Sex Differences in Brain Disorders.

A remarkable feature of the brain is its sexual dimorphism. Sexual dimorphism in brain structure and function is associated with clinical implications documented previously in healthy individuals but also in those who suffer from various brain disorders. Sex-based differences concerning some features such as the risk, prevalence, age of onset, and symptomatology have been confirmed in a range of neurological and neuropsychiatric diseases. The mechanisms responsible for the establishment of sex-based differences between men and women are not fully understood. The present paper provides up-to-date data on sex-related dissimilarities observed in brain disorders and highlights the most relevant features that differ between males and females. The topic is very important as the recognition of disparities between the sexes might allow for the identification of therapeutic targets and pharmacological approaches for intractable neurological and neuropsychiatric disorders.

Analysis of Givinostat/ITF2357 Treatment in a Rat Model of Neonatal Hypoxic-Ischemic Brain Damage.

The histone deacetylase inhibitor (HDACi) Givinostat/ITF2357 provides neuroprotection in adult models of brain injury; however, its action after neonatal hypoxia-ischemia (HI) is still undefined. The aim of our study was to test the hypothesis that the mechanism of Givinostat is associated with the alleviation of inflammation. For this purpose, we analyzed the microglial response and the effect on molecular mediators (chemokines/cytokines) that are crucial for inducing cerebral damage after neonatal hypoxia-ischemia. Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 60 min of hypoxia (7.6% O2). Givinostat (10 mg/kg b/w) was administered in a 5-day regimen. The effects of Givinostat on HI-induced inflammation (cytokine, chemokine and microglial activation and polarization) were assessed with a Luminex assay, immunohistochemistry and Western blot. Givinostat treatment did not modulate the microglial response specific for HI injury. After Givinostat administration, the investigated chemokines and cytokines remained at the level induced by HI. The only immunosuppressive effect of Givinostat may be associated with the decrease in MIP-1α. Neonatal hypoxia-ischemia produces an inflammatory response by activating the proinflammatory M1 phenotype of microglia, disrupting the microglia-neuron (CX3CL1/CX3CR1) axis and elevating numerous proinflammatory cytokines/chemokines. Givinostat/ITF2357 did not prevent an inflammatory reaction after HI.

Neonatal Rat Glia Cultured in Physiological Normoxia for Modeling Neuropathological Conditions In Vitro.

Cell culture conditions were proven to highly affect crucial biological processes like proliferation, differentiation, intercellular crosstalk, and senescence. Oxygen tension is one of the major factors influencing cell metabolism and thus, modulating cellular response to pathophysiological conditions. In this context, the presented study aimed at the development of a protocol for efficient culture of rat neonatal glial cells (microglia, astrocytes, and oligodendrocytes) in oxygen concentrations relevant to the nervous tissue. The protocol allows for obtaining three major cell populations, which play crucial roles in sustaining tissue homeostasis and are known to be activated in response to a wide spectrum of external stimuli. The cells are cultured in media without supplement addition to avoid potential modulation of cell processes. The application of active biomolecules for coating culturing surfaces might be useful for mirroring physiological cell interactions with extracellular matrix components. The cell fractions can be assembled as cocultures to further evaluate investigated mechanisms, intercellular crosstalk, or cell response to tested pharmacological compounds. Applying additional procedures, like transient oxygen and glucose deprivation, allows to mimic in vitro the selected pathophysiological conditions. The presented culture system for neonatal rat glial cells is a highly useful tool for in vitro modeling selected neuropathological conditions.

Aberrant Complement System Activation in Neurological Disorders.

The complement system is an assembly of proteins that collectively participate in the functions of the healthy and diseased brain. The complement system plays an important role in the maintenance of uninjured (healthy) brain homeostasis, contributing to the clearance of invading pathogens and apoptotic cells, and limiting the inflammatory immune response. However, overactivation or underregulation of the entire complement cascade within the brain may lead to neuronal damage and disturbances in brain function. During the last decade, there has been a growing interest in the role that this cascading pathway plays in the neuropathology of a diverse array of brain disorders (e.g., acute neurotraumatic insult, chronic neurodegenerative diseases, and psychiatric disturbances) in which interruption of neuronal homeostasis triggers complement activation. Dysfunction of the complement promotes a disease-specific response that may have either beneficial or detrimental effects. Despite recent advances, the explicit link between complement component regulation and brain disorders remains unclear. Therefore, a comprehensible understanding of such relationships at different stages of diseases could provide new insight into potential therapeutic targets to ameliorate or slow progression of currently intractable disorders in the nervous system. Hence, the aim of this review is to provide a summary of the literature on the emerging role of the complement system in certain brain disorders.

