RESUMEN
BACKGROUND AND PURPOSE: Recent studies have suggested that H2S may be involved in the pathophysiology of subarachnoid hemorrhage (SAH). Endogenous H2S is mainly formed by cystathionine ß-synthase (CBS), d-amino-acid oxidase (DAO), and 3-mercaptopyruvate sulfotransferase (3-MST) from the substrate cysteine in the central nervous system. In this study, we assessed the expression of CBS, 3-MST, and DAO in cerebrospinal fluid (CSF) from patients with SAH and rats and the expression in the rat brain. METHODS: CSF samples were collected within 48â¯h of aneurysm rupture in SAH patients. The CBS, DAO and 3-MST levels in CSF were measured using Western blot analyses, and correlations with the inflammatory parameter Interleukin-6 (IL-6) were assessed. Six months after SAH, the clinical outcomes were assessed. RESULTS: In human CSF samples, the CBS and DAO protein levels were detected and increased after SAH. However, 3-MST was not detected in the control group CSF but increased after SAH. Strong correlations were observed between the increasing levels of CBS, DAO, and 3-MST and IL-6 2 days after SAH. Furthermore, high CBS, 3-MST and DAO levels in the CSF samples were correlated with poor outcomes at 6 months after SAH onset. We also found that the expression of CBS, DAO and 3-MST in the rat CSF and brain (parietal cortex and hippocampus) increased following SAH. We detected strong correlations between the increases in CBS, 3-MST and IL-6 in the rat CSF and brain samples. CONCLUSIONS: These results indicate that the upregulated expression of CBS, DAO and 3-MST after SAH was closely associated with the inflammatory response and neurological deficits after SAH.
Asunto(s)
Sulfuro de Hidrógeno/metabolismo , Interleucina-6/metabolismo , Hemorragia Subaracnoidea/fisiopatología , Animales , Encéfalo/fisiopatología , Cistationina betasintasa/líquido cefalorraquídeo , D-Aminoácido Oxidasa/líquido cefalorraquídeo , Femenino , Humanos , Masculino , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/fisiopatología , Ratas , Ratas Sprague-Dawley , Hemorragia Subaracnoidea/complicaciones , Sulfurtransferasas/líquido cefalorraquídeo , Factores de TiempoRESUMEN
Clinical trials demonstrated that D-serine administration improves schizophrenia symptoms, raising the possibility that altered levels of endogenous D-serine may contribute to the N-methyl D-aspartate receptor hypofunction thought to play a role in the disease. We hypothesized that cerebro-spinal fluid (CSF) D-serine levels are decreased in the patients due to reduced synthesis and/or increased degradation in brain. We now monitored amino acid levels in CSF from 12 schizophrenia patients vs. 12 controls and in postmortem parietal-cortex from 15 control subjects and 15 each of schizophrenia, major-depression and bipolar patients. In addition, we monitored postmortem brain serine racemase and D-amino acid oxidase protein levels by Western-blot analysis. We found a 25% decrease in D-serine levels and D/L-serine ratio in CSF of schizophrenia patients, while parietal-cortex D-serine was unaltered. Levels of L-serine, L-glutamine and L-glutamate were unaffected. Frontal-cortex (39%) and hippocampal (21%) serine racemase protein levels and hippocampal serine racemase/D-amino acid oxidase ratio (34%) were reduced. Hippocampal D-amino-acid-oxidase protein levels significantly correlated with duration of illness (r=0.6, p=0.019) but not age. D-amino acid oxidase levels in patients with DOI>20 years were 77% significantly higher than in the other patients and controls. Our results suggest that reduced brain serine racemase and elevated D-amino acid oxidase protein levels may contribute to the lower CSF D-serine levels in schizophrenia.