Class I HDAC Inhibition Leads to a Downregulation of FANCD2 and RAD51, and the Eradication of Glioblastoma Cells.

HDAC inhibitors (HDACi) hold great potential as anticancer therapies due to their ability to regulate the acetylation of both histone and non-histone proteins, which is frequently disrupted in cancer and contributes to the development and advancement of the disease. Additionally, HDACi have been shown to enhance the cytotoxic effects of DNA-damaging agents such as radiation and cisplatin. In this study, we found that histone deacetylase inhibits valproic acid (VPA), synergized with PARP1 inhibitor (PARPi), talazoparib (BMN-673), and alkylating agent, and temozolomide (TMZ) to induce DNA damage and reduce glioblastoma multiforme. At the molecular level, VPA leads to a downregulation of FANCD2 and RAD51, and the eradication of glioblastoma cells. The results of this study indicate that combining HDACi with PARPi could potentially enhance the treatment of glioblastoma, the most aggressive type of cancer that originates in the brain.

Bilateral subdiaphragmatic vagotomy modulates the peripheral met­enkephalin and striatal monoamine responses to peripheral inflammation in rat.

In the central nervous system, long­term effects of a vagotomy include disturbance of monoaminergic activity of the limbic system. Since low vagal activity is observed in major depression and autism spectrum disorder, the study aimed to determine whether animals fully recovered after subdiaphragmatic vagotomy demonstrates neurochemical indicators of altered well­being and social component of sickness behavior. Bilateral vagotomy or sham surgery was performed in adult rats. After one month of recovery, rats were challenged with lipopolysaccharide or vehicle to determine the role of central signaling upon sickness. Striatal monoamines and met­enkephalin concentrations were evaluated using HPLC and RIA methods. We also defined a concentration of immune­derived plasma met­enkephalin to establish a long­term effect of vagotomy on peripheral analgesic mechanisms. The data indicate that 30 days after vagotomy procedure, striatal dopaminergic, serotoninergic, and enkephalinergic neurochemistry was altered, both under physiological and inflammatory conditions. Vagotomy prevented inflammation­induced increases of plasma met­enkephalin - an opioid analgesic. Our data suggest that in a long perspective, vagotomized rats may be more sensitive to pain and social stimuli during peripheral inflammation.

Effect of selective cyclooxygenase inhibitors on animal behaviour and monoaminergic systems of the rat brain.

The long-term effects of cyclooxygenase 1 and 2 (COX-1/2) inhibitors are usually tested in terms of the periphery of the organism. Therefore, we studied the effects of SC560 (selective COX-1 inhibitor) and celecoxib (selective COX-2 inhibitor) on the activity of brain monoaminergic systems and animal behaviour. Additionally, we tested the effect of these inhibitors during inflammation. We have observed that long-term administration of celecoxib reduces the activity of the noradrenergic system, increases the activity of dopaminergic and serotonergic systems, increases locomotor activity, and enhances the exploratory behaviour of rats. Administration of SC560 also increases the activity of dopaminergic and serotonergic systems but reduces locomotor activity and impairs the exploratory behaviour of rats. The mechanism responsible for decreased activity of the noradrenergic system may be related to the weakening of activity of the positive feedback loop between the paraventricular nucleus and coeruleus locus. We suggest that the effect of used inhibitors on the dopaminergic system is associated with a possible increase in anandamide concentration and its effect on dopamine reuptake in synaptic clefts. It also appears that cyclooxygenase peroxidase activity may play a role in this process. In turn, changes in the activity of the serotonergic system may be related to the activity of indoleamine-2,3-dioxygenase, which decreases because of the decreased concentration of pro-inflammatory compounds. We believe that behavioural changes induced by COX inhibitors are the result of the modified activity of monoaminergic CNS systems in the brainstem, hypothalamus, and medial prefrontal cortex.

Hypothalamic Neurochemical Changes in Long-Term Recovered Bilateral Subdiaphragmatic Vagotomized Rats.

