Mechanism of Delayed Increases in Kynurenine Pathway Metabolism in Damaged Brain Regions Following Transient Cerebral Ischemia
Mechanism of Delayed Increases in Kynurenine Pathway Metabolism in Damaged Brain Regions Following Transient Cerebral Ischemia
复制标题
短暂性脑缺血后受损脑区犬尿氨酸途径代谢延迟增加的机制
作者：
K. Saito;T. Nowak;S. Markey;M. Heyes
摘要：沙土鼠短暂性脑缺血后，内源性N-甲基-D-天冬氨酸受体激动剂喹啉酸(Quin)水平出现迟发性升高，推测其继发于吲哚-2，3-双加氧酶和L-色氨酸-犬尿氨酸途径的其他酶的诱导。在本研究中，脑缺血10min后4d，IDO活性和Quin浓度均呈比例增加，在海马、纹状体、大脑皮质和丘脑均有这两种反应。这些增加与局部脑损伤和炎症的严重程度平行。缺血后沙土鼠小脑的IDO活性和Quin浓度没有变化，这与该区域血流的保存和病理的消失是一致的。血液奎宁和L犬尿氨酸浓度不受缺血的影响。脑缺血后4天的脑组织奎宁水平超过血液浓度，使血脑屏障的破坏作用降至最低。再灌流第4天，犬尿氨酸酶、犬尿氨酸3-羟基酶和3-羟基邻氨基苯甲酸-3，4-双加氧酶活性在海马区显著升高，而在小脑中未见明显变化。脑缺血4d动物脑室注射L-[13C6]色氨酸1h后，用质谱仪观察到[13C6]Quin在海马区的合成，而在小脑中不合成。然而，在脑室内注射3-羟基邻氨基苯甲酸后，对照组沙土鼠的小脑和海马区都显示出Quin的蓄积，这验证了脑室内给药时前体在这两个区域的可用性。值得注意的是，虽然缺血沙土鼠小脑的IDO活性和Quin含量没有变化，但在全身注射商陆丝裂原免疫刺激24 h后，小脑的IDO活性和Quin含量都增加了，与海马、纹状体、大脑皮层和丘脑的IDO活性和Quin含量几乎相同，表明小脑可以增加IDO活性和Quin含量，以响应免疫激活。与对照组相比，脑缺血后沙土鼠海马、小脑或脑脊液中犬尿酸浓度没有变化，这与犬尿氨酸转氨酶活性未受影响的情况一致。总之，这些结果支持IDO、犬尿氨酸酶、犬尿氨酸3-羟基酶和3-羟基邻氨基苯甲酸-3，4-双加氧酶在短暂性脑缺血后受损脑区加速L-色氨酸和其他底物转化为奎因的作用。免疫细胞化学结果显示，巨噬细胞在海马区和其他脑区存在，与这些生化变化的程度相平行。我们假设，脑缺血后犬尿氨酸途径代谢增加反映了脑损伤部位巨噬细胞和其他反应细胞群的存在。
Abstract: Delayed increases in the levels of an endogenous N‐methyl‐D‐aspartate receptor agonist, quinolinic acid (QUIN), have been demonstrated following transient ischemia in the gerbil and were postulated to be secondary to induction of indoleamine‐2,3‐dioxygenase (IDO) and other enzymes of the L‐tryptophan‐kynurenine pathway. In the present study, proportional increases in IDO activity and QUIN concentrations were found 4 days after 10 min of cerebral ischemia, with both responses in hippocampus > striatum > cerebral cortex > thalamus. These increases paralleled the severity of local brain injury and inflammation. IDO activity and QUIN concentrations were unchanged in the cerebellum of postischemic gerbils, which is consistent with the preservation of blood flow and resultant absence of pathology in this region. Blood QUIN and L‐kynurenine concentrations were not affected by ischemia. Brain tissue QUIN levels at 4 days postischemia exceeded blood concentrations, minimizing a role for breakdown of the blood–brain barrier. Marked increases in the activity of kynureninase, kynurenine 3‐hydroxylase, and 3‐hydroxyanthranilate‐3,4‐dioxygenase were also detected in hippocampus but not in cerebellum on day 4 of recirculation. In vivo synthesis of [13C6]QUIN was demonstrated, using mass spectrometry, in hippocampus but not in cerebellum of 4‐day postischemic animals 1 h after intracisternal administration of L‐[13C6]tryptophan. However, accumulation of QUIN was demonstrated in both cerebellum and hippocampus of control gerbils following an intracisternal injection of 3‐hydroxyanthranilic acid, which verifies the availability of precursor to both regions when administered intracisternally. Notably, although IDO activity and QUIN concentrations were unchanged in the cerebellum of ischemic gerbils, both IDO activity and QUIN content were increased in cerebellum to approximately the same degree as in hippocampus, striatum, cerebral cortex, and thalamus 24 h after immune stimulation by systemic pokeweed mitogen administration, demonstrating that the cerebellum can increase IDO activity and QUIN content in response to immune activation. No changes in kynurenic acid concentrations in either hippocampus, cerebellum, or cerebrospinal fluid were observed in the postischemic gerbils compared with controls, in accordance with the unaffected activity of kynurenine aminotransferase activity. Collectively, these results support roles for IDO, kynureninase, kynurenine 3‐hydroxylase, and 3‐hydroxyanthranilate‐3,4‐dioxygenase in accelerating the conversion of L‐tryptophan and other substrates to QUIN in damaged brain regions following transient cerebral ischemia. Immunocytochemical results demonstrated the presence of macrophage infiltrates in hippocampus and other brain regions that parallel the extent of these biochemical changes. We hypothesize that increased kynurenine pathway metabolism after ischemia reflects the presence of macrophages and other reactive cell populations at sites of brain injury.
神经化学物质与选择性神经元脆弱性相关。
影响因子：
--
作者：
Wieloch,T
通讯作者：
Wieloch,T
DOI：
10.1089/cns.1985.2.299
发表时间：
1985
期刊：
Central nervous system trauma : journal of the American Paralysis Association
影响因子：
--
作者：
A. Blight
通讯作者：
A. Blight
DOI：
10.1073/pnas.85.11.4079
发表时间：
1988-06-01
影响因子：
11.1
作者：
SCHWARCZ, R;OKUNO, E;WHETSELL, WO
通讯作者：
WHETSELL, WO