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

Abstract

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.

Targeting Protein Kinase C in Glioblastoma Treatment

“…For example, the proliferation of NSCs isolated from the SVZ of induced adult mice is stimulated with classical PKC activating diterpenes with a 12-deoxyphorbols or lathyrane structure [ 109 , 110 , 112 ]. This facilitates the ADAM17-mediated release of EGFR ligands such as TGFα [ 113 ] and activates the PI3K-AKT and MAPK pathways [ 114 ], in addition to also activating cyclin D1 expression [ 109 ]. On the contrary, PKC inhibition facilitates the differentiation of NSCs towards a neuronal phenotype, reducing their proliferation rate [ 115 ].…”

“…We hypothesize that the combination of these PKC targeting drugs with current treatments may enhance prognosis and survival time. Diterpenes with the capacity to individually regulate classical and novel PKC have recently been described for use in neuronal regeneration [113,114] and as putative treatments for other cancer types [111]. Thus, these agents could prove useful in the development of drugs either in standalone or in combined strategies with other compounds (e.g., PI3K inhibitors).…”

Molecular probes for cellular imaging of post-translational proteoforms

“…Ectodomain shedding of TGFα can be monitored in a similar manner. 157 Similarly, processing and secretion of insulin in live Min6β cells could be visualized by fusion of GFP and mCherry to the A-peptide and C-peptide of proinsulin. Changes in the GFP-to-mCherry fluorescence intensity ratio indicated release of mature insulin, allowing effects of stimulation and drugs on insulin secretion to be measured.…”

Evolution of Experimental Models in the Study of Glioblastoma: Toward Finding Efficient Treatments

“…Thus, each in vitro model has its advantages and disadvantages and it is necessary to select the cell system appropriate for each experimental question (128). Some of these systems have been widely used not only in the study of GSC but also in the study of NSC giving a great deal of information about the physiology of these cells (129)(130)(131)(132) or about the finding of small pharmacological molecules that regulate these activities (133).…”