Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.
Indoleamine 2,3-dioxygenase-dependent neurotoxic kynurenine metabolism mediates inflammation-induced deficit in recognition memory.
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DOI：
10.1016/j.bbi.2015.06.022
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发表时间：
2015-11
期刊：
影响因子：
--
通讯作者：
O'Connor JC
中科院分区：
文献类型：
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作者：
Heisler JM;O'Connor JC
抑郁症的认知功能障碍是一种普遍的和衰弱的症状，目前可用的药物治疗效果不佳。过去十年的研究提供了证据，证明促炎性参与了抑郁症的神经生物学和与这些疾病相关的症状，包括记忆功能障碍的方面。最近的临床研究表明，犬尿氨酸代谢的炎症相关变化是一系列抑郁症状（包括认知和记忆缺陷）发展的潜在致病因素。此外，临床前工作已经证明了许多情绪相关的抑郁样行为依赖于吲哚胺2，3-双加氧酶-1（IDO 1），这是犬尿氨酸途径的炎症诱导限速酶。在这里，我们证明了在小鼠模型中，外周给药内毒素诱导识别记忆缺陷。IDO缺陷的小鼠免受认知障碍。此外，内毒素诱导的炎症增加了嗅周/内嗅皮质内的犬尿氨酸代谢，这些脑区与识别记忆有关。犬尿氨酸（IDO 1的代谢产物）的单次外周注射足以在对照和IDO缺失小鼠中诱导识别记忆缺陷。最后，犬尿氨酸单加氧酶（KMO）缺陷小鼠也受到保护，免受炎症诱导的新物体识别缺陷的影响。这些数据表明IDO依赖性神经毒性犬尿氨酸代谢是炎症诱导的抑郁症中认知功能障碍的致病因素，也是治疗这些疾病的潜在新靶点。
Cognitive dysfunction in depression is a prevalent and debilitating symptom that is poorly treated by the currently available pharmacotherapies. Research over the past decade has provided evidence for proinflammatory involvement in the neurobiology of depressive disorders and symptoms associated with these disorders, including aspects of memory dysfunction. Recent clinical studies implicate inflammation-related changes in kynurenine metabolism as a potential pathogenic factor in the development of a range of depressive symptoms, including deficits in cognition and memory. Additionally, preclinical work has demonstrated a number of mood-related depressive-like behaviors to be dependent on indoleamine 2,3-dioxygenase-1 (IDO1), the inflammation-induced rate-limiting enzyme of the kynurenine pathway. Here, we demonstrate in a mouse model, that peripheral administration of endotoxin induced a deficit in recognition memory. Mice deficient in IDO were protected from cognitive impairment. Furthermore, endotoxin-induced inflammation increased kynurenine metabolism within the perirhinal/entorhinal cortices, brain regions which have been implicated in recognition memory. A single peripheral injection of kynurenine, the metabolic product of IDO1, was sufficient to induce a deficit in recognition memory in both control and IDO null mice. Finally, kynurenine monooxygenase (KMO) deficient mice were also protected from inflammation-induced deficits on novel object recognition. These data implicate IDO-dependent neurotoxic kynurenine metabolism as a pathogenic factor for cognitive dysfunction in inflammation-induced depressive disorders and a potential novel target for the treatment of these disorders.