Impact of a Histone Deacetylase Inhibitor-Trichostatin A on Neurogenesis after Hypoxia-Ischemia in Immature Rats.

Hypoxia-ischemia (HI) in the neonatal brain frequently results in neurologic impairments, including cognitive disability. Unfortunately, there are currently no known treatment options to minimize ischemia-induced neural damage. We previously showed the neuroprotective/neurogenic potential of a histone deacetylase inhibitor (HDACi), sodium butyrate (SB), in a neonatal HI rat pup model. The aim of the present study was to examine the capacity of another HDACi-Trichostatin A (TSA)-to stimulate neurogenesis in the subgranular zone of the hippocampus. We also assessed some of the cellular/molecular processes that could be involved in the action of TSA, including the expression of neurotrophic factors (glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF), and brain-derived neurotrophic factor (BDNF)) as well as the TrkB receptor and its downstream signalling substrate- cAMP response element-binding protein (CREB). Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by hypoxia for 1 h. TSA was administered directly after the insult (0.2 mg/kg body weight). The study demonstrated that treatment with TSA restored the reduced by hypoxia-ischemia number of immature neurons (neuroblasts, BrdU/DCX-positive) as well as the number of oligodendrocyte progenitors (BrdU/NG2+) in the dentate gyrus of the ipsilateral damaged hemisphere. However, new generated cells did not develop the more mature phenotypes. Moreover, the administration of TSA stimulated the expression of BDNF and increased the activation of the TrkB receptor. These results suggest that BDNF-TrkB signalling pathways may contribute to the effects of TSA after neonatal hypoxic-ischemic injury.

Impact of neonatal hypoxia-ischaemia on oligodendrocyte survival, maturation and myelinating potential.

Hypoxic-ischaemic episodes experienced at the perinatal period commonly lead to a development of neurological disabilities and cognitive impairments in neonates or later in childhood. Clinical symptoms often are associated with the observed alterations in white matter in the brains of diseased children, suggesting contribution of triggered oligodendrocyte/myelin pathology to the resulting disorders. To date, the processes initiated by perinatal asphyxia remain unclear, hampering the ability to develop preventions. To address the issue, the effects of temporal hypoxia-ischaemia on survival, proliferation and the myelinating potential of oligodendrocytes were evaluated ex vivo using cultures of hippocampal organotypic slices and in vivo in rat model of perinatal asphyxia. The potential engagement of gelatinases in oligodendrocyte maturation was assessed as well. The results pointed to a significant decrease in the number of oligodendrocyte progenitor cells (OPCs), which is compensated for to a certain extent by the increased rate of OPC proliferation. Oligodendrocyte maturation seemed however to be significantly altered. An ultrastructural examination of selected brain regions performed several weeks after the insult showed however that the process of developing central nervous system myelination proceeds efficiently resulting in enwrapping the majority of axons in compact myelin. The increased angiogenesis in response to neonatal hypoxic-ischaemic insult was also noticed. In conclusion, the study shows that hypoxic-ischaemic episodes experienced during the most active period of nervous system development might be efficiently compensated for by the oligodendroglial cell response triggered by the insult. The main obstacle seems to be the inflammatory process modulating the local microenvironment.

The Differentiation of Rat Oligodendroglial Cells Is Highly Influenced by the Oxygen Tension: In Vitro Model Mimicking Physiologically Normoxic Conditions.

