精氨酸对 MELAS（线粒体脑肌病伴高乳酸血症和卒中样发作）综合征患者脑血管反应性、灌注和神经血管耦联的影响。
L-arginine effects on cerebrovascular reactivity, perfusion and neurovascular coupling in MELAS (mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes) syndrome.
机构信息
Division of Neurology, Dept. of Pediatrics, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
Dept. of Medical Imaging, The Toronto Western Hospital, University of Toronto, Toronto, Ontario, Canada.
出版信息
PLoS One. 2020 Sep 3;15(9):e0238224. doi: 10.1371/journal.pone.0238224. eCollection 2020.
OBJECTIVE
We previously showed that MELAS patients have decreased cerebrovascular reactivity (CVR) (p≤ 0.002) and increased cerebral blood flow (CBF) (p<0.0026); changes correlated with disease severity and % mutant mtDNA (inversely for CVR; directly for CBF). We ran a prospective pilot in 3 MELAS sibs (m.3243A>G tRNALeu(UUR)) with variable % mutant blood mtDNA to assess effects of L-Arginine (L-Arg) (single dose and 6-wk steady-state trial) on regional CBF, arterial CVR and neurovascular coupling.
METHODS
Patients were studied with 3T MRI using arterial spin labeling (ASL) to measure CBF and changes in % Blood Oxygen Level Dependent (BOLD) signal to changes in arterial partial pressure of CO2 to measure CVR. Task fMRI consisted of an alternating black and white checkerboard to evaluate visual cortex response in MELAS and controls.
RESULTS
Following L-Arg, there was restoration of serum Arg (76-230 μM) in MELAS sibs and a trend towards increasing CVR in frontal and corresponding decrease in occipital cortex; CVR was unchanged globally. There was a 29-37% reduction in baseline CBF in one patient following 6 wks of L-Arg. Pre-treatment fMRI activation in response to visual cortex stimulus was markedly decreased in the same patient compared to controls in primary visual striate cortex V1 and extrastriate regions V2 to V5 with a marked increase toward control values following a single dose and 6 wks of L-Arg.
CONCLUSION
Proposed "healing" effect may be due to more efficient utilization of energy substrates with increased cellular energy balances and ensuing reduction in signalling pathways that augment flow in the untreated state.
CLASSIFICATION OF EVIDENCE
This prospective pilot study provides Class III evidence that oral L-Arginine (100 mg/kg single dose or 100 mg/kg three times daily po X 6 weeks) normalizes resting blood flow from elevated pre-treatment levels in patients with MELAS syndrome, selectively increases their CVR from reduced pre-treatment levels in regions most impaired at the expense of less abnormal regions, and normalizes reduced BOLD fMRI activation in response to visual cortex stimulus.
CLINICAL TRIALS.GOV (NIH): NCT01603446.
目的
我们之前发现 MELAS 患者的脑血管反应性（CVR）降低（p≤0.002），脑血流（CBF）增加（p<0.0026）；这些变化与疾病严重程度和突变型 mtDNA 的百分比（与 CVR 呈负相关；与 CBF 呈正相关）相关。我们对 3 名 MELAS 兄弟姐妹（m.3243A>G tRNALeu(UUR)）进行了前瞻性试点研究，他们的血液 mtDNA 突变百分比不同，以评估 L-精氨酸（L-Arg）（单次剂量和 6 周稳态试验）对区域性 CBF、动脉 CVR 和神经血管耦联的影响。
方法
使用 3T MRI 对患者进行动脉自旋标记（ASL），以测量 CBF，并通过改变动脉二氧化碳分压来测量动脉 CVR 以改变血氧水平依赖性（BOLD）信号的百分比。任务 fMRI 由交替的黑白棋盘组成，以评估 MELAS 和对照组的视觉皮层反应。
结果
在 MELAS 兄弟姐妹中，L-Arg 后血清 Arg（76-230 μM）恢复正常，额皮质 CVR 有上升趋势，枕皮质相应下降；但整体 CVR 无变化。在一名患者中，经过 6 周的 L-Arg 治疗后，基线 CBF 降低了 29-37%。在同一名患者中，与对照组相比，视觉皮层刺激的预处理 fMRI 激活明显减少，初级视觉纹状皮层 V1 和纹外区域 V2 至 V5 明显增加，而在单次剂量和 6 周 L-Arg 治疗后，增加幅度接近对照组。
结论
提出的“愈合”效应可能是由于能量底物的更有效利用，导致细胞能量平衡增加，从而减少了未治疗状态下增加血流的信号通路。
证据分类
这项前瞻性试点研究提供了 III 类证据，表明口服 L-精氨酸（100mg/kg 单次剂量或 100mg/kg 每日 3 次口服 X 6 周）可使 MELAS 综合征患者的静息血流从升高的治疗前水平正常化，选择性地增加他们从降低的治疗前水平的 CVR，以牺牲较少异常的区域为代价，使视觉皮层刺激反应的减少的 BOLD fMRI 激活正常化。
临床试验.gov（NIH）：NCT01603446。
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