Brain Levels of Reduced Glutathione and Malondialdehyde in Honey-Fed Wistar Rats

This research sought to verify the effect of natural honey on brain levels of malondialdehyde (MDA) and reduced glutathione (GSH) in rats. Forty nine male and female Wistar rats were used for the experiment. The rats were allotted into seven groups of seven rats in each group. For one month, rats in groups 1-4 were fed with 100% feed, 20%, 30% and 40% honey respectively. The remaining 3 groups were fed with amounts of refined fructose and glucose equivalent to those in 20%, 30% and 40% honey. The brains were then excised, homogenized and used for biochemical analysis. Results showed that honey in all concentrations caused a significant increase in GSH levels but only 20% honey caused a significant decrease in MDA level when compared with control. Also, fructose feeding at 20%, 30% and 40% increased both brain GSH and MDA levels. Consequently, the influence of GSH as an antioxidant against brain lipid peroxidation needs further studies for better understanding since an increase in GSH for fructose- and honey-fed rats did not cause a simultaneous decrease in MDA content.

Psychopathic traits mediate guilt-related anterior midcingulate activity under authority pressure

Coercive power has different effects on individuals, and which were unable to be fully addressed in Milgram’s famous studies on obedience to authority. While some individuals exhibited high levels of guilt-related anxiety and refused orders to harm, others followed coercive orders throughout the whole event. The lack of guilt is a well-known characteristic of psychopathy, and recent evidence portrays psychopathic personalities on a continuum of clustered traits, while being pervasive in a significant proportion in the population. To investigate whether psychopathic traits better explain discrepancies in antisocial behavior under coercion, we applied a virtual obedience paradigm, in which an experimenter ordered subjects to press a handheld button to initiate successive actions that carry different moral consequences, during fMRI scanning. Psychopathic traits modulated the association between harming actions and guilt feelings on both behavioral and brain levels. This study sheds light on the individual variability in response to coercive power.

Microglial Heterogeneity and Its Potential Role in Driving Phenotypic Diversity of Alzheimer’s Disease

Alzheimer’s disease (AD) is increasingly recognized as a highly heterogeneous disorder occurring under distinct clinical and neuropathological phenotypes. Despite the molecular determinants of such variability not being well defined yet, microglial cells may play a key role in this process by releasing distinct pro- and/or anti-inflammatory cytokines, potentially affecting the expression of the disease. We carried out a neuropathological and biochemical analysis on a series of AD brain samples, gathering evidence about the heterogeneous involvement of microglia in AD. The neuropathological studies showed differences concerning morphology, density and distribution of microglial cells among AD brains. Biochemical investigations showed increased brain levels of IL-4, IL-6, IL-13, CCL17, MMP-7 and CXCL13 in AD in comparison with control subjects. The molecular profiling achieved by measuring the brain levels of 25 inflammatory factors known to be involved in neuroinflammation allowed a stratification of the AD patients in three distinct “neuroinflammatory clusters”. These findings strengthen the relevance of neuroinflammation in AD pathogenesis suggesting, in particular, that the differential involvement of neuroinflammatory molecules released by microglial cells during the development of the disease may contribute to modulate the characteristics and the severity of the neuropathological changes, driving—at least in part—the AD phenotypic diversity.

The effects of methylated flavonoids on depression-like activity and pro-inflammatory cytokine thresholds in mice induced by repeated finasteride administration

