Actions of octocoral and tobacco cembranoids on nicotinic receptors.
Nicotinic acetylcholine receptors (AChRs) are pentameric proteins that form agonist-gated cation channels through the plasma membrane. AChR agonists and antagonists are potential candidates for the treatment of neurodegenerative diseases. Cembranoids are naturally occurring diterpenoids that contain a 14-carbon ring. These diterpenoids interact with AChRs in complex ways: as irreversible inhibitors at the agonist sites, as noncompetitive inhibitors, or as positive modulators, but no cembranoid was ever shown to have agonistic activity on AChRs. The cembranoid eupalmerin acetate displays positive modulation of agonist-induced currents in the muscle-type AChR and in the related gamma-aminobutyric acid (GABA) type A receptor. Moreover, cembranoids display important biological effects, many of them mediated by nicotinic receptors. Cembranoids from tobacco are neuroprotective through a nicotinic anti-apoptotic mechanism preventing excitotoxic neuronal death which in part could result from anti-inflammatory properties of cembranoids. Moreover, tobacco cembranoids also have anti-inflammatory properties which could enhance their neuroprotective properties. Cembranoids from tobacco affect nicotine-related behavior: they increase the transient initial ataxia caused by first nicotine injection into naive rats and inhibit the expression of locomotor sensitization to repeated injections of nicotine. In addition, cembranoids are known to act as anti-tumor compounds. In conclusion, cembranoids provide a promising source of lead drugs for many clinical areas, including neuroprotection, smoking-cessation, and anti-cancer therapies.
Ferchmin
P A
PA
Department of Biochemistry, Universidad Central del Caribe, Bayamon, PR, USA.
Pagán
Oné R
OR
Ulrich
Henning
H
Szeto
Ada C
AC
Hann
Richard M
RM
Eterović
Vesna A
VA
D000818:Animals; D037421:Anthozoa / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D004224:Diterpenes / Q000378:metabolism / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D014026:Nicotiana
D000970:Antineoplastic Agents; D004224:Diterpenes; D018696:Neuroprotective Agents; D011978:Receptors, Nicotinic; C037071:cembrane