Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain
Pharmacological blockade of GluN2B-containing NMDA receptors induces antidepressant-like effects lacking psychotomimetic action and neurotoxicity in the perinatal and adult rodent brain
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DOI：
10.1016/j.pnpbp.2013.04.017
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发表时间：
2013-08-01
影响因子：
5.6
通讯作者：
Inta, Dragos
中科院分区：
文献类型：
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作者：
Lima-Ojeda, Juan M.;Vogt, Miriam A.;Inta, Dragos
NMDA受体（NMDAR）拮抗剂氯胺酮和MK-801具有显著的抗抑郁作用，起效快。然而，它们过度刺激压后皮质，引起精神病样效应和神经元损伤，通过从头诱导热休克蛋白70（Hsp 70）揭示。此外，在发育早期，MK-801触发广泛的皮质细胞凋亡，诱导广泛的caspase-3表达。总之，这些数据引起了对NMDAR拮抗剂治疗的临床适用性的强烈关注。因此，有必要开发更特异性靶向NMDAR的新疗法以避免拟精神病效应。在这里，我们研究了GluN 2B（NR 2B）拮抗剂在大鼠的行为和神经毒性范例，以评估其作为非特异性NMDA受体拮抗剂的可能替代品的潜力。我们发现，用GluN 2B特异性拮抗剂Ro 25-6981治疗引起了强烈的抗抑郁样作用。此外，Ro 25-6981不会引起多动，如用非特异性NMDAR拮抗剂治疗后所显示的，这与啮齿动物中的精神病样作用相关。此外，与MK-801不同，Ro 25-6981不会诱导caspase-3和HSP 70表达，这两种表达分别是围产期和成人大脑中的神经毒性标志物。此外，出乎意料的是，在成人压后皮质中，Ro 25-6981预处理显著降低了MK-801引发的神经毒性。我们的研究结果表明，GluN 2B拮抗剂可能是非特异性NMDAR拮抗剂的有价值的替代品，具有强大的抗抑郁疗效和更有利的副作用。(c)2013 Elsevier Inc. All rights reserved.
NMDA receptor (NMDAR) antagonists like ketamine and MK-801 possess remarkable antidepressant effects with fast onset. However, they over-stimulate the retrosplenial cortex, evoking psychosis-like effects and neuronal injury, revealed by de novo induction of the heat shock protein 70 (Hsp70). Moreover, early in the development MK-801 triggers widespread cortical apoptosis, inducing extensive caspase-3 expression. Altogether these data raise strong concerns on the clinical applicability of NMDAR antagonist therapies. Therefore, the development of novel therapeutics targeting more specifically NMDAR to avoid psychotomimetic effects is necessary. Here we investigated a GluN2B (NR2B) antagonist in behavioral and neurotoxicity paradigms in rats to assess its potential as possible alternative to unspecific NMDA receptor antagonists. We found that treatment with the GluN2B specific antagonist Ro 25-6981 evoked robust antidepressant-like effects. Moreover, Ro 25-6981 did not cause hyperactivity as displayed after treatment with unspecific NMDAR antagonists, a correlate of psychosis-like effects in rodents. Additionally, Ro 25-6981, unlike MK-801, did not induce caspase-3 and HSP70 expression, markers of neurotoxicity in the perinatal and adult brain, respectively. Moreover, unexpectedly, in the adult retrosplenial cortex Ro 25-6981 pretreatment significantly reduced MK-801-triggered neurotoxicity. Our results suggest that GluN2B antagonists may represent valuable alternatives to unspecific NMDAR antagonists with robust antidepressant efficacy and a more favorable side-effect profile. (c) 2013 Elsevier Inc. All rights reserved.