Department of Pharmacology and Toxicology, Faculty of Pharmacy, Cairo University, Kasr El-Aini St., Cairo, 11562, Egypt.
Central Mubarak Hospital, Giza, Egypt.
Eur J Pharmacol. 2024 Oct 5;980:176869. doi: 10.1016/j.ejphar.2024.176869. Epub 2024 Aug 6.
Depressive pseudodementia (DPD) is a debilitating cognitive dysfunction that accompanies major and/or frequent depressive attacks. DPD has gained significant research attention owing to its negative effects on the patients' quality of life and productivity. This study tested the procognitive potential of Flibanserin (FBN), the serotonin (5HT) receptor modulator, against propranolol (PRP), as β/5HT1A receptors blocker. Serving this purpose, female Wistar Albino rats were subjected to chronic unpredictable stress (CUS) and subsequently treated with FBN only (3 mg/kg/day, p.o), PRP only (10 mg/kg/day, p.o), or PRP followed by FBN, using the same doses. FBN ameliorated the behavioral/cognitive alterations and calmed the hypothalamic-pituitary-adrenal (HPA) axis storm by reducing the levels of stress-related hormones, viz, corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), corticosterone (CORT) parallel to epinephrine (EPI) hyperstimulation. The maladaptive inflammatory response, comprising of interleukin (IL)-1β/6, and tumor necrosis factor (TNF)-α, was consequently blunted. This was contemporaneous to the partial restoration of the protein kinase-B (AKT)/glycogen synthase kinase (GSK)3β/signal transducer and activator of transcription (STAT)-3 survival trajectory and the reinstatement of the levels of brain derived neurotrophic factor (BDNF). Microscopically, FBN repaired the hippocampal architecture and lessened CD68/GFAP immunoreactivity. Pre-administration of PRP partially abolished FBN effect along the estimated parameters, except for 5HT2A receptor expression and epinephrine level, to prove 5HT1A receptor as a fulcrum initiator of the investigated pathway, while its sole administration worsened the underlying condition. Ultimately, these findings highlight the immense procognitive potential of FBN, offering a new paradigm for halting DPD advancement via synchronizing adrenergic/serotonergic circuitry.
抑郁性假性痴呆（DPD）是一种伴随重度和/或频繁抑郁发作的使人衰弱的认知功能障碍。由于其对患者生活质量和生产力的负面影响，DPD 引起了广泛的研究关注。本研究测试了氟班色林（FBN）作为 5-羟色胺（5HT）受体调节剂，对普萘洛尔（PRP）的促认知潜力，PRP 是 β/5HT1A 受体阻断剂。为此，雌性 Wistar 白化大鼠接受慢性不可预测应激（CUS），随后单独用 FBN（3mg/kg/天，口服）、PRP（10mg/kg/天，口服）或 PRP 后用 FBN 治疗，剂量相同。FBN 通过降低应激相关激素（如促肾上腺皮质激素释放激素（CRH）、促肾上腺皮质激素（ACTH）、皮质酮（CORT）和肾上腺素（EPI）的过度刺激），改善了行为/认知改变，并平息了下丘脑-垂体-肾上腺（HPA）轴风暴。随之而来的是适应性炎症反应（包括白细胞介素（IL）-1β/6 和肿瘤坏死因子（TNF）-α）减弱。这与蛋白激酶-B（AKT）/糖原合酶激酶（GSK）3β/信号转导和转录激活因子（STAT）-3 生存轨迹的部分恢复以及脑源性神经营养因子（BDNF）水平的恢复同时发生。显微镜下，FBN 修复了海马结构，减少了 CD68/GFAP 免疫反应性。PRP 的预先给药部分消除了 FBN 对估计参数的影响，除了 5HT2A 受体表达和肾上腺素水平外，以证明 5HT1A 受体是研究途径的启动子，而其单独给药则使潜在情况恶化。最终，这些发现强调了 FBN 巨大的促认知潜力，为通过同步肾上腺素能/血清素能电路来阻止 DPD 进展提供了一个新的范例。
