Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ(1-42)-Injected, Wild-Type Mouse Model of AD.
Impact of Two Neuronal Sigma-1 Receptor Modulators, PRE084 and DMT, on Neurogenesis and Neuroinflammation in an Aβ(1-42)-Injected, Wild-Type Mouse Model of AD.
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DOI：
10.3390/ijms23052514
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发表时间：
2022-02-24
影响因子：
5.6
通讯作者：
Fülöp L
中科院分区：
文献类型：
--
作者：
Borbély E;Varga V;Szögi T;Schuster I;Bozsó Z;Penke B;Fülöp L
阿尔茨海默病（AD）是以认知功能障碍为特征的最常见的痴呆形式。正在深入研究减缓AD进展的药物干预。潜在的方向靶向神经元σ-1受体（S1 R）。S1 R配体被认为是可能减轻AD症状严重程度的有前景的治疗剂，其可能通过阻止淀粉样蛋白-β-（Aβ-）诱导的内质网应激相关通路的神经毒性。此外，S1受体也可以调节成人神经发生，并且据报道，该过程的损伤与AD相关。我们的目的是研究两种S1 R激动剂二甲基色胺（DMT）和PRE 084在Aβ诱导的AD神经源性和抗神经炎症症状的体内小鼠模型中的作用，并通过免疫组织化学方法和蛋白质印迹分析S1 R激动剂的调节作用。DMT与S1 R适度结合，但对5-HT受体具有高亲和力，对神经发生产生负面影响，可能是由于激活两种受体的不同。相反，高选择性S1受体激动剂PRE 084刺激海马细胞增殖和分化。关于神经炎症，DMT和PRE 084显著减少Aβ1-42诱导的星形胶质细胞增生，但对小胶质细胞活化均无显著影响。因此，高选择性S1 R激动剂PRE 084可能是一种很有前途的AD治疗药物。需要进一步的研究来阐明这些激动剂的多方面神经原性和抗神经炎症作用。
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 Aβ1–42-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.
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影响因子：
82.9
作者：
Eriksson, PS;Perfilieva, E;Gage, FH
通讯作者：
Gage, FH
DOI：
10.1126/science.1166127
发表时间：
2009-02-13
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Fontanilla D;Johannessen M;Hajipour AR;Cozzi NV;Jackson MB;Ruoho AE
通讯作者：
Ruoho AE
影响因子：
4.6
作者：
Dakic V;Minardi Nascimento J;Costa Sartore R;Maciel RM;de Araujo DB;Ribeiro S;Martins-de-Souza D;Rehen SK
通讯作者：
Rehen SK
影响因子：
14
作者：
通讯作者：
--
影响因子：
6
作者：
Edler MK;Mhatre-Winters I;Richardson JR
通讯作者：
Richardson JR