Sigma receptor 1 (Sig1R) and 2 (Sig2R) are expressed in central nervous system, in neurons and microglia. Modulation of these receptors has been identified for the treatment of inflammatory and neurodegenerative disorders, including Alzheimer's disease (AD). This research evaluated the impact of BBZI, a novel pan‐selective Sig1R‐Sig2R ligand in mouse models of Alzheimer's disease and microglia activation.BBZI has high affinity Sig1R‐Sig2R (Sig1R: Ki=0.8nM; Sig2R: Ki=2.5nM), with 100‐fold selectivity over a panel of 30 other receptors. Twelve‐month old Senescence Accelerated Mouse Prone‐8 (SAMP8) and 3xTg AD mice were treated with BBZI (i.c.v.) across a dosing range (0, 0.001, 0.01, 0.1, 1.0μg), and assessed for memory response via T‐maze. BBZI was also evaluated in BV2 microglia cells concurrent with inflammatory activation via lipopolysaccharide (LPS). After plating for 24hrs, cells were treated for 24hrs with BBZI (0, 10, 100, 1000nM) against LPS (0, 10, 100ng/mL). Alamar Blue (cellular proliferation) and nitrite (surrogate of nitric oxide) output in media.BBZI significantly enhanced memory in SAMP8 mice at both 0.001μg and 0.01μg doses (p<0.01), and in 3xTg mice at 0.01μg dose (p<0.05), compared to vehicle controls. The mean percent reduction of alamar blue decreased with increasing concentrations of BBZI (p<0.05). The mean percent reduction of alamar blue was significantly lower for 1000nM BBZI compared to 0nM BBZI (p<0.05). No significant difference in nitrite level was observed with increasing concentrations of BBZI (p=0.65).These results identify pan‐selective Sig1R‐Sig2R ligand capacity to enhance memory in two age mouse models of AD, with further capacity to impact of microglial proliferation. Such a pan‐selective ligand shows viability for treatment of cognitive and neurodegenerative conditions.Support or Funding InformationThis work was supported by the School of Pharmacy, Southern Illinois University Edwardsville.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The impact of diet on brain health extends to the blood‐brain barrier (BBB). Western diets high in saturated fatty acids, such as lard, increase the risk for neurodegenerative disease and cerebrovascular dysfunction. Whereas, fish‐oil (FO) diets containing long‐chain polyunsaturated fatty acids can form products that reduce inflammation and have been identified to have cerebrovascular benefit. However, the impact of dietary fats on the BBB endothelial cell tight junctions remains unclear. BBB tight junction integrity is governed by key proteins, including claudin‐5, occludin, and zonula occluden‐1 (ZO1). This study examined the effect of lard and FO based diets on these key tight junctional proteins. Male C57BL/6J mice received a diet containing either 10% lard, 10% FO, 41% lard or 41% FO over 32 weeks. Cortical brain tissue was harvested at conclusion of treatment, with protein (Western blot) and mRNA (RT‐qPCR) expression analyses performed. Body weights and blood chemistry measures were also evaluated. Two‐way ANOVAs performed, with Tukey post‐hoc test used to determine if means significantly differed, with significance set at P<0.05. No differences in mRNA expression were observed across diets. Neither the type or percentage of fat had any impact on occludin protein expression. ZO1 protein expression was significantly higher with FO compared to lard. A significant interaction was found between the type and percentage of fat on claudin‐5 protein expression. Respective to lard, claudin‐5 protein expression significantly decreased as the percentage of fat increased from 10 to 41%. Respective to FO, claudin‐5 protein expression significantly increased as the percentage of fat increased from 10 to 41%. Respective to 10% fat, claudin‐5 protein expression was significantly lower in FO compared to lard. Respective to 41% fat, claudin‐5 protein expression was significantly lower in lard compared to FO. Study identified ZO1 and Claudin‐5 protein expression changes within the brain are linked to diet. Data supports that diets high in FO have a greater expression of key tight junctional proteins, which suggests enhanced BBB integrity. Support or Funding Information Supported by the NIH, National Institute of Neurological Disorders and Stroke (grant R21NS090282).
This research evaluated the impact of novel somatostatin receptor subtype‐4 (SSTR4) agonist SM‐I‐26 on microglia inflammatory activation. SSTR4 shows particular promise as a treatment target for Alzheimer's disease (AD) given its microglia and neuronal localization in the brain. A hallmark of AD progression is microgliosis, associated with inflammatory activation. A SSTR4 agonist that lessens microglial inflammatory activity could help mitigate AD progression.The selective and high affinity SSTR4 agonist SM‐I‐26 (Ki: 12nM, EC50: 17nM) was evaluated in BV2 microglia cells concurrent with inflammatory activation via lipopolysaccharide (LPS) treatment. After plating for 24hrs, cells were treated for 24hrs with SM‐I‐26 (0, 10, 1000nM) against LPS (0, 10, 100ng/mL). Nitrite (surrogate of nitric oxide, Griess assay) output in media and mRNA expression (RT‐qPCR) from cells of key inflammatory species (Tnf‐α, Il‐6, Il‐1β) were measured. Two‐way ANOVAs with Tukey post‐hoc tests were used to determine significance (α= 0.05).A significant interaction between LPS and SM‐I‐26 (p<0.0001) was found on mean nitrite. Within no LPS, mean nitrite was similar across all concentrations of SM‐I‐26. Within 10 ng/ml LPS, a trend was found with decreased nitrite with 10 and 1000 nM SM‐I‐26 compared to vehicle. Within 100 ng/ml LPS, both 10 and 1000 nM SM‐I‐26 significantly decreased nitrite compared to vehicle control (p<0.0001).Significant interactions were found between SM‐I‐26 and LPS on the mean ddcts of Tnf‐α (p<0.0001) and Il‐β, (p<0.0001). At 0 and 10 ng/mL LPS, 1000 nM SM‐I‐26 significantly increased the mean ddct of Tnf‐α compared to their vehicle controls (p<0.0001). Within 100 ng/ml LPS, SM‐I‐26 dose‐dependently increased the mean ddct for Tnf‐α (10 nM: p= 0.0067, 1000nM: p<0.0001, Tukey) compared to vehicle. These results indicate that 1000 nM SM‐I‐26 significantly decreased Tnf‐α mRNA expression under inflammatory conditions. For Il‐1β, the mean ddcts were similar across all concentrations of SM‐I‐26 with no LPS. At 100 ng/ml LPS, 10 nM and 1000 nM SM‐I‐26 significantly increased the mean ddcts for Il‐β (p<0.0001, and p=0.0040, respectively), indicating these concentrations of SM‐I‐26 decreased Il‐1β mRNA expression with inflammation. For Il‐6, LPS (p<0.0001) and SM‐I‐26 (p<0.0001), but not their interaction (p=0.1106) significantly impacted the mean ddct. SM‐I‐26 at 10 and 1000 nM significantly increased the mean ddct of Il‐6 compared to no SM‐I‐26 (p<0.0001 and p=0.0009, respectively), indicating that SM‐I‐26 decreased Il‐6 mRNA expression.These results show treatment with SM‐I‐26 significantly decreased Tnf‐α, Il‐6, and Il‐1β mRNA expression and mean nitrite levels with increasing LPS inflammatory stimulation. These results support the use of SSTR4 agonists for the mitigation of microglial activation, which could help in the treatment of AD progression.Support or Funding InformationThis work is supported by the National Institutes of Health, National Institute of Aging (R01AG047858)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.