Search

Attention-deficit/hyperactivity disorder (ADHD) is a highly heterogeneous disorder characterized by impairing levels of hyperactivity, impulsivity and inattention. Oxidative and inflammatory parameters have been recognized among its multiple predisposing pathways, and clinical studies indicate that ADHD patients have increased oxidative stress. In this study, we aimed to evaluate oxidative (DCFH oxidation, glutathione levels, glutathione peroxidase, catalase and superoxide dismutase activities) and inflammatory (TNF-α, IL-1β and IL-10) parameters in the most widely accepted animal model of ADHD, the spontaneously hypertensive rats (SHR). Prefrontal cortex, cortex (remaining regions), striatum and hippocampus of adult male SHR and Wistar Kyoto rats were studied. SHR presented increased reactive oxygen species (ROS) production in the cortex, striatum and hippocampus. In SHR, glutathione peroxidase activity was decreased in the prefrontal cortex and hippocampus. TNF-α levels were reduced in the prefrontal cortex, cortex (remaining regions), hippocampus and striatum of SHR. Besides, IL-1β and IL-10 levels were decreased in the cortex of the ADHD model. Results indicate that SHR presented an oxidative profile that is characterized by an increase in ROS production without an effective antioxidant counterbalance. In addition, this strain showed a decrease in cytokine levels, mainly TNF-α, indicating a basal deficit. These results may present a new approach to the cognitive disturbances seen in the SHR.

Alcoholism has been characterized as a systemic pro-inflammatory condition and alcohol withdrawal has been linked to various changes in the brain homeostasis, including oxidative stress and glutamate hyperactivity. N-acetylcysteine (NAC) is an anti-inflammatory and antioxidant multi-target drug with promising results in psychiatry, including drug addiction. We assessed the effects of NAC on the serum and brain inflammatory cytokines after cessation of chronic alcohol treatment in rats. Male Wistar rats received 2 g/kg alcohol or vehicle twice a day by oral gavage for 30 days. Rats were treated, from day 31 to 34, with NAC (60 or 90 mg/kg) or saline, intraperitoneally, once daily. Rats were sacrificed at day 35, trunk blood was collected and the frontal cortex and hippocampus dissected for assessment of TNF-α, IL-1β, IL-6, IL-18, IL-10. NAC prevented the increase of pro-inflammatory cytokines and the decrease of anti-inflammatory cytokine in the frontal cortex and hippocampus. No changes were observed on serum cytokines. We conclude that NAC protects against inflammation induced by chronic (30 days) alcohol ingestion followed by 5 days cessation in two rat brain areas. Because inflammation has been documented and associated with craving and relapse in alcoholics, the data revealed by this study points to the validity of NAC clinical evaluation in the context of alcohol detoxification and withdrawal.

Astrocytes are multitasking players in brain complexity, possessing several receptors and mechanisms to detect, participate and modulate neuronal communication. The functionality of astrocytes has been mainly unraveled through the study of primary astrocyte cultures, and recently our research group characterized a model of astrocyte cultures derived from adult Wistar rats. We, herein, aim to characterize other basal functions of these cells to explore the potential of this model for studying the adult brain. To characterize the astrocytic phenotype, we determined the presence of GFAP, GLAST and GLT 1 proteins in cells by immunofluorescence. Next, we determined the concentrations of thirteen amino acids, ATP, ADP, adenosine and calcium in astrocyte cultures, as well as the activities of Na(+)/K(+)-ATPase and acetylcholine esterase. Furthermore, we assessed the presence of the GABA transporter 1 (GAT 1) and cannabinoid receptor 1 (CB 1) in the astrocytes. Cells demonstrated the presence of glutamine, consistent with their role in the glutamate-glutamine cycle, as well as glutamate and D-serine, amino acids classically known to act as gliotransmitters. ATP was produced and released by the cells and ADP was consumed. Calcium levels were in agreement with those reported in the literature, as were the enzymatic activities measured. The presence of GAT 1 was detected, but the presence of CB 1 was not, suggesting a decreased neuroprotective capacity in adult astrocytes under in vitro conditions. Taken together, our results show cellular functionality regarding the astrocytic role in gliotransmission and neurotransmitter management since they are able to produce and release gliotransmitters and to modulate the cholinergic and GABAergic systems.

Resveratrol, a phytoalexin found in grapes and wine, exhibits antioxidant, anti-inflammatory, anti-aging and antitumor activities. Resveratrol also protects neurons and astrocytes in several neurological disease models. Astrocytes are responsible for modulating neurotransmitter systems, synaptic information, ionic homeostasis, energy metabolism, antioxidant defense and inflammatory response. In previous work, we showed that resveratrol modulates important glial functions, including glutamate uptake, glutamine synthetase activity, glutathione (GSH) levels and inflammatory response. Furthermore, astrocytes express toll-like receptors that specifically recognize lipopolysaccharide (LPS), which has been widely used to study experimentally inflammatory response. In this sense, LPS may stimulate pro-inflammatory cytokines release and oxidative stress. Moreover, there is interplay between these signals through signaling pathways such as NFκB, HO-1 and MAPK. Thus, here, we evaluated the effects of resveratrol on LPS-stimulated inflammatory response in hippocampal primary astrocyte cultures and the putative role of HO-1, p38 and ERK pathways in the protective effect of resveratrol. LPS increased the levels of TNF-α, IL-1β, IL-6 and IL-18 and resveratrol prevented these effects. Resveratrol also prevented the oxidative and nitrosative stress induced by LPS as well as the decrease in GSH content. Additionally, we demonstrated the involvement of NFκB, HO-1, p38 and ERK signaling pathways in the protective effect of resveratrol, providing the first mechanistic explanation for these effects in hippocampal astrocytes. Our findings reinforce the neuroprotective effects of resveratrol, which are mainly associated with anti-inflammatory and antioxidant activities.