Department of Pathophysiology and Transplants, University of Milan, Milan, Italy; and Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Cardiovascular Medicine, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Anesthesiology. 2023 Nov 1;139(5):628-645. doi: 10.1097/ALN.0000000000004713.
The catabolism of the essential amino acid tryptophan to kynurenine is emerging as a potential key pathway involved in post-cardiac arrest brain injury. The aim of this study was to evaluate the effects of the modulation of kynurenine pathway on cardiac arrest outcome through genetic deletion of the rate-limiting enzyme of the pathway, indoleamine 2,3-dioxygenase.
Wild-type and indoleamine 2,3-dioxygenase-deleted (IDO-/-) mice were subjected to 8-min cardiac arrest. Survival, neurologic outcome, and locomotor activity were evaluated after resuscitation. Brain magnetic resonance imaging with diffusion tensor and diffusion-weighted imaging sequences was performed, together with microglia and macrophage activation and neurofilament light chain measurements.
IDO-/- mice showed higher survival compared to wild-type mice (IDO-/- 11 of 16, wild-type 6 of 16, log-rank P = 0.036). Neurologic function was higher in IDO-/- mice than in wild-type mice after cardiac arrest (IDO-/- 9 ± 1, wild-type 7 ± 1, P = 0.012, n = 16). Indoleamine 2,3-dioxygenase deletion preserved locomotor function while maintaining physiologic circadian rhythm after cardiac arrest. Brain magnetic resonance imaging with diffusion tensor imaging showed an increase in mean fractional anisotropy in the corpus callosum (IDO-/- 0.68 ± 0.01, wild-type 0.65 ± 0.01, P = 0.010, n = 4 to 5) and in the external capsule (IDO-/- 0.47 ± 0.01, wild-type 0.45 ± 0.01, P = 0.006, n = 4 to 5) in IDO-/- mice compared with wild-type ones. Increased release of neurofilament light chain was observed in wild-type mice compared to IDO-/- (median concentrations [interquartile range], pg/mL: wild-type 1,138 [678 to 1,384]; IDO-/- 267 [157 to 550]; P < 0.001, n = 3 to 4). Brain magnetic resonance imaging with diffusion-weighted imaging revealed restriction of water diffusivity 24 h after cardiac arrest in wild-type mice; indoleamine 2,3-dioxygenase deletion prevented water diffusion abnormalities, which was reverted in IDO-/- mice receiving l-kynurenine (apparent diffusion coefficient, μm2/ms: wild-type, 0.48 ± 0.07; IDO-/-, 0.59 ± 0.02; IDO-/- and l-kynurenine, 0.47 ± 0.08; P = 0.007, n = 6).
The kynurenine pathway represents a novel target to prevent post-cardiac arrest brain injury. The neuroprotective effects of indoleamine 2,3-dioxygenase deletion were associated with preservation of brain white matter microintegrity and with reduction of cerebral cytotoxic edema.
色氨酸分解为犬尿氨酸的过程作为潜在的关键途径，参与了心脏骤停后脑损伤。本研究旨在通过基因敲除限速酶吲哚胺 2,3-双加氧酶（IDO），评估色氨酸通路调节对心脏骤停结果的影响。
野生型和吲哚胺 2,3-双加氧酶敲除（IDO-/-）小鼠接受 8 分钟的心脏骤停。复苏后评估存活率、神经功能结果和运动活动。进行弥散张量和弥散加权成像序列的脑磁共振成像，以及小胶质细胞和巨噬细胞激活和神经丝轻链测量。
IDO-/- 小鼠的存活率高于野生型小鼠（IDO-/- 16 只中有 11 只，野生型 16 只中有 6 只，对数秩 P=0.036）。心脏骤停后 IDO-/- 小鼠的神经功能高于野生型小鼠（IDO-/- 9±1，野生型 7±1，P=0.012，n=16）。IDO 缺失维持了心脏骤停后的运动功能，并保持了生理昼夜节律。弥散张量成像的脑磁共振成像显示，在胼胝体（IDO-/- 0.68±0.01，野生型 0.65±0.01，P=0.010，n=4 至 5）和外囊（IDO-/- 0.47±0.01，野生型 0.45±0.01，P=0.006，n=4 至 5）中，IDO-/- 小鼠的平均各向异性分数增加。与 IDO-/- 相比，野生型小鼠的神经丝轻链释放增加（中位数浓度[四分位间距]，pg/mL：野生型 1138[678 至 1384]；IDO-/- 267[157 至 550]；P＜0.001，n=3 至 4）。心脏骤停后 24 小时，弥散加权成像显示野生型小鼠的水扩散受限；IDO 缺失可防止水扩散异常，而 IDO-/- 接受 l-犬尿氨酸后异常恢复（表观扩散系数，μm2/ms：野生型 0.48±0.07；IDO-/- 0.59±0.02；IDO-/- 和 l-犬尿氨酸 0.47±0.08；P=0.007，n=6）。
犬尿氨酸途径是预防心脏骤停后脑损伤的新靶点。IDO 缺失的神经保护作用与脑白质微观完整性的保持和脑细胞毒性水肿的减少有关。
