Search

ObjectivesThere is a need to explore novel mechanisms of action of existing/new antipsychotics. One potential candidate is the endocannabinoid system (ECS). The present study tried to elucidate the effects of the antipsychotic paliperidone on stress-induced ECS alterations.MethodsWister rats were submitted to acute/chronic restraint stress. Paliperidone (1 mg/kg) was given prior each stress session. Cannabinoid receptors and endocannabinoids (eCBs) synthesis and degradation enzymes were measured in prefrontal cortex (PFC) samples by RT-PCR and Western Blot.ResultsIn the PFC of rats exposed to acute stress, paliperidone increased CB1 receptor (CB1R) expression. Furthermore, paliperidone increased the expression of the eCB synthesis enzymesN-acylphosphatidylethanolamine- hydrolysing phospholipase D and DAGLα, and blocked the stress-induced increased expression of the degrading enzyme fatty acid amide hydrolase. In chronic conditions, paliperidone prevented the chronic stress-induced down-regulation of CB1R, normalised DAGLα expression and reverted stress-induced down-regulation of the 2-AG degrading enzyme monoacylglycerol lipase. ECS was analysed also in periphery. Acute stress decreased DAGLα expression, an effect prevented by paliperidone. Contrarily, chronic stress increased DAGLα and this effect was potentiated by paliperidone.ConclusionsThe results obtained described a preventive effect of paliperidone on stress-induced alterations in ECS. Considering the diverse alterations on ECS described in psychotic disease, targeting ECS emerges as a new therapeutic possibility. [ABSTRACT FROM PUBLISHER]

Background: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile. Methods: We tested whether oleoylethanolamide/palmitoylethanolamide (10mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5mg/kg, i.p.) in rats. Results: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2-) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1β, cyclooxygenase-2, and prostaglandin E2 and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test. Conclusions: Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinlammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinlammatory component. [ABSTRACT FROM AUTHOR]

A colloidal synthesis' proof-of-concept based on the Bligh-Dyer emulsion inversion method was designed for integrating into lipid nanoparticles (LNPs) cell-permeating DNA antisense oligonucleotides (ASOs), also known as GapmeRs (GRs), for mRNA interference. The GR@LNPs were formulated to target brain border-associated macrophages (BAMs) as a central nervous system (CNS) therapy platform for silencing neuroinflammation-related genes. We specifically aim at inhibiting the expression of the gene encoding for lipocalin-type prostaglandin D synthase (L-PGDS), an anti-inflammatory enzyme expressed in BAMs, whose level of expression is altered in neuropsychopathologies such as depression and schizophrenia. The GR@LNPs are expected to demonstrate a bio-orthogonal genetic activity reacting with L-PGDS gene transcripts inside the living system without interfering with other genetic or biochemical circuitries. To facilitate selective BAM phagocytosis and avoid subsidiary absorption by other cells, they were functionalized with a mannosylated lipid as a specific MAN ligand for the mannose receptor presented by the macrophage surface. The GR@LNPs showed a high GR-packing density in a compact multilamellar configuration as structurally characterized by light scattering, zeta potential, and transmission electronic microscopy. As a preliminary biological evaluation of the mannosylated GR@LNP nanovectors into specifically targeted BAMs, we detected in vivo gene interference after brain delivery by intracerebroventricular injection (ICV) in Wistar rats subjected to gene therapy protocol. The results pave the way towards novel gene therapy platforms for advanced treatment of neuroinflammation-related pathologies with ASO@LNP nanovectors., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Calero, Moleiro, Sayd, Dorca, Miquel-Rio, Paz, Robledo-Montaña, Enciso, Acción, Herráez-Aguilar, Hellweg, Sánchez, Bortolozzi, Leza, García-Bueno and Monroy.)

Physiologically, lipopolysaccharide (LPS) is present in the bloodstream and can be bound to several proteins for its transport (i.e.) LPS binding protein (LBP) and plasma lipoproteins). LPS receptors CD14 and TLR-4 are constitutively expressed in the Central Nervous System (CNS). To our knowledge, LPS infiltration in CNS has not been clearly demonstrated. A naturalistic experiment with healthy rats was performed to investigate whether LPS is present with its receptors in brain. Immunofluorescences showed that lipid A and core LPS were present in circumventricular organs, choroid plexus, meningeal cells, astrocytes, tanycytes and endothelial cells. Co-localization of LPS regions with CD14/TLR-4 was found. The role of lipoprotein receptors (SR-BI, ApoER2 and LDLr) in the brain as targets for a LPS transport mechanism by plasma apolipoproteins (i.e. ApoAI) was studied. Co-localization of LPS regions with these lipoproteins markers was observed. Our results suggest that LPS infiltrates in the brain in physiological conditions, possibly, through a lipoprotein transport mechanism, and it is bound to its receptors in blood-brain interfaces.

Background: The acylethanolamides oleoylethanolamide and palmitoylethanolamide are endogenous lipid mediators with proposed neuroprotectant properties in central nervous system (CNS) pathologies. The precise mechanisms remain partly unknown, but growing evidence suggests an antiinflammatory/antioxidant profile., Methods: We tested whether oleoylethanolamide/palmitoylethanolamide (10 mg/kg, i.p.) attenuate neuroinflammation and acute phase responses (hypothalamus-pituitary-adrenal (HPA) stress axis stress axis activation, thermoregulation, and anhedonia) induced by lipopolysaccharide (0.5 mg/kg, i.p.) in rats., Results: Lipopolysaccharide increased mRNA levels of the proinflammatory cytokines tumor necrosis factor-α, interleukin-1β, and interleukin-6, nuclear transcription factor-κB activity, and the expression of its inhibitory protein IκBα in cytoplasm, the inducible isoforms of nitric oxide synthase and cyclooxygenase-2, microsomal prostaglandin E2 synthase mRNA, and proinflammatory prostaglandin E2 content in frontal cortex 150 minutes after administration. As a result, the markers of nitrosative/oxidative stress nitrites (NO2(-)) and malondialdehyde were increased. Pretreatment with oleoylethanolamide/ palmitoylethanolamide reduced plasma tumor necrosis factor-α levels after lipopolysaccharide, but only oleoylethanolamide significantly reduced brain tumor necrosis factor-α mRNA. Oleoylethanolamide and palmitoylethanolamide prevented lipopolysaccharide-induced nuclear transcription factor-κB (NF-κB)/IκBα upregulation in nuclear and cytosolic extracts, respectively, the expression of inducible isoforms of nitric oxide synthase, cyclooxygenase-2, and microsomal prostaglandin E2 synthase and the levels of prostaglandin E2. Additionally, both acylethanolamides reduced lipopolysaccharide-induced oxidative/nitrosative stress. Neither oleoylethanolamide nor palmitoylethanolamide modified plasma corticosterone levels after lipopolysaccharide, but both acylethanolamides reduced the expression of hypothalamic markers of thermoregulation interleukin-1β, cyclooxygenase-2, and prostaglandin E2, and potentiated the hypothermic response after lipopolysaccharide. Interestingly, only oleoylethanolamide disrupted lipopolysaccharide-induced anhedonia in a saccharine preference test., Conclusions: Results indicate that oleoylethanolamide and palmitoylethanolamide have antiinflammatory/neuroprotective properties and suggest a role for these acylethanolamides as modulators of CNS pathologies with a neuroinflammatory component., (© The Author 2015. Published by Oxford University Press on behalf of CINP.)