Analgesic and neuropsychological effects of Echinacea N-alkylamides
Echinacea purpurea and E. angustifolia preparations are widely used to treat symptoms of upper respiratory infections, such as those occuring during common cold. The lipophilic N-alkylamides potently activate the human cannabinoid CB2 receptor and lead to anti-inflammatory effects [1,2]. Since the CB2 receptor is also expressed in the CNS, we have investigated the effects of inhaled Echinacea N-alkylamides in a human pilot study using a placebo-controlled randomized crossover design. Results from neuropsychological AVLT and CANTAB test batteries show that the inhaled N-alkylamides decrease reaction time and motor coordination. Animal studies of the major Echinacea N-alkylamide dodeca-2E,4E-dienoic acid isobutylamide (A2) (10mg/Kg i.p.) reveal that this compound is centrally active and results in reduced motility, catalepsy, and significant analgesia. Since the analgesic effects were independent of the CB2 receptor we tested other potential targets relevant to pain. Intriguingly, A2 was found to interfere with voltage-gated sodium channels with a selectivity towards Nav1.8. At 1µM, A2 shifts the steadystate activation gating kinetics significantly to more positive potentials. Given the physiological voltage range in which Nav1.8 is active, this means that such a shift equals an apparent block of Na current in the range of -40 to approx. 0 or +10 mV.
These results provide the first evidence of the analgesic effects exerted by Echinacea N-alkylamides and clearly indicate that A2 modulates neurophysiological processes. Moreover, in addition to the CB2 receptor we show for the first time that the voltage-gated sodium channels are a pharmacological target of Echinacea N-alkylamides.
References: 1. Gertsch, J. (2008). Immunomodulatory Lipids in Plants: Plant Fatty Acid Amides and the Human Endocannabinoid System. Planta Medica, Feb 14, ahead of print. 2. Raduner, S. et al. (2006) Alkylamides from Echinacea are a new class of cannabinomimetics. Cannabinoid type 2 receptor-dependent and -independent immunomodulatory effects. J. Biol. Chem. 281:14192–206.