Melatonin is an indolamine synthesized and secreted by the pineal gland along with other extrapineal sources including immune system cells, the brain, skin and the gastrointestinal tract. Growing interest in this compound as a potential therapeutic agent in several diseases stems from its pleiotropic effects. Thus, melatonin plays a key role in various physiological activities that include regulation of circadian rhythms, immune responses, the oxidative process, apoptosis or mitochondrial homeostasis. Most of these processes are altered during inflammatory pathologies, among which neurodegenerative and bowel diseases stand out. Therapeutic assays with melatonin indicate that it has a beneficial therapeutic value in the treatment of several inflammatory diseases, such as Alzheimer, Amiotrophic Lateral, Multiple Sclerosis and Huntigton´s disease as well as ulcerative colitis. However, contradictory effects have been demonstrated in Parkinson´s and Chron´s diseases, which, in some cases, the reported effects were beneficial while in others the pathology was exacerbated. These various results may be related to several factors. In the first place, it should be taken into account that at the beginning of the inflammation phase there is a production of reactive oxygen species (ROS) that should not be blocked by exclusively antioxidant molecules, since, on the one hand, it would be interfering with the action of neutrophils and macrophages and, on the other, with the apoptotic signals activated by ROS. It is also important to keep in mind that the end result of an anti-inflammatory molecule will depend on the degree of inflammation or whether or not it has been resolved and has therefore become chronic. In this review we present the use of melatonin in the control of inflammation underlying the above mentioned diseases. These actions are mediated through their receptors but also with their direct antioxidant action and melatonin's ability to break the vicious cycle of ROSinflammation. This review is aimed at evaluating the effect of melatonin on activity of the inflammatory process and at its immunomodulator effects.
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.
Alert-chronic studies show that ocular motoneurons (Mns) exhibit a phasic and tonic firing correlated with eye saccade-velocity and position (fixation), respectively. Differences in the phasic and tonic firing among Mns depend on synaptic inputs and/or the intrinsic membrane properties. We have used in vitro slice preparation to investigate the contribution of membrane properties to firing properties of Wistar rat oculomotor nucleus Mns. We recorded different discharge patterns and focused on Mns with sustained discharge (type I) because they were the most abundant, and their firing pattern resembles that reported in alert preparations. Various differences divided these Mns into types I(A) and I(B); the afterhyperpolarization (AHP) phase of the spike was monophasic in I(A) and biphasic in I(B); I(A) Mns showed tonic or phasic-tonic firing depending on the current intensity, while I(B) Mns showed phasic-tonic discharge; the phasic firing was higher in I(B) than in I(A) Mns; I(A) Mns fired in a narrower range than did I(B) Mns; and I(A) Mns showed lower maximum frequency than did I(B) Mns. In conclusion, I(A) and I(B) Mns show different phasic firing properties and dynamic range, supported by intrinsic membrane properties. We suggest that I(A) and I(B) Mns innervate fast-twitch muscle fibres with different contraction speeds, and could contribute to generating a fine phasic signal for a graded muscle contraction. Finally, we have demonstrated an inverse relationship between Mn thresholds and tonic firing gain, concluding that intrinsic membrane properties could not support the covariation between tonic firing gain and recruitment thresholds reported in alert studies.
Glioblastoma (GBM) is the most common form of brain tumor characterized by its resistance to conventional therapies, including temozolomide, the most widely used chemotherapeutic agent in the treatment of GBM. Within the tumor, the presence of glioma stem cells (GSC) seems to be the reason for drug resistance. The discovery of GSC has boosted the search for new experimental models to study GBM, which allow the development of new GBM treatments targeting these cells. In here, we describe different strategies currently in use to study GBM. Initial GBM investigations were focused in the development of xenograft assays. Thereafter, techniques advanced to dissociate tumor cells into single-cell suspensions, which generate aggregates referred to as neurospheres, thus facilitating their selective expansion. Concomitantly, the finding of genes involved in the initiation and progression of GBM tumors, led to the generation of mice models for the GBM. The latest advances have been the use of GBM organoids or 3D-bioprinted mini-brains. 3D bio-printing mimics tissue cytoarchitecture by combining different types of cells interacting with each other and with extracellular matrix components. These in vivo models faithfully replicate human diseases in which the effect of new drugs can easily be tested. Based on recent data from human glioblastoma, this review critically evaluates the different experimental models used in the study of GB, including cell cultures, mouse models, brain organoids, and 3D bioprinting focusing in the advantages and disadvantages of each approach to understand the mechanisms involved in the progression and treatment response of this devastating disease.
Key points• This study deals with the cellular mechanisms involved in firing rate modulation in vivo in the oculomotor system where there are requirements for high firing rates by motoneurons.• The study demonstrates that glutamate effects depend on the recruitment threshold and, presumably, motoneuron size.• Mid-and high-threshold motoneurons in response to glutamate decrease their voltage threshold and strengthened the tonic and phasic components of the firing rate.• In a functional context, motoneurons could be recruited at lower recruitment threshold and could generate a strong muscle contraction under glutamate modulation to perform saccadic eye movements with different velocities and/or to maintain the eye in different eccentric positions in the orbit.• Our results suggest that the recruitment and firing behaviour of ocular motoneurons can be modified in vivo by glutamatergic synaptic inputs. It provides a link between cellular function and behavioural motoneuron output.Abstract Studies in alert preparations have demonstrated that ocular motoneurons exhibit a phasic-tonic firing rate related to eye velocity and position, respectively. The slopes of these relationships are higher in motoneurons with higher recruitment threshold and have been proposed to depend upon synaptic input. To investigate this hypothesis, motoneurons of the rat oculomotor nucleus were recorded in a brain slice preparation in control conditions and during glutamate (5 μM) application to the bath. Glutamate did not affect membrane potential or input resistance, but produced a decrease in rheobase and depolarization voltage as a function of the current needed for generating a maintained repetitive discharge (recruitment threshold current). In addition, glutamate compressed the range of recruitment threshold current (0.1-0.4 nA) as compared to the control (0.15-0.7 nA). Glutamate exposed motoneurons showed an increase in the tonic frequency gain and the peak frequency. Such increments depended on the recruitment threshold current and the last recruited motoneurons almost doubled the tonic frequency gain (35.2 vs. 57.9 spikes s −1 nA −1 ) and the peak frequency (52.4 vs. 102.6 spikes s −1 ). Finally, glutamate increased the spike frequency adaptation due to a significant increase in the phasic firing component as compared to the tonic one. In conclusion, glutamate modulates tonic and phasic discharge properties as a function of the recruitment threshold current and, presumably, motoneuron size. These findings contribute to understand the link between cellular functions and motoneuron discharge during oculomotor behaviour.
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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