochondrial function and cellular health.