Background: Vagus nerve is one of the crucial routes in communication between the immune and central nervous systems. The impaired vagal nerve function may intensify peripheral inflammatory processes. This effect subsides along with prolonged recovery after permanent nerve injury. One of the results of such compensation is a normalized plasma concentration of stress hormone corticosterone - a marker of hypothalamic-pituitary-adrenal (HPA) axis activity. In this work, we strive to explain this corticosterone normalization by studying the mechanisms responsible for compensation-related neurochemical alterations in the hypothalamus. Materials and Methods: Using microarrays and high performance liquid chromatography (HPLC), we measured genome-wide gene expression and major amino acid neurotransmitters content in the hypothalamus of bilaterally vagotomized rats, 1 month after surgery. Results: Our results show that, in the long term, vagotomy affects hypothalamic amino acids concentration but not mRNA expression of tested genes. Discussion: We propose an alternative pathway of immune to CNS communication after vagotomy, leading to activation of the HPA axis, by influencing central amino acids and subsequent monoaminergic neurotransmission.

Peripheral and central compensatory mechanisms for impaired vagus nerve function during peripheral immune activation.

BACKGROUND: Determining the etiology and possible treatment strategies for numerous diseases requires a comprehensive understanding of compensatory mechanisms in physiological systems. The vagus nerve acts as a key interface between the brain and the peripheral internal organs. We set out to identify mechanisms compensating for a lack of neuronal communication between the immune and the central nervous system (CNS) during infection. METHODS: We assessed biochemical and central neurotransmitter changes resulting from subdiaphragmatic vagotomy and whether they are modulated by intraperitoneal infection. We performed a series of subdiaphragmatic vagotomy or sham operations on male Wistar rats. Next, after full, 30-day recovery period, they were randomly assigned to receive an injection of Escherichia coli lipopolysaccharide or saline. Two hours later, animal were euthanized and we measured the plasma concentration of prostaglandin E2 (with HPLC-MS), interleukin-6 (ELISA), and corticosterone (RIA). We also had measured the concentration of monoaminergic neurotransmitters and their metabolites in the amygdala, brainstem, hippocampus, hypothalamus, motor cortex, periaqueductal gray, and prefrontal medial cortex using RP-HPLC-ED. A subset of the animals was evaluated in the elevated plus maze test immediately before euthanization. RESULTS: The lack of immunosensory signaling of the vagus nerve stimulated increased activity of discrete inflammatory marker signals, which we confirmed by quantifying biochemical changes in blood plasma. Behavioral results, although preliminary, support the observed biochemical alterations. Many of the neurotransmitter changes observed after vagotomy indicated that the vagus nerve influences the activity of many brain areas involved in control of immune response and sickness behavior. Our studies show that these changes are largely eliminated during experimental infection. CONCLUSIONS: Our results suggest that in vagotomized animals with blocked CNS, communication may transmit via a pathway independent of the vagus nerve to permit restoration of CNS activity for peripheral inflammation control.

Fullerenol C60(OH)36 at relatively high concentrations impairs hippocampal theta oscillations (in vivo and in vitro) and triggers epilepsy (in vitro) - A dose response study.

Since the first identification of fullerenes (C60) and their synthesis in 1985, those compounds have been extensively studied in the biomedical field. In particular, their water-soluble derivatives, fullerenols (C60(OH)n, n = 2-48), have recently been the subject of numerous investigations concerning their antioxidant and prooxidant properties in biological systems. A small fraction of that research has focused on the possible use of C60 and C60(OH)n in neuroscience and the therapy of pathologies such as dementia, amyloid-ß (Aß) formation, and Parkinson's disease. However, only a few studies have focused on their direct effects on neuronal network viability and excitability, especially with the use of electrophysiological and electrochemical approaches. Therefore, we addressed the issue of the direct effect of hydroxylated fullerene nanoparticles C60(OH)36 on local field potentials at the hippocampal formation (HPC) level. With the use of in vitro hippocampal formation slices as a stable model of inducing theta oscillations, and an in vivo model of an anesthetized rat, herein we provide the first convergent electropharmacological evidence that C60(OH)36 at relatively high concentrations (60 µM and 80 µM in vitro; 0.2 µg/µl in vivo) is capable of attenuating the amplitude, power, and frequency of theta oscillations in the HPC neuronal network. At the same time, lower concentrations did not induce any apparent changes. Theta band oscillations constitute a key physiological phenotypic property, which served here as a sensitive assay enabling the study of neural network excitability. Moreover, we report that C60(OH)36 at the concentrations of 60 µM and 80 µM is capable of producing epilepsy in the HPC in vitro, which suggests that C60(OH)n, when applied at higher doses, may have a deleterious effect on the functioning of neuronal networks.