Intrathecal and systemic alterations of L-arginine metabolism in patients after intracerebral hemorrhage

Abstract

Alterations in the concentration of nitric oxide (NO) and L-arginine metabolites have been associated with the pathophysiology of different vascular diseases. Here, we describe striking changes in L-arginine metabolism after hemorrhagic stroke. Blood and cerebrospinal fluid (CSF) samples of patients with intracerebral hemorrhage (ICH) and/or intraventricular hemorrhage were collected over a ten-day period. Liquid chromatography-tandem mass spectrometry was used to quantify key substrates and products of L-arginine metabolizing enzymes as well as asymmetric (ADMA) and symmetric dimethylarginine (SDMA). Changes in the plasma were limited to early reductions in L-ornithine, L-lysine, and L-citrulline concentrations. Intrathecally, we observed signs of early NO synthase (NOS) upregulation followed by a decrease back to baseline accompanied by a rise in the level of its endogenous NOS-inhibitor ADMA. SDMA demonstrated increased levels throughout the observation period. For arginase, a pattern of persistently elevated activity was measured and arginine:glycine amidinotransferase (AGAT) appeared to be reduced in its activity at later time points. An early reduction in CSF L-arginine concentration was an independent risk factor for poor outcome. Together, these findings further elucidate pathophysiological mechanisms after ICH potentially involved in secondary brain injury and may reveal novel therapeutic targets.

Arginase-1 Released into CSF After Aneurysmal Subarachnoid Hemorrhage Decreases Arginine/Ornithine Ratio: a Novel Prognostic Biomarker

“…In patients with EVD after tumor resection or traumatic brain injury, exemplary Arg/Orn samples showed comparable levels to healthy controls. Inconsistent results were seen in patients with intracerebral hemorrhage and ventricular blood clots, comparable to the study by Mader et al [41].…”

“…In patients suffering from intracerebral hemorrhage, early reduction in CSF L-arginine concentration was an independent risk factor for poor outcome, comparable to our study [41]. Microvascular dysfunction leading to secondary brain damage is well described after intracerebral hemorrhage and might follow similar mechanisms like in SAH.…”

ANAID‐ICH nomogram for predicting unfavorable outcome after intracerebral hemorrhage

“…Besides the primary brain injury, the parenchymal hematoma triggers a series of adverse events causing secondary injury, which plays an essential role in neurological impairment. 25 , 26 , 27 According to the body of literature to date, the presence of DWILs may indicate advanced cerebral small vessel disease burden, which suggests severe endothelial failure, 28 , 29 reduced connectivity of the brain, 30 and susceptibility to the cytokines and prothrombotic milieu generated by a hematoma, 31 , 32 , 33 all of which may affect post‐ICH recovery.…”

Regulated Arginine Metabolism in Immunopathogenesis of a Wide Range of Diseases: Is There a Way to Pass between Scylla and Charybdis?

“…Mader et al analyzed the level of L-Arg and its metabolizing enzymes in peripheral blood and cerebrospinal fluid in patients with cerebral hemorrhages [ 239 ]. It turned out that, in addition to decreased L-Arg, there was an early increase in the NOS level followed by its decline to the baseline, whereas arginase activity was elevated throughout the follow-up period [ 239 ]. These data are consistent with previous studies in a cohort of ICU trauma patients [ 240 ].…”