Title: Pharmacological characterization of the neurotrophic sesquiterpene jiadifenolide reveals a non-convulsant signature and potential for progression in neurodegenerative disease studies

Abstract

The ‘neurotrophic sesquiterpenes’ refer to a group of molecules derived from the Illicium genus of flowering plant. They display neurotrophic effects in cultured neuron preparations and have been suggested to be cognitive enhancers and potential therapeutics for neurodegenerative disorders and dementias. Recent synthetic advances generated sufficient quantities of jiadifenolide for in vivo investigation into its biological effects. Jiadifenolide did not induce convulsions in mice nor did it enhance or diminish convulsions induced by pentylenetetrazole. Other negative allosteric modulators of GABA_A receptors, picrotoxin, tetramethylenedisulfotetramine (TETS), and bilobalide all induced convulsions. Either i.p. or i.c.v. dosing generated micromolar plasma and brain levels of jiadifenolide but only small effects on locomotion of mice. However, jiadifenolide decreased d-amphetamine-induced hyperlocomotion in mice, an antipsychotic-like drug effect. Jiadifenolide did not significantly alter body temperature or behavior in the forced-swim test in mice. Molecular simulation data suggested a potential site in the pore/M2 helix region that is at an overlapping, yet lower position than those observed for other ‘cage convulsant’ compounds such as TETS and picrotoxin. We hypothesize here that a position nearer to the entrance of the pore channel may allow for easier displacement of jiadifenolide from its blocking location leading to lower potency and lowermore » side-effect liability. Like jiadifenolide, memantine (Namenda), one of the few drugs used in the symptomatic treatment of dementias, occupies a unique site on the NMDA receptor complex that creates low binding affinity that is associated with its reduced side-effect profile. Given the potential therapeutic applications of jiadifenolide and its relatively inert effects on overt behavior, the possibility of clinical utility for jiadifenolide and related compounds becomes intriguing.« less

Authors:

Witkin, Jeffrey M. ^[1]; Shenvi, Ryan A. ^[2]; Li, Xia ^[1]; Gleason, Scott D. ^[1]; Weiss, Julie ^[1]; Morrow, Denise ^[1]; Catow, John T. ^[1]; Wakulchik, Mark ^[1]; Ohtawa, Masaki ^[2]; Lu, Hai-Hua ^[2]; Martinez, Michael D. ^[2]; Schkeryantz, Jeffrey M. ^[1]; Carpenter, Timothy S. ^[3]; Lightstone, Felice C. ^[3]; Cerne, Rok ^[1]

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+ Show Author Affiliations

1. Eli Lilly and Company, Indianapolis, IN (United States). The Lilly Research Labs
2. Scripps Research Inst., La Jolla, CA (United States). Dept. of Chemistry
3. Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Biosciences and Biotechnology Division

Publication Date:

Fri Jun 22 00:00:00 EDT 2018

Research Org.:

Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States); Eli Lilly and Company, Indianapolis, IN (United States)

Sponsoring Org.:

USDOE; National Inst. of Health (NIH) (United States)

OSTI Identifier:

1515334

Alternate Identifier(s):

OSTI ID: 1582855

Report Number(s):

LLNL-JRNL-746138
Journal ID: ISSN 0006-2952; 930585

Grant/Contract Number:  

AC52-07NA27344; R35 GM122606; LLNL-JRNL-746138

Resource Type:

Accepted Manuscript

Journal Name:

Biochemical Pharmacology

Additional Journal Information:

Journal Volume: 155; Journal ID: ISSN 0006-2952

Publisher:

Elsevier

Country of Publication:

United States

Language:

English

Subject:

59 BASIC BIOLOGICAL SCIENCES; jiadifenolide; bilobalide; neurotrophic; neurodegenerative disorders; convulsions