Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ1–42-Injected, Wild-Type Mouse Model of AD

International Journal of Molecular Sciences

Lívia Fülöp¹  Ildikó Schuster¹  Botond Penke¹  Emőke Borbély¹  Zsolt Bozsó¹  Viktória Varga¹  Titanilla Szögi¹ 

[1] Department of Medical Chemistry, University of Szeged, Dóm Tér 8, H-6720 Szeged, Hungary;

关键词: Alzheimer’s disease;    Aβ_1–42-induce mouse model;    neurogenesis;    neuroinflammation;    sigma-1 receptor;    dimethyltryptamine;   

DOI  :  10.3390/ijms23052514

来源: DOAJ

【 摘 要 】

Alzheimer’s disease (AD) is the most common form of dementia characterized by cognitive dysfunctions. Pharmacological interventions to slow the progression of AD are intensively studied. A potential direction targets neuronal sigma-1 receptors (S1Rs). S1R ligands are recognized as promising therapeutic agents that may alleviate symptom severity of AD, possibly via preventing amyloid-β-(Aβ-) induced neurotoxicity on the endoplasmic reticulum stress-associated pathways. Furthermore, S1Rs may also modulate adult neurogenesis, and the impairment of this process is reported to be associated with AD. We aimed to investigate the effects of two S1R agonists, dimethyltryptamine (DMT) and PRE084, in an Aβ-induced in vivo mouse model characterizing neurogenic and anti-neuroinflammatory symptoms of AD, and the modulatory effects of S1R agonists were analyzed by immunohistochemical methods and western blotting. DMT, binding moderately to S1R but with high affinity to 5-HT receptors, negatively influenced neurogenesis, possibly as a result of activating both receptors differently. In contrast, the highly selective S1R agonist PRE084 stimulated hippocampal cell proliferation and differentiation. Regarding neuroinflammation, DMT and PRE084 significantly reduced Aβ_1–42-induced astrogliosis, but neither had remarkable effects on microglial activation. In summary, the highly selective S1R agonist PRE084 may be a promising therapeutic agent for AD. Further studies are required to clarify the multifaceted neurogenic and anti-neuroinflammatory roles of these agonists.

【 授权许可】

Unknown