Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder.
Ganaxolone improves behavioral deficits in a mouse model of post-traumatic stress disorder.
复制标题
DOI：
10.3389/fncel.2014.00256
复制
发表时间：
2014
影响因子：
5.3
通讯作者：
Rasmusson AM
中科院分区：
文献类型：
--
作者：
Pinna G;Rasmusson AM
别孕烯醇酮及其等效立体异构体孕烯醇酮（统称为ALLO）是神经活性类固醇，其积极和变构调节γ-氨基丁酸（GABA）在GABAA受体的作用。患有创伤后应激障碍（PTSD）的女性绝经前患者的脑脊液中ALLO水平降低，PTSD是一种严重的神经精神疾病，影响数百万人，但没有持续有效的治疗方法。这表明恢复PTSD中下调的大脑ALLO水平可能是有益的。ALLO生物合成也减少与社会隔离（SI）小鼠中PTSD样行为的出现相关。与PTSD患者相似，SI小鼠也表现出GABAA受体亚单位的额皮质和海马表达的变化，导致对苯二氮卓介导的镇静和抗焦虑的抵抗。与苯二氮卓类药物相比，ALLO作用于更大范围的GABAA受体亚基，通过注射ALLO或用选择性脑类固醇生成刺激剂（如S-去甲氟西汀）刺激ALLO生物合成（剂量远低于阻断5-羟色胺再摄取的剂量），增加SI小鼠皮质边缘ALLO水平，降低这些小鼠的PTSD样行为。这表明ALLO的合成类似物，如加奈索酮，也可以改善SI小鼠模型中的焦虑，攻击和其他PTSD样行为。与该假设一致，加奈索酮（3.75-30 mg/kg，s.c.）在SI小鼠测试前60分钟注射，诱导了对同性入侵者的攻击性和高架十字迷宫中的焦虑样行为的剂量依赖性降低。在这些测试中使用的加奈索酮的EC 50剂量也使夸大的情境恐惧条件反射正常化，并且显著地增强了SI小鼠中的恐惧消退保持。在这些剂量下，加奈索酮在开放场地测试中未能改变运动。因此，与苯二氮卓类药物不同，非镇静浓度的加奈索酮似乎可以改善与小鼠ALLO缺陷相关的功能失调性情绪行为，并可能为ALLO合成缺陷的PTSD患者提供替代治疗。选择性5-羟色胺再吸收抑制剂（SSRI）是目前FDA批准用于治疗创伤后应激障碍（PTSD）的唯一药物，尽管它们对大部分创伤后应激障碍（PTSD）患者无效。因此，ALLO类似物如加奈索酮可以提供SSRI的治疗性GABA能替代物，用于治疗PTSD或其中ALLO生物合成可能受损的其他病症。
Allopregnanolone and its equipotent stereoisomer, pregnanolone (together termed ALLO), are neuroactive steroids that positively and allosterically modulate the action of gamma-amino-butyric acid (GABA) at GABAA receptors. Levels of ALLO are reduced in the cerebrospinal fluid of female premenopausal patients with post-traumatic stress disorder (PTSD), a severe, neuropsychiatric condition that affects millions, yet is without a consistently effective therapy. This suggests that restoring downregulated brain ALLO levels in PTSD may be beneficial. ALLO biosynthesis is also decreased in association with the emergence of PTSD-like behaviors in socially isolated (SI) mice. Similar to PTSD patients, SI mice also exhibit changes in the frontocortical and hippocampal expression of GABAA receptor subunits, resulting in resistance to benzodiazepine-mediated sedation and anxiolysis. ALLO acts at a larger spectrum of GABAA receptor subunits than benzodiazepines, and increasing corticolimbic ALLO levels in SI mice by injecting ALLO or stimulating ALLO biosynthesis with a selective brain steroidogenic stimulant, such as S-norfluoxetine, at doses far below those that block serotonin reuptake, reduces PTSD-like behavior in these mice. This suggests that synthetic analogs of ALLO, such as ganaxolone, may also improve anxiety, aggression, and other PTSD-like behaviors in the SI mouse model. Consistent with this hypothesis, ganaxolone (3.75–30 mg/kg, s.c.) injected 60 min before testing of SI mice, induced a dose-dependent reduction in aggression toward a same-sex intruder and anxiety-like behavior in an elevated plus maze. The EC50 dose of ganaxolone used in these tests also normalized exaggerated contextual fear conditioning and, remarkably, enhanced fear extinction retention in SI mice. At these doses, ganaxolone failed to change locomotion in an open field test. Therefore, unlike benzodiazepines, ganaxolone at non-sedating concentrations appears to improve dysfunctional emotional behavior associated with deficits in ALLO in mice and may provide an alternative treatment for PTSD patients with deficits in the synthesis of ALLO. Selective serotonin reuptake inhibitors (SSRIs) are the only medications currently approved by the FDA for treatment of PTSD, although they are ineffective in a substantial proportion of PTSD patients. Hence, an ALLO analog such as ganaxolone may offer a therapeutic GABAergic alternative to SSRIs for the treatment of PTSD or other disorders in which ALLO biosynthesis may be impaired.
登录
查看更多内容
影响因子：
17.7
作者：
Bremner, JD;Innis, RB;Charney, DS
通讯作者：
Charney, DS
影响因子：
5.3
作者：
Chhatwal, JP;Myers, KM;Davis, M
通讯作者：
Davis, M
影响因子：
--
作者：
Davidson, JRT;Rothbaum, BO;Farfel, GM
通讯作者：
Farfel, GM
DOI：
10.1615/critreveukaryotgeneexpr.v12.i1.30
发表时间：
2002-01-01
影响因子：
1.6
作者：
Dussault, I;Forman, BM
通讯作者：
Forman, BM
影响因子：
3
作者：
Frye, Cheryl A.;Koonce, Carolyn J.;Walf, Alicia A.
通讯作者：
Walf, Alicia A.