The NADPH oxidase NOX2 as a novel biomarker for suicidality: Evidence from human post mortem brain samples

Recent evidence points towards a role of oxidative stress in suicidality. However, few studies were carried out on the sources of reactive oxygen species (ROS) in subjects with suicidal behaviour. We have previously demonstrated that the NADPH oxidase NOX2-derived oxidative stress has a major role in the development of neuropathological alterations observed in an animal model of psychosis. Here, we investigated the possible increase in NOX2 in post mortem brain samples of subjects who died by asphyctic suicide (AS) compared with controls (CTRL) and subjects who died by non-suicidal asphyxia (NSA). We found that NOX2 expression was significantly higher in the cortex of AS subjects than in the other two experimental groups. NOX2 immunostaining was mainly detected in GABAergic neurons, with a minor presence of NOX2-positive-stained cells in glutamatergic and dopaminergic neurons, as well as astrocytes and microglia. A sustained increase in the expression of 8-hydroxy-2'-deoxyguanosine, an indirect marker of oxidative stress, was also detected in the cortex of AS subjects, compared with CTRL and NSA subjects. A significant elevation in cortical interleukin-6 immunoreactivity in AS subjects suggested an involvement of cytokine-associated molecular pathways in NOX2 elevations. Our results suggest that the increase in NOX2-derived oxidative stress in the brain might be involved in the neuropathological pathways leading to suicidal behaviour. These results may open innovative insights in the identification of new pathogenetic and necroscopic biomarkers, predictive for suicidality and potentially useful for suicide prevention

Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity

Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorder, is a fatal global burden for the elder population. Although many efforts have been made, the search of a curative therapy is still ongoing. Individuating phenotypic traits that might help in investigating treatment response is of growing interest in AD research. AD is a complex pathology characterized by many comorbidities, such as depression and increased susceptibility to pain perception, leading to postulate that these conditions may rely on common biological substrates yet to be determined. In order to investigate those biological determinants to be associable with phenotypic traits, we used the rat model of amyloid beta-induced toxicity. This established model of early phase of AD is obtained by the intracerebroventricular injection of soluble amyloid beta1-42 (Aβ) peptide 7 days before performing experiments. In this model, we have previously reported increased immobility in the forced swimming test, reduced cortical serotonin levels and subtle alterations in the cognitive domain a depressive-like phenotype associated with subtle alteration in memory processes. In light of evaluating pain perception in this animal model, we performed two different behavioral tests commonly used, such as the paw pressure test and the cold plate test, to analyze mechanical hyperalgesia and thermal allodynia, respectively. Behavioural outcomes confirmed the memory impairment in the social recognition test and, compared to sham, Aβ-injected rats showed an increased selective susceptibility to mechanical but not to thermal stimulus. Behavioural data were then corroborated by neurochemical and biochemical biomarker analyses either at central or peripheral level. Data showed that the peptide injection evoked a significant increase in hypothalamic glutamate, kynurenine and dopamine content, while serotonin levels were reduced. Plasma Cystatin-C, a cysteine protease, was increased while serotonin and melatonin levels were decreased in Aβ-injected rats. Urinary levels paralleled plasma quantifications, indicating that Aβ-induced deficits in pain perception, mood and cognitive domain may also depend on these biomarkers. In conclusion, in the present study, we demonstrated that this animal model can mimic several comorbid conditions typical of the early phase of AD. Therefore, in the perspective of generating novel therapeutic strategies relevant to precision medicine in AD, this animal model and the biomarkers evaluated herein may represent an advantageous approach

Anabolic androgenic steroid abuse in the United Kingdom: An update

© 2020 The British Pharmacological Society. This is the peer reviewed version of the following article: Mullen, C, Whalley, BJ, Schifano, F, Baker, JS. Anabolic Androgenic Steroid Abuse in the United Kingdom; An Update The increasing popularity of anabolic androgenic steroids. Br J Pharmacol. 2020, which has been published in final form at https://doi.org/10.1111/bph.14995. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.Anabolic androgenic steroids (AASs) are prescribed for medical conditions related to low testosterone. Abuse of AASs has surged as they become recognised as potent image enhancement drugs. The primary goal of most abusers is to obtain a more attractive outward appearance. Abuse is complex. There are a vast range of AAS substances illegally available, the nature of their true composition is difficult to evaluate. Users follow dosing patterns which incorporate a number of different AASs, in addition to other pharmaceutical substances believed to complement the desired physical effects or manage unwanted effects. Animal work and medical case reports suggest potential to cause serious hepatotoxicity, plus possible neurotoxicity, nephrotoxicity and damage to the cardiovascular and reproductive systems. As the long-term AASs users reach maturity, further controlled experimentation, with larger sample sizes, is required. Data gathering should be directed towards the most vulnerable group of AAS users, females and adolescent boys.Peer reviewedFinal Accepted Versio

Precision Medicine in Alzheimer’s Disease: Investigating Comorbid Common Biological Substrates in the Rat Model of Amyloid Beta-Induced Toxicity