Oligodendrocyte progenitor cells (OPCs) constitute one of the main populations of dividing cells in the central nervous system (CNS). Physiologically, OPCs give rise to mature, myelinating oligodendrocytes and confer trophic support to their neighboring cells within the nervous tissue. OPCs are known to be extremely sensitive to the influence of exogenous clues which might affect their crucial biological processes, like survival, proliferation, differentiation, and the ability to generate a myelin membrane. Alterations in their differentiation influencing their final potential for myelinogenesis are usually the leading cause of CNS dys- and demyelination, contributing to the development of leukodystrophic disorders. The evaluation of the mechanisms that cause oligodendrocytes to malfunction requires detailed studies based on designed in vitro models. Since OPCs readily respond to changes in local homeostasis, it is crucial to establish restricted culture conditions to eliminate the potential stimuli that might influence oligodendrocyte biology. Additionally, the in vitro settings should mimic the physiological conditions to enable the obtained results to be translated to future preclinical studies. Therefore, the aim of our study was to investigate OPC differentiation in physiological normoxia (5% O2) and a restricted in vitro microenvironment. To evaluate the impact of the combined microenvironmental clues derived from other components of the nervous tissue, which are also influenced by the local oxygen concentration, the process of generating OPCs was additionally analyzed in organotypic hippocampal slices. The obtained results show that OPC differentiation, although significantly slowed down, proceeded correctly through its typical stages in the physiologically relevant conditions created in vitro. The established settings were also conducive to efficient cell proliferation, exerting also a neuroprotective effect by promoting the proliferation of neurons. In conclusion, the performed studies show how oxygen tension influences OPC proliferation, differentiation, and their ability to express myelin components, and should be taken into consideration while planning preclinical studies, e.g., to examine neurotoxic compounds or to test neuroprotective strategies.

Imipramine administration induces changes in the phosphorylation of FAK and PYK2 and modulates signaling pathways related to their activity.

BACKGROUND: Antidepressants can modify neuronal functioning by affecting many levels of signal transduction pathways that are involved in neuroplasticity. We investigated whether the phosphorylation status of focal adhesion kinase (FAK/PTK2) and its homolog, PYK2/PTK2B, and their complex with the downstream effectors (Src kinase, p130Cas, and paxillin) are affected by administration of the antidepressant drug, imipramine. The treatment influence on the levels of ERK1/2 kinases and their phosphorylated forms (pERK1/2) or the Gαq, Gα11 and Gα12 proteins were also assessed. METHODS: Rats were injected with imipramine (10 mg/kg, twice daily) for 21 days. The levels of proteins investigated in their prefrontal cortices were measured by Western blotting. RESULTS: Imipramine induced contrasting changes in the phosphorylation of FAK and PYK2 at Tyr397 and Tyr402, respectively. The decreased FAK phosphorylation and increased PYK2 phosphorylation were reflected by changes in the levels of their complex with Src and p130Cas, which was observed predominantly after chronic imipramine treatment. Similarly only chronic imipramine decreased the Gαq expression while Gα11 and Gα12 proteins were untouched. Acute and chronic treatment with imipramine elevated ERK1 and ERK2 total protein levels, whereas only the pERK1 was significantly affected by the drug. CONCLUSION: The enhanced activation of PYK2 observed here could function as compensation for FAK inhibition. GENERAL SIGNIFICANCE: These data demonstrate that treatment with imipramine, which is a routine in counteracting depressive disorders, enhances the phosphorylation of PYK2, a non-receptor kinase instrumental in promoting synaptic plasticity. This effect documents as yet not considered target in the mechanism of imipramine action.

The potential neuroprotective role of a histone deacetylase inhibitor, sodium butyrate, after neonatal hypoxia-ischemia.

