Apremilast regulates acute effects of ethanol and other GABAergic drugs via protein kinase A-dependent signaling.
Apremilast regulates acute effects of ethanol and other GABAergic drugs via protein kinase A-dependent signaling.
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DOI：
10.1016/j.neuropharm.2020.108220
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发表时间：
2020-11-01
影响因子：
4.7
通讯作者：
Messing RO
中科院分区：
文献类型：
--
作者：
Blednov YA;Borghese CM;Dugan MP;Pradhan S;Thodati TM;Kichili NR;Harris RA;Messing RO
4型磷酸二酯酶（PDE 4）抑制剂可防止环磷酸腺苷的水解并增加蛋白激酶A（PKA）介导的磷酸化。PDE 4抑制剂还调节对乙醇和GABA能药物的反应。我们研究了PDE 4抑制剂阿普斯特在雄性和雌性小鼠中调节乙醇和GABA能药物急性效应的机制。阿普斯特延长了加波沙朵、唑吡坦和丙泊酚的镇静催眠作用，但没有改变依托咪酯的作用，并且意外地缩短了地西泮的镇静催眠作用。阿普斯特延长了唑吡坦、丙泊酚和洛瑞唑诱导的旋转杆共济失调，缩短了地西泮的恢复时间，但对加波沙朵或依托咪酯诱导的共济失调没有影响。PKA抑制剂H89阻断了阿普斯特延长乙醇、加波沙朵和丙泊酚的镇静催眠作用以及延长乙醇和丙泊酚诱导的共济失调的能力。H89还阻断了阿普斯特缩短地西泮的镇静催眠和共济失调作用的能力。β1-特异性拮抗剂水杨酰肼（SCS）可使乙醇和地西泮诱导的共济失调更快恢复，但不能改变丙泊酚或依托咪酯诱导的共济失调。SCS缩短了乙醇和地西泮的镇静催眠作用，但不缩短丙泊酚的作用。在非洲爪蟾卵母细胞中，β1亚基PKA磷酸化位点的磷酸化模拟物（天冬氨酸）突变降低了含有α1或α3亚基的受体的最大GABA电流，但不降低α2亚基。相反，β3亚基中PKA位点的磷酸化突变增加了含有α1或α2的受体的最大GABA电流，但不增加α3亚基。乙醇、丙泊酚、依托咪酯、唑吡坦、氟硝西泮或地西泮的GABA效力和变构调节未被这些突变改变。我们提出了一种模型，通过该模型，阿普斯特增加PKA介导的含β1和β3的GABAA受体的磷酸化，并选择性地改变对乙醇和GABA能药物的急性耐受性。
Phosphodiesterase type 4 (PDE4) inhibitors prevent hydrolysis of cyclic adenosine monophosphate and increase protein kinase A (PKA)-mediated phosphorylation. PDE4 inhibitors also regulate responses to ethanol and GABAergic drugs. We investigated mechanisms by which the PDE4 inhibitor, apremilast, regulates acute effects of ethanol and GABAergic drugs in male and female mice. Apremilast prolonged the sedative-hypnotic effects of gaboxadol, zolpidem, and propofol but did not alter etomidate effects, and unexpectedly shortened the sedative-hypnotic effects of diazepam. Apremilast prolonged rotarod ataxia induced by zolpidem, propofol, and loreclezole, shortened recovery from diazepam, but had no effect on ataxia induced by gaboxadol or etomidate. The PKA inhibitor H89 blocked apremilast’s ability to prolong the sedative-hypnotic effects of ethanol, gaboxadol, and propofol and to prolong ethanol- and propofol-induced ataxia. H89 also blocked apremilast’s ability to shorten the sedative-hypnotic and ataxic effects of diazepam. The β1-specific antagonist, salicylidene salicylhydrazide (SCS), produced faster recovery from ethanol- and diazepam-induced ataxia, but did not alter propofol- or etomidate-induced ataxia. SCS shortened the sedative-hypnotic effects of ethanol and diazepam but not of propofol. In Xenopus oocytes, a phosphomimetic (aspartate) mutation at the PKA phosphorylation site in β1 subunits decreased the maximal GABA current in receptors containing α1 or α3, but not α2 subunits. In contrast, phosphomimetic mutations at PKA sites in β3 subunits increased the maximal GABA current in receptors containing α1 or α2, but not α3 subunits. The GABA potency and allosteric modulation by ethanol, propofol, etomidate, zolpidem, flunitrazepam, or diazepam were not altered by these mutations. We propose a model whereby apremilast increases PKA-mediated phosphorylation of β1- and β3-containing GABAA receptors and selectively alters acute tolerance to ethanol and GABAergic drugs.
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影响因子：
4
作者：
Diao HL;Xue Y;Han XH;Wang SY;Liu C;Chen WF;Chen L
通讯作者：
Chen L
影响因子：
3.3
作者：
Hörtnagl H;Tasan RO;Wieselthaler A;Kirchmair E;Sieghart W;Sperk G
通讯作者：
Sperk G
影响因子：
4.8
作者：
Brandon, NJ;Delmas, P;Moss, SJ
通讯作者：
Moss, SJ
影响因子：
2.9
作者：
HIDAKA, H;INAGAKI, M;SASAKI, Y
通讯作者：
SASAKI, Y
影响因子：
4.7
作者：
Avila DV;Myers SA;Zhang J;Kharebava G;McClain CJ;Kim HY;Whittemore SR;Gobejishvili L;Barve S
通讯作者：
Barve S