Laukkanen Liina, Diniz Cassiano R A F, Foulquier Sebastien, Prickaerts Jos, Castrén Eero, Casarotto Plinio C
Neuroscience Center, HiLife, University of Helsinki, 00014 Helsinki, Finland.
Department of Pharmacology, Ribeirão Preto School of Medicine, University of São Paulo, Ribeirão Preto 14049-900, SP, Brazil.
Pharmaceuticals (Basel). 2021 Aug 6;14(8):773. doi: 10.3390/ph14080773.
Blockers of angiotensin II type 1 receptor (AT1R) exert antidepressant-like effects by indirectly facilitating the activation of the angiotensin II type 2 receptor (AT2R), which leads to increased surface expression and transactivation of tropomyosin-related kinase B receptors (TRKB). Compound 21 (C21) is a non-peptide AT2R agonist that produces neuroprotective effects. However, the behavioral effects of C21 and its involvement with the brain-derived neurotrophic factor (BDNF)-TRKB system still need further investigation. The aim of the present study was to assess the effect of C21 on the activation of TRKB and its consequences on conditioned fear. The administration of C21 (0.1-10 μM/15 min) increased the surface levels of TRKB but was not sufficient to increase the levels of phosphorylated TRKB (pTRKB) in cultured cortical neurons from rat embryos. Consistent with increased TRKB surface expression, C21 (10 μM/15 min or 3 days) facilitated the effect of BDNF (0.1 ng/mL/15 min) on pTRKB in these cells. In contextual fear conditioning, the freezing time of C21-treated (administered intranasally) wild-type mice was decreased compared to the vehicle-treated group, but no effect of C21 was observed in BDNF.het animals. We observed no effect of C21 in the elevated plus-maze test for anxiety. Taken together, our results indicate that C21 facilitated BDNF effect by increasing the levels of TRKB on the cell surface and reduced the freezing time of mice in a BDNF-dependent manner, but not through a general anxiolytic-like effect.
血管紧张素II 1型受体（AT1R）阻滞剂通过间接促进血管紧张素II 2型受体（AT2R）的激活发挥类抗抑郁作用，这会导致原肌球蛋白相关激酶B受体（TRKB）的表面表达增加和反式激活。化合物21（C21）是一种产生神经保护作用的非肽类AT2R激动剂。然而，C21的行为效应及其与脑源性神经营养因子（BDNF）-TRKB系统的关系仍需进一步研究。本研究的目的是评估C21对TRKB激活的影响及其对条件性恐惧的后果。给予C21（0.1 - 10 μM/15分钟）可增加大鼠胚胎培养皮质神经元中TRKB的表面水平，但不足以增加磷酸化TRKB（pTRKB）的水平。与TRKB表面表达增加一致，C21（10 μM/15分钟或3天）促进了BDNF（0.1 ng/mL/15分钟）对这些细胞中pTRKB的作用。在情境恐惧条件反射中，与给予赋形剂的组相比，经C21处理（经鼻给药）的野生型小鼠的僵住时间减少，但在BDNF杂合动物中未观察到C21的作用。我们在高架十字迷宫焦虑测试中未观察到C21的作用。综上所述，我们的结果表明，C21通过增加细胞表面TRKB的水平促进BDNF的作用，并以BDNF依赖的方式减少小鼠的僵住时间，但不是通过一般的类抗焦虑作用。
