Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice.
Ceftriaxone reverses ketamine-induced lasting EEG and astrocyte alterations in juvenile mice.
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DOI：
10.1016/j.drugalcdep.2015.07.1198
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发表时间：
2015-11-01
影响因子：
4.2
通讯作者：
Siegel SJ
中科院分区：
文献类型：
--
作者：
Dodman K;Featherstone RE;Bang J;Liang Y;Siegel SJ
氯胺酮是一种N-甲基-D-天冬氨酸受体拮抗剂，因其良好的安全性而被用作儿科麻醉剂。它也被作为一种抗抑郁剂进行了研究。不幸的是，氯胺酮会引起包括幻觉在内的不良反应，并与青少年滥用的高流行率有关。尽管长期使用氯胺酮已被证明会在戒烟数年后产生认知障碍，但对其对青少年的长期影响知之甚少。β-内酰胺头孢曲松已被证明可以减轻酒精戒断，并减轻蛛网膜下腔出血后早期的脑损伤和记忆障碍。然而，它逆转青少年氯胺酮暴露的影响的能力尚不清楚。先前的数据表明，氯胺酮导致含有兴奋性氨基酸转运蛋白2(EAAT2)的星形胶质细胞数量减少。此外，β-内酰胺类抗生素头孢曲松增加了EAAT2的表达。由于EAAT2是从突触清除谷氨酸的主要机制，目前的研究验证了头孢曲松可能逆转氯胺酮暴露的功能后果的假设。我们用脑电(EEG)研究了慢性氯胺酮对幼鼠的影响以及头孢曲松的逆转作用。随后，我们用胶质纤维酸性蛋白(GFAP)评估了这些治疗对星形胶质细胞增殖标记物的影响，并用EAAT2证明了其功能。暴露于慢性氯胺酮的幼鼠在脑电测量以及星形胶质细胞数量和功能的标记物上显示出持久的变化。这些改变可被头孢曲松逆转。数据表明，头孢曲松可能能够改善氯胺酮引起的青少年大脑的长期障碍。
Ketamine, an N-Methyl-D-aspartate receptor antagonist, is used as a pediatric anesthetic because of its favorable safety profile. It is also being investigated as an antidepressant. Unfortunately, ketamine causes adverse reactions including hallucinations and is associated with a high prevalence of abuse among adolescents. Although chronic ketamine use has been shown to produce cognitive impairments even years following cessation, little is known about its long-term consequences on adolescents. The beta-lactam ceftriaxone has been shown to attenuate alcohol withdrawal, and alleviate early brain injury and memory impairments following subarachnoid hemorrhage. However, its ability to reverse the effects of adolescent ketamine exposure is not known. Previous data indicate that ketamine causes a reduction in the number of Excitatory Amino Acid Transporter Type 2 (EAAT2)-containing astrocytes. Additionally, the beta lactam antibiotic ceftriaxone increased expression of EAAT2. As EAAT2 is a principal mechanism of glutamate clearance from the synapse, the current study tests the hypothesis that ceftriaxone may reverse functional consequences of ketamine exposure. We examined the effects of chronic ketamine in juvenile mice as well as reversal by ceftriaxone using electroencephalography (EEG). Subsequently, we assessed the effects of these treatments on markers of astrocyte proliferation, using Glial Fibrillary Acidic Protein (GFAP), and function, as evidenced by EAAT2. Juvenile mice exposed to chronic ketamine showed lasting alterations in EEG measurements as well as markers of astrocyte number and function. These alterations were reversed by ceftriaxone. Data suggest that ceftriaxone may be able to ameliorate ketamine-induced long-term disturbances in adolescent brains.