| Autor: |
Sandoval K; Department of Pharmaceutical Sciences Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park Drive., Building 220, Edwardsville, IL, 62025, USA., Umbaugh D; Department of Pharmaceutical Sciences Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park Drive., Building 220, Edwardsville, IL, 62025, USA., House A; Department of Pharmaceutical Sciences Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park Drive., Building 220, Edwardsville, IL, 62025, USA., Crider A; Department of Pharmaceutical Sciences Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park Drive., Building 220, Edwardsville, IL, 62025, USA., Witt K; Department of Pharmaceutical Sciences Pharmaceutical Sciences, School of Pharmacy, Southern Illinois University Edwardsville, 200 University Park Drive., Building 220, Edwardsville, IL, 62025, USA. kwitt@siue.edu. |
| Abstrakt: |
Alzheimer's disease (AD) is a progressive neurodegenerative disorder resulting in memory and cognitive impairment. The use of somatostatin receptor subtype-4 (SSTR 4 ) agonists have been proposed for AD treatment. This study investigated the effects of selective SSTR 4 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. Mice were administered NNC 26-9100 (0.2 µg, i.c.v.) or vehicle control, with cortical and subcortical brain tissue collected at 6 h and 24 h post-treatment. At 6 h, NNC 26-9100 treatment decreased cortical expression of cluster of differentiation-33 (Cd33) by 25%, while increasing cortical and subcortical macrophage scavenger receptor-1 (Msr1) by 1.8 and 2.0-fold, respectively. The Cd33 downregulation and Msr1 upregulation support a state of microglia associated Aβ phagocytosis. At 24 h, NNC 26-9100 treatment increased the cortical expression of Sstr4 (4.9-fold), Aβ-degrading enzymes neprilysin (9.3-fold) and insulin degrading enzyme (14.8-fold), and the antioxidant catalase (3.6-fold). Similar effects at 24 h were found in subcortical tissue with NNC 26-9100 treatment, but did not reach statistical significance. No changes in pro-inflammatory cytokine expression were found. These data demonstrated NNC 26-9100 facilitates transcriptional changes in brain tissue identified with Aβ phagocytosis and clearance, further supporting SSTR 4 as a treatment target for AD. |
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