Izquierdo-Altarejos Paula, Arenas Yaiza M, Martínez-García Mar, Vázquez Lola, Mincheva Gergana, Doverskog Magnus, Blackburn Thomas P, Bohnen Nicolaas I, Llansola Marta, Felipo Vicente
Laboratory of Neurobiology, Centro de Investigación Príncipe Felipe, Valencia, Spain.
Umecrine Cognition AB, Solna, Stockholm, Sweden.
Front Aging Neurosci. 2024 Jun 21;16:1417938. doi: 10.3389/fnagi.2024.1417938. eCollection 2024.
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 GABA receptors. We hypothesized that golexanolone (GR3027), a well-tolerated GABA receptor-modulating steroid antagonist (GAMSA), may improve Parkinson's symptoms in a rat model of PD.
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.
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.
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.
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.
帕金森病（PD）在全球影响着超过600万人。除了运动障碍外，表现出PD症状的患者和动物模型还会经历认知障碍、疲劳、焦虑和抑郁。目前，尚无能够改变PD疾病进展的药物。大量证据表明，γ-氨基丁酸（GABA）水平升高会导致酪氨酸羟化酶（TH）表达降低以及伴随的行为缺陷。阻断GABA受体可能会恢复TH表达。我们推测，戈勒克索诺龙（GR3027），一种耐受性良好的GABA受体调节类固醇拮抗剂（GAMSA），可能会改善PD大鼠模型的帕金森症状。
本研究的目的是评估戈勒克索诺龙是否能改善PD大鼠模型的运动和非运动症状，并确定一些潜在机制。
我们使用了单侧6-羟基多巴胺（6-OHDA）大鼠PD模型。戈勒克索诺龙治疗在手术后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）、快感缺失（通过蔗糖偏好测试）、焦虑（采用旷场试验）和短期记忆（使用Y迷宫）。使用免疫组织化学和蛋白质印迹法分析胶质细胞活化以及参与PD发病机制的关键蛋白。
PD大鼠表现出运动不协调和运动步态受损、疲劳增加、焦虑、抑郁以及短期记忆受损。戈勒克索诺龙治疗使运动不协调、运动步态的某些方面、疲劳、焦虑、抑郁和短期记忆得到改善。值得注意的是，戈勒克索诺龙减少了小胶质细胞和星形胶质细胞的活化，减轻了术后5周时TH的损失，并防止了术后10周时α-突触核蛋白水平的升高。
戈勒克索诺龙可能有助于改善对PD患者生活质量产生不利影响的运动和非运动症状，如焦虑、抑郁、疲劳、运动协调、运动步态以及某些认知改变。
