3-Thio-3,4,5-trisubstituted-1,2,4-triazoles: high affinity somatostatin receptor-4 agonist synthesis and structure-activity relationships.

Somatostatin receptor-4 (SST) is a therapeutic target for several conditions, including Alzheimer's disease, seizures, neuropsychiatric disorders, and pain. Our previous work on 1,2,4-triazole derivatives led to enhanced SST binding affinity, selectivity, and functional activity. Herein we report the discovery of 3-thio-1,2,4-triazole series as selective and high affinity SST agonists.

Somatostatin: Linking Cognition and Alzheimer Disease to Therapeutic Targeting.

Over 4 decades of research support the link between Alzheimer disease (AD) and somatostatin [somatotropin-releasing inhibitory factor (SRIF)]. SRIF and SRIF-expressing neurons play an essential role in brain function, modulating hippocampal activity and memory formation. Loss of SRIF and SRIF-expressing neurons in the brain rests at the center of a series of interdependent pathological events driven by amyloid- peptide (A), culminating in cognitive decline and dementia.

Changes in Reported Dietary Supplement Use in Cognitively Normal National Alzheimer's Coordinating Center Participants Aged 55 and Older From 2015 to 2019.

Background: Although reported dietary supplement use is common in older adults, evaluations of dietary supplement use over the past 10 y are lacking.

Objective: This analysis determined changes in reported dietary supplement use in cognitively normal older adults (aged ≥ 55 y) using the National Alzheimer's Coordinating Center data from 2015 to 2019 using a serial cross-sectional study design.

Methods: The first available visit for cognitively normal participants aged ≥ 55 y from 2015 to 2019 with a complete medication form was used, resulting in 9357 participants.

Perspectives on Participation in Clinical Trials Among Individuals With Pain, Depression, and/or Anxiety: An ACTTION Scoping Review.

For individuals experiencing pain, the decision to engage in clinical trials may be influenced by a number of factors including current and past care, illness severity, physical functioning, financial stress, and caregiver support. Co-occurring depression and anxiety may add to these challenges. The aim of this scoping review was to describe perspectives about clinical trial participation, including recruitment and retention among individuals with pain and pain comorbidities, including depression and/or anxiety.

Novel Somatostatin Receptor-4 Agonist SM-I-26 Mitigates Lipopolysaccharide-Induced Inflammatory Gene Expression in Microglia.

Somatostatin receptor subtype 4 (SSTR4) is expressed in BV2 microglia, suggesting that SSTR4 agonists may impact microglia function. This study assessed the high-affinity SSTR4 agonist SM-I-26 (SMI) (0 nM, 10 nM, 1000 nM) against lipopolysaccharide (LPS)-induced inflammation (0, 10 or 100 ng/ml) over 6 or 24 h in BV2 microglia. Cell viability, nitrite output and mRNA expression changes of genes associated with our target (Sstr4), inflammation (Tnf-α, Il-6, Il-1β, inos), anti-inflammatory and anti-oxidant actions (Il-10, Catalase), and mediators of Aβ binding/phagocytosis (Msr1, Cd33, Trem1, Trem2) were measured.

Synthesis and structure-activity relationships of 3,4,5-trisubstituted-1,2,4-triazoles: high affinity and selective somatostatin receptor-4 agonists for Alzheimer's disease treatment.

Somatostatin receptor-4 (SST) is highly expressed in brain regions affiliated with learning and memory. SST agonist treatment may act to mitigate Alzheimer's disease (AD) pathology. An integrated approach to SST agonist lead optimization is presented herein.

NNC 26-9100 increases Aβ1-42 phagocytosis, inhibits nitric oxide production and decreases calcium in BV2 microglia cells.

Microglia are the resident immune cell of the brain involved in the development and progression of Alzheimer's disease (AD). Modulation of microglia activity represents a potential mechanism for treating AD. Herein, the compound NNC 26-9100 (NNC) was evaluated in toxicity, nitric oxide release, Aβ1-42 uptake and cytosolic calcium assays during lipopolysaccharide (LPS)-activated conditions using mouse BV2 microglia cells.

Somatostatin Receptor Subtype-4 Regulates mRNA Expression of Amyloid-Beta Degrading Enzymes and Microglia Mediators of Phagocytosis in Brains of 3xTg-AD Mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR agonist NNC 26-9100 on mRNA expression of key genes associated with AD pathology (microglia mediators of Aβ phagocytosis, amyloid-beta (Aβ)-degrading enzymes, anti-oxidant enzymes and pro-inflammatory cytokines) in 3xTg-AD mice.

Discovery of a 3,4,5-trisubstituted-1,2,4-triazole agonist with high affinity and selectivity at the somatostatin subtype-4 (sst) receptor.

A series of compounds containing a 1,2,4-triazole moiety were synthesized, targeting the somatostatin receptor subtype-4 (sst). Compounds were developed in which the Phe/Phe/Phe, Trp, and Lys mimetic groups were interchanged at positions 3, 4, and 5 of the 1,2,4-triazole ring. The 1,2,4-triazoles containing an 2-(imidazol-4-yl)ethyl substituent at position-3 demonstrated moderate binding affinity at sst.

