ELAC (3,12‐di‐<i>O</i>‐acetyl‐8‐<i>O</i>‐tigloilingol), a plant‐derived lathyrane diterpene, induces subventricular zone neural progenitor cell proliferation through PKCβ activation

Murillo‐Carretero, Maribel; Geribaldi-Doldán, Noelia; Flores-Giubi, María Eugenia; García-Bernal, Francisco; Quiroz, Elkin Navarro; Carrasco, Manuel; Macı́as-Sánchez, Antonio J.; Herrero-Foncubierta, Pilar; Delgado-Ariza, Antonio; Escolano, Cristina Verástegui; Domínguez-Riscart, Jesús; Daoubi, Mourad; Hernández-Galán, Rosario; Castro, Carmen

doi:10.1111/bph.13846

Cited by 24 publications

(62 citation statements)

References 65 publications

(94 reference statements)

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“…We have studied in here the neurogenic effect of a small molecule, the diterpene with lathyrane skeleton EOF2. Unlike other lathyranes, EOF2 does not promote proliferation of NPC 22 . However, we have demonstrated that it specifically facilitates novel PKC-mediated NRG1 release, without affecting TGFα release.…”

Section: Discussionmentioning

confidence: 79%

“…The lathyrane EOF2 (CAS number 2230806-06-9) was previously described by our group as a diterpene with no effect on NPC proliferation 22 . Since other diterpenes induced proliferation of NPC 24 via classical PKC activation 23 , we analyzed its capacity to activate PKC and to facilitate the generation of neurospheres.…”

Section: Resultsmentioning

confidence: 99%

“…S1 D), it exerted no change in the size of the neurospheres and a reduction in the number of neurospheres generated. Given its capacity to activate PKC without inducing proliferation, it was possible that EOF2 specifically activated novel PKC without affecting the classical isozymes-reported as responsible of the proliferative effect 22 .…”

Section: Resultsmentioning

confidence: 99%

“…Previous reports have demonstrated the role of individual PKC isozymes as mediators of different steps in the neurogenic process 27,28 , some of them highlighting the role of non-tumor promoting diterpenes as PKC activators that promote neurogenesis in neurogenic niches 22,29 . However, neurogenic signaling molecules behave differently depending on the niche.…”

Section: Targeting Neuregulin Release To Promote Neurogenesis In Injumentioning

confidence: 99%

“…We searched for a compound able to deliver neuregulins to the injured brain tissue. We chose to study the effect of EOF2 because of its lack of effect on stimulating NPC proliferation in a classical PKC dependent manner 22 and its similarity to other classical PKC activating compounds (supplementary fig. 8).…”

Section: Targeting Neuregulin Release To Promote Neurogenesis In Injumentioning

confidence: 99%

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A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

et al. 2020

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Neural stem cells are activated within neurogenic niches in response to brain injuries. This results in the production of neuroblasts, which unsuccessfully attempt to migrate toward the damaged tissue. Injuries constitute a gliogenic/nonneurogenic niche generated by the presence of anti-neurogenic signals, which impair neuronal differentiation and migration. Kinases of the protein kinase C (PKC) family mediate the release of growth factors that participate in different steps of the neurogenic process, particularly, novel PKC isozymes facilitate the release of the neurogenic growth factor neuregulin. We have demonstrated herein that a plant derived diterpene, (EOF2; CAS number 2230806-06-9), with the capacity to activate PKC facilitates the release of neuregulin 1, and promotes neuroblasts differentiation and survival in cultures of subventricular zone (SVZ) isolated cells in a novel PKC dependent manner. Local infusion of this compound in mechanical cortical injuries induces neuroblast enrichment within the perilesional area, and noninvasive intranasal administration of EOF2 promotes migration of neuroblasts from the SVZ towards the injury, allowing their survival and differentiation into mature neurons, being some of them cholinergic and GABAergic. Our results elucidate the mechanism of EOF2 promoting neurogenesis in injuries and highlight the role of novel PKC isozymes as targets in brain injury regeneration.

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Section: Discussionmentioning

confidence: 79%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Targeting Neuregulin Release To Promote Neurogenesis In Injumentioning

confidence: 99%

Section: Targeting Neuregulin Release To Promote Neurogenesis In Injumentioning

confidence: 99%

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A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

et al. 2020

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Identification of protein kinase C beta as a therapeutic target for neuroendocrine prostate cancer and development of a nanoparticle-based therapeutic strategy

Qie

Cheng

et al. 2023

Nano Today

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

et al. 2021

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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.

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ELAC (3,12‐di‐O‐acetyl‐8‐O‐tigloilingol), a plant‐derived lathyrane diterpene, induces subventricular zone neural progenitor cell proliferation through PKCβ activation

Abstract: We propose lathyranes like ELAC as new drug candidates to modulate adult neurogenesis through PKC activation. Functional and structural comparisons between ELAC and phorboids are included.

Cited by 24 publications

References 65 publications

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

A novel PKC activating molecule promotes neuroblast differentiation and delivery of newborn neurons in brain injuries

Identification of protein kinase C beta as a therapeutic target for neuroendocrine prostate cancer and development of a nanoparticle-based therapeutic strategy

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

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