BACKGROUND: Histone deacetylase inhibitor (HDACi), sodium butyrate (SB), has been shown to be neuroprotective in adult brain injury models. Potential explanation for the inhibitor action involves among others reduced inflammation. We therefore anticipated that SB will provide a suitable option for brain injury in immature animals. The aim of our study was to test the hypothesis that one of the mechanisms of protection afforded by SB after neonatal hypoxia-ischemia is associated with anti-inflammatory action. We examined the effect of SB on the production of inflammatory factors including analysis of the microglial and astrocytic cell response. We also examined the effect of SB on molecular mediators that are crucial for inducing cerebral damage after ischemia (transcription factors, HSP70, as well as pro- and anti-apoptotic proteins). METHODS: Seven-day-old rat pups were subjected to unilateral carotid artery ligation followed by 60 min of hypoxia (7.6% O2). SB (300 mg/kg) was administered in a 5-day regime with the first injection given immediately after hypoxic exposure. The damage of the ipsilateral hemisphere was evaluated by hematoxylin-eosin staining (HE) 6 days after the insult. Samples were collected at 24 and 48 h and 6 days. Effects of SB on hypoxia-ischemia (HI)-induced inflammation (cytokines and chemokine) were assessed by Luminex assay and immunohistochemistry. Expression of molecular mediators (NFκB, p53, HSP70, COX-2, pro- and anti-apoptotic factors Bax, Bcl-2, caspase-3) were assayed by Western blot analysis. RESULTS: SB treatment-reduced brain damage, as assessed by HE staining, suppressed the production of inflammatory markers-IL-1ß, chemokine CXCL10, and blocked ischemia-elicited upregulation of COX-2 in the damaged ipsilateral hemisphere. Furthermore, administration of SB promoted the conversion of microglia phenotype from inflammatory M1 to anti-inflammatory M2. None of the investigated molecular mediators that are known to be affected by HDACis in adults were modified after SB administration. CONCLUSIONS: Administration of SB is neuroprotective in neonatal hypoxia-ischemia injury. This neuroprotective activity prevented the delayed rise in chemokine CXCL10, IL-1ß, and COX-2 in the ipsilateral hemisphere. SB appears to exert a beneficial effect via suppression of HI-induced cerebral inflammation.

Oligodendrocyte progenitor cells' fate after neonatal asphyxia-Puzzling implications for the development of hypoxic-ischemic encephalopathy.

Premature birth or complications during labor can cause temporary disruption of cerebral blood flow, often followed by long-term disturbances in brain development called hypoxic-ischemic (HI) encephalopathy. Diffuse damage to the white matter is the most frequently detected pathology in this condition. We hypothesized that oligodendrocyte progenitor cell (OPC) differentiation disturbed by mild neonatal asphyxia may affect the viability, maturation, and physiological functioning of oligodendrocytes. To address this issue, we studied the effect of temporal HI in the in vivo model in P7 rats with magnetic resonance imaging (MRI), microscopy techniques and biochemical analyses. Moreover, we recreated the injury in vitro performing the procedure of oxygen-glucose deprivation on rat neonatal OPCs to determine its effect on cell viability, proliferation, and differentiation. In the in vivo model, MRI evaluation revealed changes in the volume of different brain regions, as well as changes in the directional diffusivity of water in brain tissue that may suggest pathological changes to myelinated neuronal fibers. Hypomyelination was observed in the cortex, striatum, and CA3 region of the hippocampus. Severe changes to myelin ultrastructure were observed, including delamination of myelin sheets. Interestingly, shortly after the injury, an increase in oligodendrocyte proliferation was observed, followed by an overproduction of myelin proteins 4 weeks after HI. Results verified with the in vitro model indicate, that in the first days after damage, OPCs do not show reduced viability, intensively proliferate, and overexpress myelin proteins and oligodendrocyte-specific transcription factors. In conclusion, despite the increase in oligodendrocyte proliferation and myelin protein expression after HI, the production of functional myelin sheaths in brain tissue is impaired. Presented study provides a detailed description of oligodendrocyte pathophysiology developed in an effect of HI injury, resulting in an altered CNS myelination. The described models may serve as useful tools for searching and testing effective of effective myelination-supporting therapies for HI injuries.

Comparison of matrix metalloproteinase activation after focal cortical ischemia in young adult and aged mice.

