Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
Department of Pharmaceutical Sciences, College of Pharmacy, South Dakota State University, Brookings, SD 57007, USA.
Prog Neuropsychopharmacol Biol Psychiatry. 2018 Aug 30;86:218-228. doi: 10.1016/j.pnpbp.2018.05.018. Epub 2018 May 22.
Evidence suggests that α7 nicotinic acetylcholine receptor (α7 nAChR) in the central nervous system has a critical role in the regulation of microglial function and neuroinflammation associated with the pathophysiology of major depressive disorder. The objectives of the present study were to determine the effects of PNU 120596, an α7 nAChR positive allosteric modulator (PAM), on depressive-like behavior and expression of ionized calcium binding adaptor molecule 1 (Iba-1), a microglial marker, in male C57BL/6J mice following lipopolysaccharide (LPS) administration, an animal model for depressive-like behavior. Forced swim test (FST), tail suspension test (TST), and sucrose preference test were used to determine the effects of PNU 120596 on depressive-like behavior, measured by increased immobility time or decreased sucrose preference. We also examined the effects of PNU 120596 on Iba-1 expression by using Western blot analysis and immunofluorescence staining in the hippocampus and prefrontal cortex, the brain regions implicated in major depressive disorder. Administration of LPS (1 mg/kg, i.p.) significantly increased immobility time during FST and TST and decreased sucrose preference. The PNU 120596 (1 or 4 mg/kg, i.p.) dose-dependently prevented LPS-induced depressive-like behavior during FST, TST, and sucrose preference test. The PNU 120596 (1 or 4 mg/kg) alone did not show any significant alteration on immobility time and sucrose preference. Pretreatment of methyllycaconitine (3 mg/kg, i.p.), an α7 nAChR antagonist, significantly prevented the antidepressant-like effects of PNU (4 mg/kg). Similarly, the PNU 120596 (4 mg/kg, i.p.) significantly reduced LPS-induced increased expression of Iba-1 in the hippocampus or prefrontal cortex. Overall, these results suggest that PNU 120596 reduces LPS-induced depressive-like behavior and microglial activation in the hippocampus and prefrontal cortex in mice. Therefore, α7 nAChR PAMs could be developed as potential therapeutic utility for the treatment of major depressive disorder in humans.
有证据表明，中枢神经系统中的α7 烟碱型乙酰胆碱受体（α7 nAChR）在调节与重度抑郁症病理生理学相关的小胶质细胞功能和神经炎症方面具有关键作用。本研究的目的是确定 PNU 120596（一种α7 nAChR 正变构调节剂（PAM））对雄性 C57BL/6J 小鼠给予脂多糖（LPS）后的抑郁样行为以及小胶质细胞标志物离子钙结合接头蛋白 1（Iba-1）表达的影响，LPS 是一种抑郁样行为的动物模型。强迫游泳试验（FST）、悬尾试验（TST）和蔗糖偏好试验用于确定 PNU 120596 通过增加不动时间或降低蔗糖偏好来治疗抑郁样行为的效果。我们还通过 Western blot 分析和免疫荧光染色检查了 PNU 120596 对海马体和前额叶皮质中 Iba-1 表达的影响，这些脑区与重度抑郁症有关。LPS（1mg/kg，腹腔注射）给药显著增加了 FST 和 TST 中小鼠的不动时间，降低了蔗糖偏好。PNU 120596（1 或 4mg/kg，腹腔注射）剂量依赖性地防止了 LPS 诱导的 FST、TST 和蔗糖偏好试验中的抑郁样行为。PNU 120596（1 或 4mg/kg）单独使用时不会对不动时间和蔗糖偏好产生任何显著影响。预先给予甲基藜芦碱（3mg/kg，腹腔注射），一种α7 nAChR 拮抗剂，可显著预防 PNU（4mg/kg）的抗抑郁作用。同样，PNU 120596（4mg/kg，腹腔注射）也显著降低了 LPS 诱导的海马体或前额叶皮质中 Iba-1 表达的增加。总的来说，这些结果表明 PNU 120596 减轻了 LPS 诱导的小鼠海马体和前额叶皮质中的抑郁样行为和小胶质细胞激活。因此，α7 nAChR PAMs 可能被开发为治疗人类重度抑郁症的潜在治疗用途。
