Modulation of airway neural control by cathinone, the active constituent of Khat (Catha edulis): potential beneficial role in asthma

Véronique C. Freund-Michel1, Mark A. Birrell1, Hema J. Patel1, Iain M. Murray-Lyon2, Maria G. Belvisi1
1Imperial College London, London, United Kingdom, 2The London Clinic, London, United Kingdom

Catha edulis is an evergreen shrub growing along the Eastern coast of Africa and in the Arabian Peninsula. Fresh Khat leaves are customarily chewed in these countries because of their stimulant properties, mainly due to cathinone, acting in the central nervous system through an increase in the release of catecholamines. In these countries, infusion of Khat leaves is considered to be a herbal remedy for asthma and other airway diseases, but the precise mechanism of action has never been investigated. In this work, we have hypothesised that cathinone may have a beneficial effect in airway diseases by acting on the neural control of the airways.

The effect of cathinone (10-6 to 3x10-5M) was studied on guinea pig (male Dunkin Hartley, 300-500g) or human tracheal airway smooth muscle strips (human donor tissues, Transplant program, surplus to clinical requirement) contracted by the cholinergic agonists carbachol (10-5M) or acetylcholine (ACh, 10-9 to 10-2M), or by electrical field stimulation (EFS, 4Hz, 0.5ms pulse width, 15s every 4min). In concentration response studies, cathinone had neither contractile nor relaxant activity per se, but concentration-dependently inhibited EFS-induced contractions of either guinea pig or human airway smooth muscle, with maximal inhibition at 10-5M (guinea-pig (n=6): 45±3%, human (n=4): 38±6%, both p<0.01). Cathinone (10-5M) did not affect exogenous ACh-induced contractions of guinea pig airway smooth muscle, but significantly inhibited the EFS-induced release of ACh from parasympathetic nerves innervating the guinea pig trachea (27±5% inhibition, n=4, p<0.05), indicating a presynaptic mechanism of action. Since affinity studies showed only 5-HT7 and α2 adrenergic receptors able to bind cathinone (Rothman et al., 2003), and since activation of these presynaptic receptors has been shown previously to inhibit ACh release from tracheal parasympathetic nerves, the effect of cathinone was investigated in presence of the 5-HT7 antagonist SB269970 (SB) and/or the α2 antagonist yohimbine (Yohimb) (both at 10-5M, Sigma-Aldrich). The effect of cathinone (10-5M) was partially reversed in both guinea pig (n=6) and human smooth muscle strips (n=4) either by SB (43±3 and 57±2% inhibition respectively, p<0.05 for both) or yohimb (26±3 and 43±2% inhibition respectively, p<0.05 for both), and further inhibited with a combination of these antagonists (p<0.001 for both) (Figure 1).

In conclusion, cathinone is able to modulate cholinergic contractions of the trachea by inhibiting ACh release, through activation of both presynaptic α2 adrenergic and 5-HT7 receptors. Cathinone may therefore have a beneficial role in airway diseases especially in conditions of heightened vagal tone (e.g. nocturnal asthma or COPD).

Rothman et al. (2003) Journal of Pharmacology and Experimental Therapeutics, 307, p138-145