The aim of the study was to investigate the influence of naringenin (NGN) and its methylated derivatives (50 or 100 mg kg−1) on finasteride-caused depression-like performance in mice to identify the effects on behavior and biomarkers of inflammation in the management of depression. Depression-like behavior was induced by repeated dose of finasteride (100 mg kg−1, subcutaneously) in mice. The effects of the naringenin (50 or 100 mg kg−1) or its methylated derivatives (Ngn-M; 50 or 100 mg kg−1 or Ngn-DM; 50 or 100 mg kg−1) and duloxetine (DXT, 10 mg kg−1) were evaluated for the immobility time in tail suspension and forced swimming tests following finasteride pre-treatment. The levels of brain pro-inflammatory cytokines such as IL-1β and TNF-α were also measured by Enzyme-Linked Immunosorbent Assay to further evaluate the impact of naringenin and its methylated derivatives on inflammation. Pre-treatment with finasteride substantially increased both the immobility time spent in tail suspension and forced swimming tests and brain levels of IL-1β and TNF–α in mice. Doluxetine (DLX) was given at a dose of 10 mg kg−1, and Naringenin or its methylated derivatives were given at doses of 50 and 100 mg kg−1 orally. It reduced immobility time in both tests, restored the preference to sucrose solution, and normalized cytokine levels (p < 0.01) in mice. Similar effects were observed with DTX (10 mg kg−1) as positive control. The increased brain levels of malondialdehyde (MDA) or nitrite were considerably (p < 0.05) decreased while substantially (p < 0.05) increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels after finasteride pre-treatment relative to vehicle-control by naringenin or its methylated derivatives (50 or 100 mg kg−1). These findings demonstrated the potential for methylated flavonoids as safe and effective anti-depressive agents.

Metabolomics of Rat Brain After Treatment with Phenelzine: High-Resolution Mass Spectrometric Demonstration of Increased Brain Levels of N-Acetyl Amino Acids

Background: Phenelzine (PLZ) is a non-specific monoamine oxidase inhibitor that has demonstrated clinical efficacy in patients with treatment resistant depression. The mechanism of action with regard to this efficacy is complicated in that its metabolite, β-phenylethylidenehydrazine (PEH), is an inhibitor of amino acid transaminases resulting in dramatic brain elevations of GABA, alanine, ornithine and tyrosine. The full neurochemical profile of PLZ and PEH remain to be explored. Objective: To undertake a non-targeted metabolomics study of phenelzine on rat brain neurochemistry. Methods: We undertook a high-resolution mass spectrometric metabolomics analysis of rat cortical brain 1 and 12 hours after intraperitoneal dosing with PLZ or PEH. Tandem mass spectrometry was utilized to obtain relative quantitation data. Results: N-acetyl amino acids were found to be elevated in cortical brain tissue following either PLZ or PEH treatments. Conclusions: Our data indicate PLZ treatment significantly augments brain levels of N-acetyl amino acids and that this may involve inhibition of deacylases by PEH and/or induction of N-amino acid acetyltransferases.

Pharmacokinetic profile of the selective 5-HT3 receptor antagonist ondansetron in the rat: an original study and a minireview of the behavioural pharmacological literature in the rat

The availability of agonists and antagonists to modulate the activity of the 5-hydroxytryptamine (5-HT) type 3 (5-HT3) receptor has renewed interest in its role as a therapeutic target. Ondansetron is a highly selective 5-HT3 receptor antagonist that is well tolerated as an anti-emetic for patients undergoing chemotherapy. Preclinical studies in rat have shown the effects of small doses of ondansetron on cognition, behavioural sensitisation, and epilepsy. However, the pharmacokinetic (PK) profile of ondansetron in rat has not been described, which limits the translational relevance of these findings. Here, we aim to determine, in the rat, the PK profile of ondansetron in the plasma and to determine associated brain levels. The plasma PK profile was determined following acute subcutaneous administration of ondansetron (0.1, 1, and 10 μg/kg). Brain levels were measured following subcutaneous administration of ondansetron at 1 μg/kg. Plasma and brain levels of ondansetron were determined using high-performance liquid chromatography – tandem mass spectrometry. Following administration of all three doses, measured ondansetron plasma levels (≈30–3000 pg/mL) were below levels achieved with doses usually administered in the clinic, with a rapid absorption phase and a short half-life (≈30–40 min). We also found that brain levels of ondansetron at 1 μg/kg were significantly lower than plasma levels, with brain to plasma ratios of 0.45 and 0.46 in the motor and pre-frontal cortices. We discuss our findings in the context of a minireview of the literature. We hope that our study will be helpful to the design of preclinical studies with therapeutic end-points.