Samuel Domínguez-García

Neuropathological aging is associated with memory impairment and cognitive decline, affecting several brain areas including the neurogenic niche of the dentate gyrus of the hippocampus (DG). In the healthy brain, homeostatic mechanisms regulate neurogenesis within the DG to facilitate the continuous generation of neurons from neural stem cells (NSC). Nevertheless, aging reduces the number of activated neural stem cells and diminishes the number of newly generated neurons. Strategies that promote neurogenesis in the DG may improve cognitive performance in the elderly resulting in the development of treatments to prevent the progression of neurological disorders in the aged population. Our work is aimed at discovering targeting molecules to be used in the design of pharmacological agents that prevent the neurological effects of brain aging. We study the effect of age on hippocampal neurogenesis using the SAMP8 mouse as a model of neuropathological aging. We show that in 6‐month‐old SAMP8 mice, episodic and spatial memory are impaired; concomitantly, the generation of neuroblasts and neurons is reduced and the generation of astrocytes is increased in this model. The novelty of our work resides in the fact that treatment of SAMP8 mice with a transforming growth factor‐alpha (TGFα) targeting molecule prevents the observed defects, positively regulating neurogenesis and improving cognitive performance. This compound facilitates the release of TGFα in vitro and in vivo and activates signaling pathways initiated by this growth factor. We conclude that compounds of this kind that stimulate neurogenesis may be useful to counteract the neurological effects of pathological aging.

Harmonic mechanisms orchestrate neurogenesis in the healthy brain within specific neurogenic niches, which generate neurons from neural stem cells as a homeostatic mechanism. These newly generated neurons integrate into existing neuronal circuits to participate in different brain tasks. Despite the mechanisms that protect the mammalian brain, this organ is susceptible to many different types of damage that result in the loss of neuronal tissue and therefore in alterations in the functionality of the affected regions. Nevertheless, the mammalian brain has developed mechanisms to respond to these injuries, potentiating its capacity to generate new neurons from neural stem cells and altering the homeostatic processes that occur in neurogenic niches. These alterations may lead to the generation of new neurons within the damaged brain regions. Notwithstanding, the activation of these repair mechanisms, regeneration of neuronal tissue within brain injuries does not naturally occur. In this review, we discuss how the different neurogenic niches respond to different types of brain injuries, focusing on the capacity of the progenitors generated in these niches to migrate to the injured regions and activate repair mechanisms. We conclude that the search for pharmacological drugs that stimulate the migration of newly generated neurons to brain injuries may result in the development of therapies to repair the damaged brain tissue.

Glioblastoma (GB) is the most aggressive form of glioma and is characterized by poor prognosis and high recurrence despite intensive clinical interventions. To retrieve the key factors underlying the high malignancy of GB with potential diagnosis utility, we combined the analysis of The Cancer Gene Atlas and the REMBRANDT datasets plus a molecular examination of our own collection of surgical tumor resections. We determined a net reduction in the levels of the non-canonical histone H3 variant H3.3 in GB compared to lower-grade astrocytomas and oligodendrogliomas with a concomitant increase in the levels of the canonical histone H3 variants H3.1/H3.2. This increase can be potentially useful in the clinical diagnosis of high-grade gliomas, as evidenced by an immunohistochemistry screening of our cohort and can be at least partially explained by the induction of multiple histone genes encoding these canonical forms. Moreover, GBs showing low bulk levels of the H3.1/H3.2 proteins were more transcriptionally similar to low-grade gliomas than GBs showing high levels of H3.1/H3.2. In conclusion, this study identifies an imbalanced ratio between the H3 variants associated with glioma malignancy and molecular patterns relevant to the biology of gliomas, and proposes the examination of the H3.3 and H3.1/H3.2 levels to further refine diagnosis of low- and high-grade gliomas in future studies.

Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

Hippocampal neurogenesis has widely been linked to memory and learning performance. New neurons generated from neural stem cells (NSC) within the dentate gyrus of the hippocampus (DG) integrate in hippocampal circuitry participating in memory tasks. Several neurological and neuropsychiatric disorders show cognitive impairment together with a reduction in DG neurogenesis. Growth factors secreted within the DG promote neurogenesis. Protein kinases of the protein kinase C (PKC) family facilitate the release of several of these growth factors, highlighting the role of PKC isozymes as key target molecules for the development of drugs that induce hippocampal neurogenesis. PKC activating diterpenes have been shown to facilitate NSC proliferation in neurogenic niches when injected intracerebroventricularly. We show in here that long-term administration of diterpene ER272 promotes neurogenesis in the subventricular zone and in the DG of mice, affecting neuroblasts differentiation and neuronal maturation. A concomitant improvement in learning and spatial memory tasks performance can be observed. Insights into the mechanism of action reveal that this compound facilitates classical PKCα activation and promotes transforming growth factor alpha (TGFα) and, to a lesser extent, neuregulin release. Our results highlight the role of this molecule in the development of pharmacological drugs to treat neurological and neuropsychiatric disorders associated with memory loss and a deficient neurogenesis.

Vitamin D is an essential fat-soluble vitamin that participates in several homeostatic functions in mammalian organisms. Lower levels of vitamin D are produced in the older population, vitamin D deficiency being an accelerating factor for the progression of the aging process. In this review, we focus on the effect that vitamin D exerts in the aged brain paying special attention to the neurogenic process. Neurogenesis occurs in the adult brain in neurogenic regions, such as the dentate gyrus of the hippocampus (DG). This region generates new neurons that participate in cognitive tasks. The neurogenic rate in the DG is reduced in the aged brain because of a reduction in the number of neural stem cells (NSC). Homeostatic mechanisms controlled by the Wnt signaling pathway protect this pool of NSC from being depleted. We discuss in here the crosstalk between Wnt signaling and vitamin D, and hypothesize that hypovitaminosis might cause failure in the control of the neurogenic homeostatic mechanisms in the old brain leading to cognitive impairment. Understanding the relationship between vitamin D, neurogenesis and cognitive performance in the aged brain may facilitate prevention of cognitive decline and it can open a door into new therapeutic fields by perspectives in the elderly.

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/non-neurogenic 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.

Acute or chronic injury to the central nervous system (CNS), causes neuronal death and irreversible cognitive deficits or sensory-motor alteration. Despite the capacity of the adult CNS to generate new neurons from neural stem cells (NSC), neuronal replacement following an injury is a restricted process, which does not naturally result in functional regeneration. Therefore, potentiating endogenous neurogenesis is one of the strategies that are currently being under study to regenerate damaged brain tissue. The insignificant neurogenesis that occurs in CNS injuries is a consequence of the gliogenic/non-neurogenic environment that inflammatory signaling molecules create within the injured area. The modification of the extracellular signals to generate a neurogenic environment would facilitate neuronal replacement. However, in order to generate this environment, it is necessary to unearth which molecules promote or impair neurogenesis to introduce the first and/or eliminate the latter. Specific isozymes of the protein kinase C (PKC) family differentially contribute to generate a gliogenic or neurogenic environment in injuries by regulating the ADAM17 mediated release of growth factor receptor ligands. Recent reports describe several non-tumorigenic diterpenes isolated from plants of the Euphorbia genus, which specifically modulate the activity of PKC isozymes promoting neurogenesis. Diterpenes with 12-deoxyphorbol or lathyrane skeleton, increase NPC proliferation in neurogenic niches in the adult mouse brain in a PKCβ dependent manner exerting their effects on transit amplifying cells, whereas PKC inhibition in injuries promotes neurogenesis. Thus, compounds that balance PKC activity in injuries might be of use in the development of new drugs and therapeutic strategies to regenerate brain injuries.