In vivo biomarkers of GABAergic function in epileptic rats treated with the GAT-1 inhibitor E2730.

IF 6.6 1区医学 Q1 CLINICAL NEUROLOGY

Epilepsia Pub Date : 2024-09-20 DOI:10.1111/epi.18119

Idrish Ali, Bianca Jupp, Matthew R Hudson, Brendan Major, Juliana Silva, Glenn R Yamakawa, Pablo M Casillas-Espinosa, Emma Braine, Peravina Thergarajan, Mohammad B Haskali, Lucy Vivash, Robert Brkljaca, Sandy R Shultz, Patrick Kwan, Kazuyuki Fukushima, Pallavi Sachdev, Jocelyn Y Cheng, Richelle Mychasiuk, Nigel C Jones, David K Wright, Terence J OBrien

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引用次数: 0

Abstract

Objective: E2730, an uncompetitive γ-aminobutyric acid (GABA) transporter-1 (GAT-1) inhibitor, has potent anti-seizure effects in a rodent model of chronic temporal lobe epilepsy, the kainic acid status epilepticus (KASE) rat model. In this study, we examined purported neuroimaging and physiological surrogate biomarkers of the effect of E2730 on brain GABAergic function.

Methods: We conducted a randomized cross-over study, incorporating 1-week treatments with E2730 (100 mg/kg/day subcutaneous infusion) or vehicle in epileptic post-KASE rats. KASE rats underwent serial 9.4 T magnetic resonance spectroscopy (MRS) measuring GABA and other brain metabolites, [¹⁸F]Flumazenil positron emission tomography (PET) quantifying GABA_A receptor availability, quantitative electroencephalography (qEEG) and transcranial magnetic stimulation (TMS)-mediated motor activity, as well as continuous video-EEG recording to measure spontaneous seizures during each treatment. Age-matched, healthy control animals treated with E2730 or vehicle were also studied.

Results: E2730 treatment significantly reduced spontaneous seizures, with 8 of 11 animals becoming seizure-free. MRS revealed that E2730-treated animals had significantly reduced taurine levels. [¹⁸F]Flumazenil PET imaging revealed no changes in GABA receptor affinity or density during E2730 treatment. The power of gamma frequency oscillations in the EEG was decreased significantly in the auditory cortex and hippocampus of KASE and control rats during E2730 treatment. Auditory evoked gamma frequency power was enhanced by E2730 treatment in the auditory cortex of KASE and healthy controls, but only in the hippocampus of KASE rats. E2730 did not influence motor evoked potentials triggered by TMS.

Significance: This study identified clinically relevant changes in multimodality imaging and functional purported biomarkers of GABAergic activity during E2730 treatment in epileptic and healthy control animals. These biomarkers could be utilized in clinical trials of E2730 and potentially other GABAergic drugs to provide surrogate endpoints, thereby reducing the cost of such trials.

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用 GAT-1 抑制剂 E2730 治疗癫痫大鼠体内 GABA 能功能的生物标记物。

目的：E2730是一种非竞争性γ-氨基丁酸（GABA）转运体-1（GAT-1）抑制剂，在慢性颞叶癫痫啮齿动物模型--凯尼酸状态癫痫（KASE）大鼠模型中具有强效抗癫痫作用。在这项研究中，我们研究了E2730对大脑GABA能功能影响的所谓神经影像学和生理学替代生物标志物：我们进行了一项随机交叉研究，对癫痫后 KASE 大鼠进行为期 1 周的 E2730（100 毫克/千克/天，皮下注射）或药物治疗。在每次治疗期间，KASE大鼠接受了连续的9.4 T磁共振波谱（MRS）检查，以测量GABA和其他脑代谢物；接受了[18F]氟马西尼正电子发射断层扫描（PET）检查，以量化GABAA受体的可用性；接受了定量脑电图（qEEG）检查和经颅磁刺激（TMS）介导的运动活动检查，以及连续的视频脑电图记录，以测量自发性癫痫发作。同时还研究了接受E2730或药物治疗的年龄匹配的健康对照组动物：结果：E2730治疗可明显减少自发性癫痫发作，11只动物中有8只不再发作。MRS显示，E2730治疗动物的牛磺酸水平明显降低。[18F]氟马西尼 PET 成像显示，E2730 治疗期间 GABA 受体的亲和力或密度没有变化。在E2730治疗期间，KASE大鼠和对照组大鼠听觉皮层和海马的脑电图中伽马频率振荡的功率明显下降。E2730能增强KASE大鼠和健康对照组大鼠听觉皮层的听觉诱发伽马频率功率，但仅增强KASE大鼠海马的伽马频率功率。E2730不会影响TMS触发的运动诱发电位：本研究确定了癫痫和健康对照组动物在接受 E2730 治疗期间 GABA 能活动的多模态成像和功能性生物标志物的临床相关变化。这些生物标志物可用于E2730和其他GABA能药物的临床试验，以提供替代终点，从而降低此类试验的成本。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Epilepsia 医学-临床神经学

CiteScore

10.90

自引率

10.70%

发文量

319

审稿时长

2-4 weeks

期刊介绍： Epilepsia is the leading, authoritative source for innovative clinical and basic science research for all aspects of epilepsy and seizures. In addition, Epilepsia publishes critical reviews, opinion pieces, and guidelines that foster understanding and aim to improve the diagnosis and treatment of people with seizures and epilepsy.