Paliperidone Prevents Brain Toll-Like Receptor 4 Pathway Activation and Neuroinflammation in Rat Models of Acute and Chronic Restraint Stress

Abstract

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.

The Atypical Antipsychotic Paliperidone Regulates Endogenous Antioxidant/Anti-Inflammatory Pathways in Rat Models of Acute and Chronic Restraint Stress

“…Furthermore, NRF2 knockdown in astrocytes abrogated the neuroprotective effect of 15d-PGJ 2 , as well as 15d-PGJ 2 -facilitated ARE-dependent antioxidant enzyme gene induction [9]. Both pathways are regulated by paliperidone in animal models of acute/chronic stress and could be implicated, at least in part, in the effects reported here [25,29].…”

“…Vetoquinol®, Madrid, Spain). Paliperidone was chosen in the present study considering previous reports have showed an immunomodulatory role of paliperidone in animal models based on acute/chronic stress exposure [25]. The dose of paliperidone (1 mg/kg) was chosen on the basis of previous in vivo determinations of signaling pathways related to oxidative stress, cytokines, and synaptic plasticity in the PFCof Sprague-Dawley rats [26].…”

The Cross-Talk Between the Dopaminergic and the Immune System Involved in Schizophrenia

“…Another example illustrating the role of antipsychotic drugs is the study of the effect of paliperidone in neuroinflammation. The authors show that the pre-treatment of rats with paliperidone inhibited the stimulation of toll-like receptor 4 (TLR4) in a model of neuroinflammation induced by stress (Macdowell et al, 2014). In the same direction, another study has shown that haloperidol attenuates the activation of NF-kB, and consequently abrogated the production of pro-inflammatory cytokines in macrophages in response to lipopolysaccharide (LPS) (Yamamoto et al, 2016).…”

Evidence of activation of the Toll-like receptor-4 proinflammatory pathway in patients with schizophrenia

“…26 Finally, paliperidone regulates stress-induced activation of TLR4 in animal models. 27 Taking into consideration all this background, in the present study we aimed to determine and report putative modifications of the TLR4 signalling pathway by using 2 different approaches: 1) quantification of protein and mRNA expression in postmortem prefrontal cortex (PFC) samples and 2) genetic association analysis to identify single nucleotide polymorphisms (SNPs) associated with schizophrenia.…”