Harmane

Harmane is a β-carboline that has been found in P. harmala, as well as in cooked meats and tobacco and has diverse biological activities.^{1,2,3,4,5,6,7} It is an inhibitor of monoamine oxidase A (MAO-A; IC₅₀ = 0.5 µM) that also inhibits MAO-B (IC₅₀ = 5 µM).³ Harmane is an inverse agonist of GABA_A receptors with IC₅₀ values of 7.2 and 8.3 µM in radioligand binding assays using rat brain and bovine retina, respectively.⁴ It is a DNA intercalating agent that induces cell cycle arrest at the G₁ phase in NCI-H460 cells and the G₂ phase in T47D and HCT116 cells and induces apoptosis in HCT116 cells when used at a concentration of 50 µM.^1,5 However, it also has mutagenic and carcinogenic effects and induces the transcription of the aryl hydrocarbon receptor (AhR) target cytochrome P450 (CYP) isoform CYP1A1 in HepG2 cells when used at concentrations ranging from 1 to 50 µM.⁸ Harmane (2.5 mg/kg) prevents memory retrieval deficits induced by 24, but not 12 or 36, hours of REM sleep deprivation in mice in contextual and fear conditioning paradigms but inhibits memory consolidation when administered following training at doses of 5 and 10 mg/kg in one-trial passive-avoidance task.^6,7 Harmane is selectively neurotoxic to dopaminergic neurons in C. elegans and plasma levels of harmane are increased in patients with essential tremor and Parkinson’s disease.²

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1. Daoud, A., Song, J., Xiao, F., et al. B-9-3, a novel β-carboline derivative exhibits anti-cancer activity via induction of apoptosis and inhibition of cell migration in vitro. Eur. J. Pharmacol. 724, 219-230 (2014).

2. Sammi, S.R., Agim, Z.S., and Cannon, J.R. Harmane-induced selective dopaminergic neurotoxicity in Caenorhabditis elegans. Toxicol. Sci. 161(2), 335-348 (2018).

3. Glover, V., Liebowitz, J., Armando, I., et al. β-Carbolines as selective monoamine oxidase inhibitors: In vivo implications. J. Neural Transm. 54(3-4), 209-218 (1982).

4. Rommelspacher, H., Nanz, C., Borbe, H.O., et al. 1-Methyl-β-carboline (harmane), a potent endogenous inhibitor of benzodiazepine receptor binding. Naunyn Schmiedebergs Arch. Pharmacol. 314(1), 97-100 (1980).

5. Paul, B.K., and Guchhait, N. Exploring the strength, mode, dynamics, and kinetics of binding interaction of a cationic biological photosensitizer with DNA: Implication on dissociation of the drug-DNA complex via detergent sequestration. J. Phys. Chem. B 115(41), 11938-11949 (2011).

6. Nasehi, M., Shirkhodaei, A., Ebrahimi-Ghiri, M., et al. Abolishment of fear memory-disruptive effects REM sleep deprivation by harmane. Biomed. Pharmacother. 109, 1563-1568 (2019).

7. Nasehi, M., Piri, M., Nouri, M., et al. Involvement of dopamine D₁/D₂ receptors on harmane-induced amnesia in the step-down passive avoidance test. Eur. J. Pharmacol. 634(1-3), 77-83 (2010).

8. El Gendy, M.A., and El-Kadi, A.O.S. Harman induces CYP1A1 enzyme through an aryl hydrocarbon receptor mechanism. Toxicol. Appl. Pharmacol. 249(1), 55-64 (2010).