The Impact of the Histone Deacetylase Inhibitor-Sodium Butyrate on Complement-Mediated Synapse Loss in a Rat Model of Neonatal Hypoxia-Ischemia.

Perinatal asphyxia is one of the most important causes of morbidity and mortality in newborns. One of the key pathogenic factors in hypoxic-ischemic (HI) brain injury is the inflammatory reaction including complement system activation. Over-activated complement stimulates cells to release inflammatory molecules and is involved in the post-ischemic degradation of synaptic connections.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Sodium Butyrate, a Histone Deacetylase Inhibitor, Exhibits Neuroprotective/Neurogenic Effects in a Rat Model of Neonatal Hypoxia-Ischemia.

Neonatal hypoxic-ischemic (HI) injury still remains an important issue as it is a major cause of neonatal death and neurological dysfunctions. Currently, there are no well-established treatments to reduce brain damage and its long-term sequel in infants. Recently, reported data show that histone deacetylase inhibitors provide neuroprotection in adult stroke models.

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.

Histone deacetylases 1 and 2 are required for brain development.

Epigenetic modifications of histones have been implicated in the regulation of cell specific expression of genes required for neuronal development. The best studied post-translational (epigenetic) modification of histones is the process of reversible acetylation. Two types of enzymes - histone acetyltransferases (HATs) and histone deacetylases (HDACs) establish and maintain specific patterns of histone acetylation in balance, thereby contributing to both transcriptional activation and repression of specific sets of genes.

A simple, xeno-free method for oligodendrocyte generation from human neural stem cells derived from umbilical cord: engagement of gelatinases in cell commitment and differentiation.

Oligodendrocyte progenitors (OPCs) are ranked among the most likely candidates for cell-based strategies aimed at treating neurodegenerative diseases accompanied by dys/demyelination of the central nervous system (CNS). In this regard, different sources of stem cells are being tested to elaborate xeno-free protocols for efficient generation of OPCs for clinical applications. In the present study, neural stem cells of human umbilical cord blood (HUCB-NSCs) have been used to derive OPCs and subsequently to differentiate them into mature, GalC-expressing oligodendrocytes.

OGD induced modification of FAK- and PYK2-coupled pathways in organotypic hippocampal slice cultures.

Focal adhesion kinase (FAK) and proline-rich tyrosine kinase (PYK2) are two related non-receptor tyrosine kinases which are thought to play a role in transducing extracellular matrix (ECM)-derived survival signals into cells. The functions of FAK and PYK2 are linked to autophosphorylation of their specific tyrosine residues, Tyr-397 in FAK and Tyr-402 in PYK2, and then association with different signalling proteins which mediate activation of downstream targets such as ERK and JNK mitogen-activated kinase cascades. Thus, modulation of FAK as well as PYK2 autophosphorylation may affect several intracellular pathways and may participate in a variety of pathological settings.

Neuroprotective effects of histone deacetylase inhibitors in brain ischemia.

Stroke resulting from cerebral ischemia or haemorrhage is a common cause of the death of neuronal cells and neurological dysfunction in humans. Finding therapeutics to improve outcome from brain ischemic injury has proved to be challenging. The efficacy of neuroprotective compounds identified in experimental brain ischemia models thus far have failed to successfully translate in clinical human trials.

Current and experimental pharmacological approaches in neonatal hypoxic- ischemic encephalopathy.

Neonatal hypoxic-ischemic (HI) injury still remains an important issue as it is a frequent cause of neonatal death and life-long neurobehavioral and cognitive dysfunction. In spite of the decades of research which led us to a better knowledge of the pathological mechanism of hypoxic-ischemic brain injury, the clinical use of potential neuroprotective drugs (including, among others, excitatory amino acids antagonists, free radical inhibitors and scavengers, growth factors, xenon, cannabinoids, anti-inflammatory and anti-apoptotic agents) became avoided owing to insufficiency and /or treatment-induced undesirable side effects. The only available effective treatment, hypothermia, neither provides complete brain protection nor stimulates the repair necessary for neurodevelopmental outcome.