Analgesic and anti-inflammatory activity of diterpenoid alkaloids isolated from the Central Asian species of Aconitum and Delphinium plants

In different countries of Europe, Asia and America the plants containing diterpenoid alkaloids have been used on the folk medicine from ancient time. Aconitum and Delphinium plants (Ranunculaceae family) and their extracts are used in the Eastern medicine at present as antirheumatic, analgesic, anti-inflammatory and other remedies. More 50 species of Aconitum (300 worlwide) and 100 species of Delphinium (450 worldwide) grow on the territory of Former Soviet Union countries, including Russia, Central Asia and Kazakhstan. We investigated antinociceptive and anti-inflammatory activity of individual diterpenoid alkaloids isolated from Aconitum and Delphinium species widespread in the Central Asia and revealed 25 promising substances. Antinociceptive activity was investigated in the conventional tests for displaying analgesics with central mechanisms of analgesia (hot plate) and peripheral mechanisms (acetic writhing, local anesthesia). Anti-inflammatory activity was studied in rat formalin test. By comparison of antinociceptive activity of investigated alkaloids and underly mechanisms of their pharmacological action we divided them on the following types: activators of potential-gated Na+-channels of neurons cause shifting of the threshold of Na+-current towards membrane hyperpolarization and destroy neuronal conductivity; blockers of potential-gated Na+-channels cause inhibition of the fast intake Na+-current without changing of its activation threshold; blockers of N-cholinoreceptors.

In different countries of Europe, Asia and America the plants containing diterpenoid alkaloids have been used on the folk medicine from ancient time.
Aconitum and Delphinium plants (Ranunculaceae family) and their extracts are used in the Eastern medicine at present as antirheumatic, analgesic, anti-inflammatory and other remedies.
More 50 species of Aconitum (300 worlwide) and 100 species of Delphinium (450 worldwide) grow on the territory of Former Soviet Union countries, including Russia, Central Asia and Kazakhstan.Totally 700 diterpenoid alkaloids have been isolated from plants over the world.

Rabbit eye corneal anesthesia
Analgesic activity of the most promising diterpenoid alkaloids in acetic writhing test (mice)  It may be concluded that the antinociceptive (analgesic and local anesthetic) activity of the investigated diterpenoid alkaloids is based on braking of impulse conductivity on different stages of passing through nociceptive pathways.Analyzing of electrophysiological mechanisms of promising substances shown that the sodium channels of central and peripheral neurons are their main target sites.The investigated substances may be divided on following types: -Activators of voltage-gated Na + -channels altering selectivity of ion pore due to binding to site 2 of Na + -channel.They induce a neuronal block by permanent cell hyperpolarization; -Blockers of neuronal voltage-gated Na + -channels by interacting to BTXsensitive site.They inhibit the fast inward Na + -current by ion pore bridging; -Blockers of ligand-gated Na + -channels (N-acetylcholinoblockers) that destroy cholinergic transmission and downstream Na + -current.They selectively interact to nAChRs.
Comparison of analgesic, anti-inflammatory, local anesthetic, N-cholinoblocking* and antiarrhythmic ** activity of studied diterpenoid alkaloids doesn't display a direct correlation.Presence of one type of studied pharmacological effects not indicated presence of other ones.It may be supposed that the realization of the abovementioned types of pharmacological activity involve modulation of different types of sodium channels, and the investigated diterpenoid alkaloids have different affinity to these channels.Thus, it was revealed that TTX-sensitive Na v 1.5 being localized in cardial myocytes and skeletal muscles is a target of antiarrhythmic drugs action.The main site of local anesthetics action is Na v 1.7 distributed in central and peripheral neurons.Realization of the said pharmacological effects depends on inhibition of the fast intake sodium current.
Analgesic activity realization is attributed to interaction of a ligand to slow inactivated TTXresistant sodium channels Na v 1.8 and Na v 1.9, as well as TTX-sensitive Na v 1.6.It is supposed that Na v 1.8 and Na v 1.9 in DRG neurons may be modulated by mediators of inflammation (prostaglandins, serotonin)*** in hyperalgesia caused by inflammation.
The item of studied diterpenoid alkaloids interaction to different sodium channel types needs a deep investigation in future.

activity and toxicology of these diterpenoid alkaloids (including analgesic and anti-inflammatory activity) has been investigated in the Department of Pharmacology and Toxicology, ICPS. by nature of substituents:
Chemical composition of 32 species of Aconitum and 20 species of Delphinium growing in the Former Soviet Union countries has been studied in the Laboratory of Alkaloid Chemistry (Institute of the Chemistry of Plant Substances, ICPS, Uzbekistan).