■帕金森病(PD)影响全球600多万人。除了运动障碍,表现出PD症状的患者和动物模型也会经历认知障碍,疲劳,焦虑,和抑郁症。目前,目前尚无可改变疾病进展的PD药物.大量证据表明,GABA水平的增加有助于酪氨酸羟化酶(TH)的表达降低和伴随的行为缺陷。TH表达可通过阻断GABAA受体来恢复。我们假设golexanolone(GR3027),一种耐受性良好的GABAA受体调节类固醇拮抗剂(GAMSA),可以改善帕金森病大鼠模型的帕金森病症状。
■本研究的目的是评估golexanolone是否可以改善PD大鼠模型的运动和非运动症状,并确定一些潜在的机制。
■我们使用单侧6-OHDAPD大鼠模型。golexanolone治疗在手术后4周开始。使用Motorater和CatWalk测试评估运动症状。我们还分析了疲劳(使用跑步机测试),快感缺乏(通过蔗糖偏好测试),焦虑(有一个开放的领域测试),和短期记忆(使用Y迷宫)。使用免疫组织化学和Westernblot分析了参与PD发病的胶质细胞活化和关键蛋白。
■患有PD的大鼠表现出运动不协调和运动步态受损,增加疲劳,焦虑,抑郁症,和短期记忆受损。Golexanolone治疗导致运动不协调的改善,运动步态的某些方面,疲劳,焦虑,抑郁症,和短期记忆。值得注意的是,golexanolone减少了小胶质细胞和星形胶质细胞的激活,在手术后5周减轻TH丢失,并在10周时阻止了α-突触核蛋白水平的增加。
■Golexanolone可能有助于改善对PD患者生活质量产生不利影响的运动和非运动症状,比如焦虑,抑郁症,疲劳,电机协调,运动步态,和某些认知改变。
UNASSIGNED: Parkinson\'s disease (PD) affects more than 6 million people worldwide. Along with motor impairments, patients and animal models exhibiting PD symptoms also experience cognitive impairment, fatigue, anxiety, and depression. Currently, there are no drugs available for PD that alter the progression of the disease. A body of evidence suggests that increased GABA levels contribute to the reduced expression of tyrosine hydroxylase (TH) and accompanying behavioral deficits. TH expression may be restored by blocking GABAA receptors. We hypothesized that golexanolone (GR3027), a well-tolerated GABAA receptor-modulating steroid antagonist (GAMSA), may improve Parkinson\'s symptoms in a rat model of PD.
UNASSIGNED: The aims of this study were to assess whether golexanolone can ameliorate motor and non-motor symptoms in a rat model of PD and to identify some underlying mechanisms.
UNASSIGNED: We used the unilateral 6-OHDA rat model of PD. The golexanolone treatment started 4 weeks after surgery. Motor symptoms were assessed using Motorater and CatWalk tests. We also analyzed fatigue (using a treadmill test), anhedonia (via the sucrose preference test), anxiety (with an open field test), and short-term memory (using a Y maze). Glial activation and key proteins involved in PD pathogenesis were analyzed using immunohistochemistry and Western blot.
UNASSIGNED: Rats with PD showed motor incoordination and impaired locomotor gait, increased fatigue, anxiety, depression, and impaired short-term memory. Golexanolone treatment led to improvements in motor incoordination, certain aspects of locomotor gait, fatigue, anxiety, depression, and short-term memory. Notably, golexanolone reduced the activation of microglia and astrocytes, mitigated TH loss at 5 weeks after surgery, and prevented the increase of α-synuclein levels at 10 weeks.
UNASSIGNED: Golexanolone may be useful in improving both motor and non-motor symptoms that adversely affect the quality of life in PD patients, such as anxiety, depression, fatigue, motor coordination, locomotor gait, and certain cognitive alterations.