Matrix metalloproteinase (MMP) activity is implicated in the degradation of the extracellular matrix during cerebral ischemia. Although many studies have demonstrated spatiotemporal patterns of activation of gelatinases (MMP-9 and MMP-2) after ischemic stroke in young adult rodents, no data exist on MMP activity in old brains. In this study, we investigated the gelatinolytic activity in young adult (3-month-old) and aged (1-year-old) mice subjected to photothrombotic stroke. Using in situ zymography and gel zymography, we found that the basal gelatinolytic activity in the intact cerebral cortex was similar at both investigated ages. Similarly, after photothrombosis, the increased gelatinolytic response up to 7 days poststroke was the same in young and aged brains. At both ages, early activation of gelatinolysis in the ischemic core and the perilesional area was present in neuronal nuclei as revealed by colocalization of gelatinolytic product with NeuN immunostaining and DAPI. Additionally, application of specific antibodies against MMP-9 and MMP-2 revealed the increase in MMP-9 immunoreactivity in cell nuclei as early as 4 hr poststroke. No differences between young and aged mice were observed concerning the level and localization of MMP-9 immunoreactivity. The lack of age-related differences in the degree and pattern of activation of gelatinolysis after focal stroke and the lack of correspondence between the results of in situ and gel zymography suggest that extracellular proteolysis is not directly responsible for the more severe outcome of ischemic stroke in aged subjects.

Sexual Dimorphism in Neurodegenerative Diseases and in Brain Ischemia.

Epidemiological studies and clinical observations show evidence of sexual dimorphism in brain responses to several neurological conditions. It is suggested that sex-related differences between men and women may have profound effects on disease susceptibility, pathophysiology, and progression. Sexual differences of the brain are achieved through the complex interplay of several factors contributing to this phenomenon, such as sex hormones, as well as genetic and epigenetic differences. Despite recent advances, the precise link between these factors and brain disorders is incompletely understood. This review aims to briefly outline the most relevant aspects that differ between men and women in ischemia and neurodegenerative disorders (AD, PD, HD, ALS, and SM). Recognition of disparities between both sexes could aid the development of individual approaches to ameliorate or slow the progression of intractable disorders.

The impact of the histone deacetylase inhibitor sodium butyrate on microglial polarization after oxygen and glucose deprivation.

BACKGROUND: Microglia play a major role in the development of brain inflammation after central nervous system injury. On the other hand, microglia also participate in the repair process. The dualistic role of these cells results from the fact that various states of their activation are associated with specific phenotypes. The M1 phenotype is responsible for the production of proinflammatory mediators, whereas the M2 microglia release anti-inflammatory and trophic factors and take part in immunosuppressive and neuroprotective processes. The histone deacetylase inhibitor sodium butyrate (SB) shows anti-inflammatory and neuroprotective effects in some animal models of brain injury. The aim of this study was to examine the effects of sodium butyrate on the proliferation and M1/M2 polarization of primary microglial cells after oxygen and glucose deprivation (OGD) in vitro. METHODS: Primary microglial cultures were prepared from 1-day-old rats, subjected to the OGD procedure and treated with SB (0.1 mM, 1 mM and 10 mM). The effect of OGD and SB on microglial proliferation was assessed by double immunofluorescence, and microglial phenotypes were evaluated by qPCR. RESULTS: The OGD procedure stimulated the proliferation of microglia after 24 h of culturing, and SB treatment reduced the division of these cells. This effect was inversely proportional to the SB concentration. The OGD procedure increased proinflammatory CD86 and IL1ß gene expression and reduced the expression of the anti-inflammatory M2 markers arginase and CD200 in microglia. CONCLUSIONS: SB can change the polarization of microglia after OGD from an unfavourable M1 to a beneficial M2 phenotype. Our results show that SB is a potential immunosuppressive agent that can modulate microglial activation stimulated by ischaemic-like conditions.

The Impact of the CX3CL1/CX3CR1 Axis in Neurological Disorders.

Fractalkine (FKN, CX3CL1) is a transmembrane chemokine expressed by neurons in the central nervous system (CNS). CX3CL1 signals through its unique receptor, CX3CR1, that is expressed in microglia. Within the CNS, fractalkine acts as a regulator of microglia activation in response to brain injury or inflammation. During the last decade, there has been a growing interest in the roles that the CX3CL1/CX3CR1 signaling pathway plays in the neuropathology of a diverse array of brain disorders. However, the reported results have proven controversial, indicating that a disruption of the CX3CL1 axis induces a disease-specific microglial response that may have either beneficial or detrimental effects. Therefore, it has become clear that the understanding of neuron-to-glia signals mediated by CX3CL1/CX3CR1 at different stages of diseases could provide new insight into potential therapeutic targets. Hence, the aim of this review is to provide a summary of the literature on the emerging role of CX3CL1 in animal models of some brain disorders.

