Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice.
Glutamine antagonist JHU083 improves psychosocial behavior and sleep deficits in EcoHIV-infected mice.
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DOI：
10.1016/j.bbih.2022.100478
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发表时间：
2022-08
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影响因子：
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联合抗逆转录病毒疗法开创了一个艾滋病毒感染者可以存活的时代，在这个时代，艾滋病毒感染者（PLH）可以进行正常的生活活动，并享有可衡量的延长寿命。然而，尽管病毒控制，PLH经常经历各种认知，情感和身体表型，降低他们的生活质量，包括认知障碍，抑郁和睡眠中断。最近，越来越多的证据表明，持续的CNS免疫激活与谷氨酸的过度产生和转氨酶（GLS）活性的上调有关，特别是在小胶质细胞中，从而导致谷氨酸能失衡，并产生神经学后果。本实验室开发了谷氨酰胺拮抗剂6-重氮-5-氧代-L-正亮氨酸（DON）的脑渗透前药JHU 083，口服给药后可有效抑制小鼠脑GLS活性。为了评估JHU 083的治疗潜力，我们用EcoHIV感染小鼠并表征其神经行为表型。EcoHIV感染的小鼠表现出社会互动减少，抑制蔗糖偏好，在早期休息期间睡眠中断，睡眠碎片增加，与PLH中报告的相似，但尚未在小鼠模型中观察到。在显示抑制小胶质细胞GLS的剂量下，JHU 083治疗改善了所有异常神经行为表型。为了探索这种效应的潜在机制，分离海马小胶质细胞进行RNA测序。EcoHIV感染的海马小胶质细胞中失调的基因和途径表明这些细胞的免疫功能受到破坏，JHU 083治疗部分恢复了这些细胞的免疫功能。这些发现表明，上调小胶质细胞GLS可能会影响这些细胞的免疫功能。因此，脑穿透性GLS抑制剂如JHU 083可以作为慢性HIV感染中小胶质细胞中谷氨酸兴奋毒性和异常免疫激活的潜在治疗方式。
Combined antiretroviral therapy ushered an era of survivable HIV infection in which people living with HIV (PLH) conduct normal life activities and enjoy measurably extended lifespans. However, despite viral control, PLH often experience a variety of cognitive, emotional, and physical phenotypes that diminish their quality of life, including cognitive impairment, depression, and sleep disruption. Recently, accumulating evidence has linked persistent CNS immune activation to the overproduction of glutamate and upregulation of glutaminase (GLS) activity, particularly in microglial cells, driving glutamatergic imbalance with neurological consequences. Our lab has developed a brain-penetrant prodrug of the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON), JHU083, that potently inhibits brain GLS activity in mice following oral administration. To assess the therapeutic potential of JHU083, we infected mice with EcoHIV and characterized their neurobehavioral phenotypes. EcoHIV-infected mice exhibited decreased social interaction, suppressed sucrose preference, disrupted sleep during the early rest period, and increased sleep fragmentation, similar to what has been reported in PLH but not yet observed in murine models. At doses shown to inhibit microglial GLS, JHU083 treatment ameliorated all of the abnormal neurobehavioral phenotypes. To explore potential mechanisms underlying this effect, hippocampal microglia were isolated for RNA sequencing. The dysregulated genes and pathways in EcoHIV-infected hippocampal microglia pointed to disruptions in immune functions of these cells, which were partially restored by JHU083 treatment. These findings suggest that upregulation of microglial GLS may affect immune functions of these cells. Thus, brain-penetrable GLS inhibitors like JHU083 could act as a potential therapeutic modality for both glutamate excitotoxicity and aberrant immune activation in microglia in chronic HIV infection.
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DOI：
10.1097/nen.0000000000000026
发表时间：
2014-01-01
影响因子：
3.2
作者：
He, Hongxia;Sharer, Leroy R.;Volsky, David J.
通讯作者：
Volsky, David J.
影响因子：
3.8
作者：
Chouliaras, Leonidas;Kenis, Gunter;Rutten, Bart P. F.
通讯作者：
Rutten, Bart P. F.
影响因子：
3
作者：
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通讯作者：
Fagiolini, Michela
DOI：
10.15288/jsa.2002.63.179
发表时间：
2002-03-01
期刊：
JOURNAL OF STUDIES ON ALCOHOL
影响因子：
--
作者：
Galvan, FH;Bing, EG;Shapiro, M
通讯作者：
Shapiro, M
影响因子：
3.1
作者：
Berger, JR;Avison, M
通讯作者：
Avison, M