Mfsd2a and Glut1 Brain Nutrient Transporters Expression Increase with 32-Week Low and High Lard Compared with Fish-Oil Dietary Treatment in C57Bl/6 Mice.

Background: Diet-mediated alterations of critical brain nutrient transporters, major facilitator super family domain-containing 2a (Mfsd2a) and glucose transporter 1 (Glut1), have wide reaching implications in brain health and disease.

Objective: The aim of the study was to examine the impact of long-term low- and high-fat diets with lard or fish oil on critical brain nutrient transporters, Mfsd2a and Glut1.

Methods: Eight-week-old male C57BL/6 mice were fed 1 of the following 4 diets for 32 wk: 10% of kcal from lard, 10% of kcal from fish oil, 41% of kcal from lard, or 41% of kcal from fish oil.

Peripheral Administration of GSK-3β Antisense Oligonucleotide Improves Learning and Memory in SAMP8 and Tg2576 Mouse Models of Alzheimer's Disease.

Glycogen synthase kinase (GSK)-3β is a multifunctional protein that has been implicated in the pathological characteristics of Alzheimer's disease (AD), including the heightened levels of neurofibrillary tangles, amyloid-beta (Aβ), and neurodegeneration. We have previously shown that an antisense oligonucleotide directed at the Tyr 216 site on GSK-3β (GAO) when injected centrally can decrease GSK-3β levels, improve learning and memory, and decrease oxidative stress. In addition, we showed that GAO can cross the blood-brain barrier.

Steroids and the blood-brain barrier: therapeutic implications.

Steroids have a wide spectrum of impact, serving as fundamental regulators of nearly every physiological process within the human body. Therapeutic applications of steroids are equally broad, with a diverse range of medications and targets. Within the central nervous system (CNS), steroids influence development, memory, behavior, and disease outcomes.

Somatostatin receptor subtype-4 agonist NNC 26-9100 mitigates the effect of soluble Aβ(42) oligomers via a metalloproteinase-dependent mechanism.

Soluble amyloid-β peptide (Aβ) oligomers have been hypothesized to be primary mediators of Alzheimer's disease progression. In this regard, reduction of soluble Aβ-oligomers levels within the brain may provide a viable means in which to treat the disease. Somatostatin receptor subtype-4 (SSTR4) agonists have been proposed to reduce Aβ levels in the brain via enhancement of enzymatic degradation.

Somatostatin receptor subtype-4 agonist NNC 26-9100 decreases extracellular and intracellular Aβ₁₋₄₂ trimers.

Soluble amyloid β-protein (Aβ) oligomers are primary mediators of synaptic dysfunction associated with the progression of Alzheimer's disease. Such Aβ oligomers exist dependent on their rates of aggregation and metabolism. Use of selective somatostatin receptor-subtype agonists have been identified as a potential means to mitigate Aβ accumulation in the brain, via regulation of the enzyme neprilysin.

Age and 17β-estradiol effects on blood-brain barrier tight junction and estrogen receptor proteins in ovariectomized rats.

Age and estrogen levels alter blood-brain barrier (BBB) tight junction (TJ) regulation, impacting brain homeostasis and pathological outcomes. This examination evaluated BBB TJ and estrogen receptor (ER) protein expression changes in young (8-10 week) and middle-aged (10-12 month) ovariectomized female Fisher-344 rats with chronic 17β-estradiol or placebo treatment. Middle-aged rats showed decreased protein expression of occludin with 17β-estradiol (55 kDa band) or placebo (45, 55, 60 kDa bands) treatment compared to respective young.

Chronic peripheral administration of somatostatin receptor subtype-4 agonist NNC 26-9100 enhances learning and memory in SAMP8 mice.

Selective somatostatin receptor subtype agonists have been proposed as a means to mitigate learning and memory loss associated with Alzheimer's disease. The first aim of this study evaluated blood-to-brain transport and regional brain distribution of NNC 26-9100, a selective somatostatin subtype-4 (sst4) receptor agonist. The entry rate of (131)I-NNC 26-9100 was K(i)=0.

Blood-brain barrier tight junction permeability and ischemic stroke.

The blood-brain barrier (BBB) is formed by the endothelial cells of cerebral microvessels, providing a dynamic interface between the peripheral circulation and the central nervous system. The tight junctions (TJs) between the endothelial cells serve to restrict blood-borne substances from entering the brain. Under ischemic stroke conditions decreased BBB TJ integrity results in increased paracellular permeability, directly contributing to cerebral vasogenic edema, hemorrhagic transformation, and increased mortality.

Reoxygenation stress on blood-brain barrier paracellular permeability and edema in the rat.

The blood-brain barrier (BBB) serves as a critical regulator of brain homeostasis. Following hypoxia (i.e.