Phorbol Diesters and 12-Deoxy-16-hydroxyphorbol 13,16-Diesters Induce TGFα Release and Adult Mouse Neurogenesis

Abstract

A small library of phorbol 12,13-diesters bearing low lipophilicity ester chains was prepared as potential neurogenic agents in the adult brain. They were also used in a targeted UHPLC–HRMS screening of the latex of Euphorbia resinifera. Two new 12-deoxy-16-hydroxyphorbol 13,16-diesters were isolated, and their structures were deduced using two-dimensional NMR spectroscopy and NOE experiments. The ability of natural and synthetic compounds to stimulate transforming growth factor alpha (TFGα) release, to increase neural progenitor cell proliferation, and to stimulate neurogenesis was evaluated. All compounds that facilitated TGFα release promoted neural progenitor cell proliferation. The presence of two acyloxy moieties on the tigliane skeleton led to higher levels of activity, which decreased when a free hydroxyl group was at C-12. Remarkably, the compound bearing isobutyryloxy groups was the most potent on the TGFα assay and at inducing neural progenitor cell proliferation in vitro, also leading to enhanced neurogenesis in vivo when administered intranasally to mice.

Rescue of neurogenesis and age-associated cognitive decline in SAMP8 mouse: role of transforming growth factor alpha

“…In general, sample size used in statistical analysis were n = 6-10 for in vivo experiments, n = 5-9 for in vitro experiments and n = 9-12 in behavioral tests. Sample sizes were chosen based on previous works related to this one (Carrasco et al, 2014;Dominguez-Garcia et al, 2021;Geribaldi-Doldan et al, 2018;Murillo-Carretero et al, 2017;Rabaneda et al, 2016).…”

“…Isolation and purification of the 12-deoxyphorbol 13-isobutyrate also referred to as DPB (Ezzanad et al, 2021) or ER272 (Dominguez-Garcia et al, 2021;Geribaldi-Doldan et al, 2015) (CAS:25090-74-8) was performed in our laboratory as described in supplementary methods of Geribaldi-Doldan et al (Geribaldi-Doldan et al, 2015). PKC inhibitors were purchased from Sigma-Aldrich (St. Louis, MO) and Calbiochem (Millipore, Billerica, MA).…”

“…Confocal imaging was taken every 1.50 μm in the Z-plane using 20X objective. Cell density was calculated for each section relative to the DG volume (mm 3 ) and averaged for each animal as reported previously (Dominguez-Garcia et al, 2021).…”

Targeting transforming growth factor alpha to recruit newly generated neuroblasts in cortical brain injuries

“…Confocal imaging was taken every 2 µm in the Z-plane using 20X, 40X, or 63X objectives. Cell density was calculated for each section relative to the SVZ volume (mm 3 ) and averaged for each animal as reported previously 40 . Both SVZ quanti cation was performed using the ImageJ software.…”

Euphorbiaditerpenoids: isolation, structure, bioactivity, biosynthesis, and synthesis (2013–2021)

“…An SAR study revealed that the presence of two acyloxy groups, especially isobutyryloxy, played a vital role for activity. 263 3,12-Di- O -acetyl-8- O -tigloilingol ( K43 ), a lathyrane diterpenoid, could also activate PKCβ and significantly increase postnatal NPC proliferation in vitro , particularly in synergy with neurogenic-niche factor FGF2. 327 A cyclomyrsinol diterpenoid ( 893 ) from E. Sogdiana reduced anxiety and depression-like behavior in experimental autoimmune encephalomyelitis (EAE)-induced C57BL/6 mice.…”