Oligodendrocyte Response to Pathophysiological Conditions Triggered by Episode of Perinatal Hypoxia-Ischemia: Role of IGF-1 Secretion by Glial Cells.

Differentiation of oligodendrocyte progenitors towards myelinating cells is influenced by a plethora of exogenous instructive signals. Insulin-like growth factor 1 (IGF-1) is one of the major factors regulating cell survival, proliferation, and maturation. Recently, there is an ever growing recognition concerning the role of autocrine/paracrine IGF-1 signaling in brain development and metabolism. Since oligodendrocyte functioning is altered after the neonatal hypoxic-ischemic (HI) insult, a question arises if the injury exerts any influence on the IGF-1 secreted by neural cells and how possibly the change in IGF-1 concentration affects oligodendrocyte growth. To quantify the secretory activity of neonatal glial cells, the step-wise approach by sequentially using the in vivo, ex vivo, and in vitro models of perinatal asphyxia was applied. A comparison of the results of in vivo and ex vivo studies allowed evaluating the role of autocrine/paracrine IGF-1 signaling. Accordingly, astroglia were indicated to be the main local source of IGF-1 in the developing brain, and the factor secretion was shown to be significantly upregulated during the first 24 h after the hypoxic-ischemic insult. And conversely, the IGF-1 amounts released by oligodendrocytes and microglia significantly decreased. A morphometric examination of oligodendrocyte differentiation by means of the Sholl analysis showed that the treatment with low IGF-1 doses markedly improved the branching of oligodendroglial cell processes and, in this way, promoted their differentiation. The changes in the IGF-1 amounts in the nervous tissue after HI might contribute to the resulting white matter disorders, observed in newborn children who experienced perinatal asphyxia. Pharmacological modulation of IGF-1 secretion by neural cells could be reasonable solution in studies aimed at searching for therapies alleviating the consequences of perinatal asphyxia.

Effect of the HDAC Inhibitor, Sodium Butyrate, on Neurogenesis in a Rat Model of Neonatal Hypoxia-Ischemia: Potential Mechanism of Action.

Neonatal hypoxic-ischemic (HI) brain injury likely represents the major cause of long-term neurodevelopmental disabilities in surviving babies. Despite significant investigations, there is not yet any known reliable treatment to reduce brain damage in suffering infants. Our recent studies in an animal model of HI revealed the therapeutic potential of a histone deacetylase inhibitor (HDACi). The neuroprotective action was connected with the stimulation of neurogenesis in the dentate gyrus subgranular zone. In the current study, we investigated whether HDACi-sodium butyrate (SB)-would also lead to neurogenesis in the subventricular zone (SVZ). By using a neonatal rat model of hypoxia-ischemia, we found that SB treatment stimulated neurogenesis in the damaged ipsilateral side, based on increased DCX labeling, and restored the number of neuronal cells in the SVZ ipsilateral to lesioning. The neurogenic effect was associated with inhibition of inflammation, expressed by a transition of microglia to the anti-inflammatory phenotype (M2). In addition, the administration of SB increased the activation of the TrkB receptor and the phosphorylation of the transcription factor-CREB-in the ipsilateral hemisphere. In contrast, SB administration reduced the level of HI-induced p75NTR. Together, these results suggest that BDNF-TrkB signaling plays an important role in SB-induced neurogenesis after HI. These findings provide the basis for clinical approaches targeted at protecting the newborn brain damage, which may prove beneficial for treating neonatal hypoxia-ischemia.

Directed glial differentiation and transdifferentiation for neural tissue regeneration.

