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Dihydrokavain

Marindinin

Dihydrokavain is one of the six major kavalactones found in the kava plant. It showed the highest systemic exposure among all six major kavalactones tested, indicating it may play a central role in kava's pharmacological effects in humans. The anxiolytic effects of kava are primarily attributed to dihydrokavain.

In animal models, such as socially isolated chicks, dihydrokavain reduces anxiety-related distress without causing the sedation typically seen with standard anxiolytic drugs. Beyond its anxiolytic properties, dihydrokavain has demonstrated anti-inflammatory and analgesic effects, including inhibition of cyclooxygenase (COX) enzymes and suppression of tumor necrosis factor alpha (TNFα). It also shows potential anti-diabetic activity by activating AMP-activated protein kinase (AMPK) signaling and improving glycemic control in Drosophila models. Additionally, dihydrokavain inhibits several cytochrome P450 enzymes, indicating a potential for drug interactions, and shares structural similarities with strobilurins, contributing to mild fungicidal activity.

Pharmacology

Kava extract reduces anxiety-related distress in chicks mainly due to its dihydrokavain content, which provides anxiolytic effects without the sedation caused by standard drugs like chlordiazepoxide. Dihydrokavain showed the highest systemic exposure among all six major kavalactones tested, indicating it may play a central role in kava's pharmacological effects in humans. Additionally, intraperitoneal administration of dihydrokavain (150 mg/kg) in mice produced a significant analgesic effect.

Among the six major kavalactones, it showed the strongest inhibition of norepinephrine-induced calcium signaling in lung cancer cells by antagonizing β-adrenergic receptors, suggesting its potential role in kava's anxiolytic and cancer-preventive effects.

Dihydrokavain has been shown to inhibit cyclooxygenase enzymes, reducing COX-1 activity by approximately 58% and COX-2 by 28%, suggesting potential anti-inflammatory effects. It also reduces TNFα secretion in lipopolysaccharide-stimulated THP-1 cells (a human acute monocytic leukemia-derived cell line) at a concentration of 50 μg/mL.

In vitro studies show that dihydrokavain inhibits the cytochrome P450 enzymes CYP2C9 (IC50 = 130.95 μM), CYP2C19 (IC50 = 10.05 μM), and CYP3A4 (IC50 = 78.59 μM), indicating potential drug interaction risks.

Dihydrokavain bears some structural similarity to the strobilurins and has some fungicidal activity.

An analogue of the molecule, 56DHK, is a compound in Alpinia mutica and improves hyperglycemia in a diabetic Drosophila model by activating AMP-activated protein kinase (AMPK) signaling and modulating related metabolic genes, showing potential as a novel anti-diabetic agent.

References

References

  1. Malani, Joji. (2002-12-03). "Evaluation of the effects of Kava on the Liver". Fiji School of Medicine.
  2. Feltenstein, MW. (March 2003). "Anxiolytic properties of Piper methysticum extract samples and fractions in the chick social-separation-stress procedure.". Phytotherapy Research.
  3. (28 October 2022). "Clinical pharmacokinetics of kavalactones after oral dosing of standardized kava extract in healthy volunteers". Journal of Ethnopharmacology.
  4. (1990). "Non-surgical treatment of critical limb ischaemia". European Journal of Vascular Surgery.
  5. (2020). "Kava and its Kavalactones Inhibit Norepinephrine-induced Intracellular Calcium Influx in Lung Cancer Cells". Planta Medica.
  6. (2012). "A novel strategy for encapsulating poorly soluble drug into nanostructured lipid carriers for intravenous administration". Pharmaceutical Development and Technology.
  7. (2020). "The study protocol: Neuroendocrinology and (Epi-) genetics of female reproductive transition phase mood disorder - an observational, longitudinal study from pregnancy to postpartum". BMC Pregnancy and Childbirth.
  8. (2004). "Morphological and functional changes induced by the amino acid analogue 3-nitrotyrosine in mouse neuroblastoma and rat glioma cell lines". Neuroscience Letters.
  9. (1998-06-30). "Natural compounds of the strobilurin series and their synthetic analogues as cell respiration inhibitors". [[Russian Chemical Reviews]].
  10. (2022). "5,6-dehydrokawain improves glycaemic control by modulating AMPK target genes in Drosophila with a high-sucrose diet-induced hyperglycaemia". Phytomedicine Plus.
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kavalactones anxiolytics gabaa-receptor-positive-allosteric-modulators monoamine-oxidase-inhibitors
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