Department of Pharmacology and Therapeutics, State University of Maringá, Maringá, Paraná, Brazil.
Neurolixis Inc., Park Ridge, NJ, USA.
Neurobiol Aging. 2023 Apr;124:52-59. doi: 10.1016/j.neurobiolaging.2022.12.013. Epub 2022 Dec 31.
5-HT serotonin receptors may play a role in cognitive function changes related to advanced age. Here, we investigated the effects of acute and repeated treatment with NLX-101 (F15599), a postsynaptic 5-HT receptor-biased agonist, and F13714, a presynaptic 5-HT receptor-biased agonist on spatial object pattern separation (OPS) in aged (22-24 months) rats. Neuroplasticity markers including brain-derived neurotrophic factor, PSD95, synaptophysin, and doublecortin were evaluated in the hippocampus. Unlike younger rats, aged rats were incapable of discriminating any new position of the objects in the arena, reflecting the detrimental effect of aging on pattern separation. However, aged animals treated with NLX-101 showed a significant cognitive improvement in the OPS test, accompanied by increases in hippocampal brain-derived neurotrophic factor and PSD95 protein levels. In contrast, no improvement in OPS performance was observed when aged rats received F13714. Both F13714 and NLX-101 increased the number of newborn neurons in the hippocampi of aged rats. These findings provide a rationale for targeting post-synaptic 5-HT as a treatment for cognitive deficits related to aging.
5-羟色胺（5-HT）能受体可能在与年龄相关的认知功能变化中发挥作用。在这里，我们研究了突触后 5-HT 受体偏向激动剂 NLX-101（F15599）和突触前 5-HT 受体偏向激动剂 F13714 对 22-24 月龄老年大鼠的空间物体模式分离（OPS）的急性和重复治疗的影响。在海马体中评估了神经可塑性标志物，包括脑源性神经营养因子、PSD95、突触素和双皮质素。与年轻大鼠不同，老年大鼠无法区分竞技场中物体的任何新位置，这反映了衰老对模式分离的不利影响。然而，用 NLX-101 治疗的老年动物在 OPS 测试中表现出显著的认知改善，伴随着海马体脑源性神经营养因子和 PSD95 蛋白水平的增加。相比之下，老年大鼠接受 F13714 治疗时，OPS 性能没有改善。F13714 和 NLX-101 均增加了老年大鼠海马中的新生神经元数量。这些发现为针对突触后 5-HT 作为治疗与衰老相关的认知缺陷提供了依据。