Alzheimer’s disease (AD), one of the most widespread neurodegenerative disorder, is a fatal global burden for the elder population. Although many efforts have been made, the search of a curative therapy is still ongoing. Individuating phenotypic traits that might help in investigating treatment response is of growing interest in AD research. AD is a complex pathology characterized by many comorbidities, such as depression and increased susceptibility to pain perception, leading to postulate that these conditions may rely on common biological substrates yet to be determined. In order to investigate those biological determinants to be associable with phenotypic traits, we used the rat model of amyloid beta-induced toxicity. This established model of early phase of AD is obtained by the intracerebroventricular injection of soluble amyloid beta1-42 (Aβ) peptide 7 days before performing experiments. In this model, we have previously reported increased immobility in the forced swimming test, reduced cortical serotonin levels and subtle alterations in the cognitive domain a depressive-like phenotype associated with subtle alteration in memory processes. In light of evaluating pain perception in this animal model, we performed two different behavioral tests commonly used, such as the paw pressure test and the cold plate test, to analyze mechanical hyperalgesia and thermal allodynia, respectively. Behavioural outcomes confirmed the memory impairment in the social recognition test and, compared to sham, Aβ-injected rats showed an increased selective susceptibility to mechanical but not to thermal stimulus. Behavioural data were then corroborated by neurochemical and biochemical biomarker analyses either at central or peripheral level. Data showed that the peptide injection evoked a significant increase in hypothalamic glutamate, kynurenine and dopamine content, while serotonin levels were reduced. Plasma Cystatin-C, a cysteine protease, was increased while serotonin and melatonin levels were decreased in Aβ-injected rats. Urinary levels paralleled plasma quantifications, indicating that Aβ-induced deficits in pain perception, mood and cognitive domain may also depend on these biomarkers. In conclusion, in the present study, we demonstrated that this animal model can mimic several comorbid conditions typical of the early phase of AD. Therefore, in the perspective of generating novel therapeutic strategies relevant to precision medicine in AD, this animal model and the biomarkers evaluated herein may represent an advantageous approach

Role of CREB-binding protein on histone acetylation and cocaine-associated behaviors

Evidence shows that cocaine exposure triggers altered gene expression within the nucleus accumbens, contributing to the development and persistence of drug addiction. Chromatin modification is emerging as a major molecular mechanism involved in the regulation of gene expression critical for long lasting forms of synaptic plasticity, memory processes, and drug-induced neural and behavioral change. Cocaine induces specific chromatin modifications, such as histone acetylation, that modulate histone-DNA interactions and the recruitment of transcriptional regulatory complexes, leading to changes in transcription that may underlie aspects of cocaine addiction. Although changes in histone acetylation in response to cocaine have been documented, relatively little is known about the specific histone acetylation enzymes involved in cocaine-induced plasticity. The enzymes that regulate levels of histone acetylation are histone acetyltransferases (HATs) and histone deacetylases (HDACs), which generally promote or silence gene expression, respectively. Studies have demonstrated that HDACs may negatively regulate cocaine-induced behaviors, but very little is known about the role of specific HATs in long-lasting drug induced plasticity. The histone acetyltransferase CREB-binding protein (CBP) mediates transcriptional activation by recruiting basal transcription machinery and acetylating histones. CBP is a critically important chromatin modifying enzyme involved in regulating gene expression required for long-term plasticity and memory. However, the role of CBP in cocaine-induced behaviors remains largely unknown. We examined the role of CBP in drug-induced plasticity using CBP-FLOX genetically modified mice in combination with adeno-associated virus expressing Cre-recombinase to generate focal homozygous deletions of Cbp in the nucleus accumbens (NAc). A complete loss of CBP in NAc neurons results in decreased histone acetylation and significantly altered c-fos expression in response to cocaine. Furthermore, the deletion of CBP in the NAc correlates with significant impairments in cocaine sensitivity and context-cocaine associated memory. This is the first study to demonstrate a definitive role for CBP in modulating gene expression that may subserve drug-seeking behaviors

The heme oxygenase/biliverdin reductase system as effector of the neuroprotective outcomes of herb-based nutritional supplements

Over the last few years, several preclinical studies have shown that some herbal products, such as ferulic acid, Ginkgo biloba, and resveratrol, exert neuroprotective effects through the modulation of the heme oxygenase/biliverdin reductase system. Unfortunately, sufficient data supporting the shift of knowledge from preclinical studies to humans, particularly in neurodegenerative diseases, are not yet available in the literature. The purpose of this review is to summarize the studies and the main results achieved on the potential therapeutic role of the interaction between the heme oxygenase/biliverdin reductase system with ferulic acid, G. biloba, and resveratrol. Some critical issues have also been reported, mainly concerning the safety profile and the toxicological sequelae associated to the supplementation with the herbs mentioned above, based on both current literature and specific reports issued by the competent Regulatory Authorities