Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress
نویسندگان
چکیده
BACKGROUND Alterations in the innate immune/inflammatory system have been proposed to underlie the pathophysiology of psychotic disease, but the mechanisms implicated remain elusive. The main agents of the innate immunity are the family of toll-like receptors (TLRs), which detect circulating pathogen-associated molecular patterns and endogenous damage-associated molecular patterns (DAMPS). Current antipsychotics are able to modulate pro- and anti-inflammatory pathways, but their actions on TLRs remain unexplored. METHODS This study was conducted to elucidate the effects of paliperidone (1mg/Kg i.p.) on acute (6 hours) and chronic (6 hours/day during 21 consecutive days) restraint stress-induced TLR-4 pathway activation and neuroinflammation, and the possible mechanism(s) related (bacterial translocation and/or DAMPs activation). The expression of the elements of a TLR-4-dependent proinflammatory pathway was analyzed at the mRNA and protein levels in prefrontal cortex samples. RESULTS Paliperidone pre-treatment prevented TLR-4 activation and neuroinflammation in the prefrontal cortices of stressed rats. Regarding the possible mechanisms implicated, paliperidone regulated stress-induced increased intestinal inflammation and plasma lipopolysaccharide levels. In addition, paliperidone also prevented the activation of the endogenous activators of TLR-4 HSP70 and HGMB-1. CONCLUSIONS Our results showed a regulatory role of paliperidone on brain TLR-4, which could explain the therapeutic benefits of its use for the treatment of psychotic diseases beyond its effects on dopamine and serotonin neurotransmission. The study of the mechanisms implicated suggests that gut-increased permeability, inflammation, and bacterial translocation of Gram-negative microflora and HSP70 and HGMB1 expression could be potential adjuvant therapeutic targets for the treatment of psychotic and other stress-related psychiatric pathologies.
منابع مشابه
P 79: Neuroinflammation: A Common Phenomenon between Chronic Pain and Opioids
Chronic pain is a prevalent and debilitating condition, conveying immense human burden. Suffering from chronic pain is not only caused by painful symptomatology, but also through a wide range of psychopathological and physical consequences, including depression and anxiety disorders, impaired sleep and cognition, cardiovascular morbidity and impaired sexual function, all contributing to diminis...
متن کاملP 61: MicroRNA as a Therapeutic Tool to Prevent Blood Brain Barrier Dysfunction in Neuroinflammation
Endothelial cells present in brain are unique and differ from other peripheral tissues in a number of ways, which ensures specific brain endothelial barrier properties. Endothelial dysfunction is the earliest event in the initiation of vascular damage caused by inflammation. Various microRNAs (miRNA) have been discovered in different cellular components of the blood bran barrier (BBB). miRNAs a...
متن کاملP 115: Potential Therapeutic Targets Related to Neuroinflammation in Treatment and Prevention of Autism
Autism spectrum disorder (ASD) is a mental condition, present from early childhood, characterized by great difficulty in communicating and forming relationships with others and using language. In the last four decades many studies have shown that immune responses in different regions of brain play an important role in ASD pathogenicity. A conservative estimate based on the research suggests tha...
متن کاملEvaluation of the role of TLR4 in endotoxin-induced hepatic encephalopathy in rats with biliary cirrhosis
Background: Hepatic encephalopathy is defined as a neuropsychiatric brain dysfunction in acute or chronic liver failure. Infection and inflammation have crucial role in its pathophysiology. The purpose of our study was to demonstrate the relationship between toll-like receptor 4 (TLR4) expression and the encephalopathy induced with endotoxin in biliary cirrhotic rats. Methods: The present stud...
متن کاملLipopolysaccharide Induced Activation of Toll Like Receptor 4 in Isolated Rat Heart Suggests a Local Immune Response in Myocardium
Background: Myocardial dysfunction is one of the major complications in patients with sepsis where there is a relationship between the blood level of cytokines and the onset of myocardial depression. In many cases of sepsis, the presence of Lipopolysaccharide (LPS) has been established. LPS Binding Protein (LBP) bound endotoxin is recognized by CD14/toll-like receptor-4 (TLR4) complexes in inna...
متن کامل