Glial cells which are indispensable for the central nervous system development and functioning, are proven to be vulnerable to a harmful influence of pathological cues and tissue misbalance. However, they are also highly sensitive to both in vitro and in vivo modulation of their commitment, differentiation, activity and even the fate-switch by different types of bioactive molecules. Since glial cells (comprising macroglia and microglia) are an abundant and heterogeneous population of neural cells, which are almost uniformly distributed in the brain and the spinal cord parenchyma, they all create a natural endogenous reservoir of cells for potential neurogenerative processes required to be initiated in response to pathophysiological cues present in the local tissue microenvironment. The past decade of intensive investigation on a spontaneous and enforced conversion of glial fate into either alternative glial (for instance from oligodendrocytes to astrocytes) or neuronal phenotypes, has considerably extended our appreciation of glial involvement in restoring the nervous tissue cytoarchitecture and its proper functions. The most effective modulators of reprogramming processes have been identified and tested in a series of pre-clinical experiments. A list of bioactive compounds which are potent in guiding in vivo cell fate conversion and driving cell differentiation includes a selection of transcription factors, microRNAs, small molecules, exosomes, morphogens and trophic factors, which are helpful in boosting the enforced neuro-or gliogenesis and promoting the subsequent cell maturation into desired phenotypes. Herein, an issue of their utility for a directed glial differentiation and transdifferentiation is discussed in the context of elaborating future therapeutic options aimed at restoring the diseased nervous tissue.

Histone Deacetylase Inhibitors: A Therapeutic Key in Neurological Disorders?

Understanding the contribution of imbalance in protein acetylation levels and dysfunction of transcription to neurodegenerative diseases provides the rationale for the use of epigenetic modulators such as histone deacetylase (HDAC) inhibitors to combat neurodegenerative conditions. It is now widely recognized that various low-molecular weight HDAC inhibitors are broadly neuroprotective, preventing or delaying neuronal death and dysfunction in many rodent models of neurodegeneration. The beneficial effects result in part from modifications of histones and nonhistone proteins. This review describes evidence indicating that HDAC inhibitors have emerged as a promising new strategy in treating neurodegenerative disorders and summarizes treatment strategies from clinical trials currently underway.

Transient forebrain ischemia effects FAK-coupled signaling in gerbil hippocampus.

Focal adhesion kinase (FAK) is thought to play a major role in transducing extracellular matrix (ECM)-derived survival signals into cells. The function of FAK is linked to its autophosphorylation at Tyr-397 and then recruitment of several effector molecules. Thus, modulation of FAK activity may affect several intracellular signaling pathways and may participate in a variety of pathological settings. In the present study, we investigated the effect of short-term 5 min forebrain ischemia on levels and Tyr-397 phosphorylation of focal adhesion kinase and the interaction of this enzyme with Src protein tyrosine kinase and adapter protein p130Cas, involved in FAK-mediated signaling pathway in gerbil hippocampus. The total amount of focal adhesion kinase as well as its Tyr-397 phosphorylation declined substantially between 24 and 48 h after the insult, particularly in CA1 region of hippocampus. Concomitantly, a decreased amount of FAK/Src kinase complex has been observed. These data indicate that inhibition of FAK/Src-coupled signaling pathway may participate in the ischemia-induced neuronal degeneration in gerbil hippocampus. The temporal profile of FAK down-regulation in CA1 area coincides with metalloproteinases (MMPs) activation. These results suggest that extracellular proteolysis might belong to the mechanisms which govern the FAK-coupled pathway in ischemic hippocampus.

Insights Into the Neuroinflammatory Responses After Neonatal Hypoxia-Ischemia.

Neonatal hypoxia-ischemia (HI) is one of the major causes of death and/or lifelong neurobehavioral and cognitive dysfunction. Undoubtedly, brain damage following HI insult is a complex process with multiple contributing mechanisms and pathways resulting in both early and delayed injury. It is increasingly recognized that one of the leading pathogenic factors of neonatal brain damage is inflammation, induced by activation of the central and peripheral immune system. Immune responses are induced within minutes and can expand for weeks and even months after the insult. Both activated intrinsic (glia) and infiltrating cells (mast cells, monocytes/macrophages) produce soluble inflammatory molecules such as cytokines, chemokines, reactive oxygen, and nitrogen species, which are thought to be pivotal mediators of persistent neuronal injury. This manuscript provides a brief summary of the current knowledge concerning the specific contribution of different cell types and soluble factors to injury of the developing brain caused by neonatal HI. Finally, we discuss the potential forthcoming treatments aimed at targeting inflammation and then attenuation of damaging effects caused by neonatal HI.