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Background: Early brain injury (EBI) has recently been identified as the main factor of poor prognosis for subarachnoid hemorrhage (SAH), and apoptosis has an important function in EBI. Although nitric oxide (NO) and caspase-12, a specific molecule related to endoplasmic reticulum (ER) stress-induced apoptosis signaling pathways, are involved in brain injury after SAH, the relationship between NO and ER stress has not been reported yet. We examined the NO and caspase-12 contents and investigated the relationship between NO and ER stress-induced apoptosis., Methods: Sprague-Dawley rats (n = 90), weighing 300 g to 350 g, were used for the SAH model. SAH was induced in rats by blood injection into the prechiasmatic cistern. NO, caspase-12, and apoptosis were measured by nitrate reductase method, real-time polymerase chain reaction, and terminal deoxynucleotidy1 transferase-mediated dUTP nick-end labeling staining, respectively, at different time points after SAH. Pearson correlation coefficients were used to examine correlation., Results: NO level of cerebrospinal fluid significantly increased in the SAH group at 3, 24, 48, and 72 h compared with other groups. Caspase-12 also significantly increased at 1, 3, 6, 24, 48, and 72 h. Cell apoptosis significantly increased at 24, 48, and 72 h. A significant correlation between the number of apoptotic neurons and caspase-12 was found. NO was also correlated with caspase-12., Conclusions: Our results suggest that NO is involved in the pathophysiological events of EBI after SAH by increasing caspase-12, which results in neuronal apoptosis.

Nitric oxide has a definitive role in the complex pathophysiology of traumatc brain injury (TBI). This prospective cohort study investigated the changes in nitric oxide metabolite (NOx) levels in cerebrospinal fluid (CSF) and their correlation with factors associated with severity and prognosis after severe TBI. NOx levels were measured in CSF obtained via ventriculostomy in 44 adult patients admitted after severe TBI (Glasgow Coma Scale ≤ 8/15). The overall mean level of CSF NOx in the study population was 7.40 ± 1.59 μmol/L. Levels of CSF NOx were found to be significantly higher in subgroups of patients with poorer outcome measured by Glasgow Outcome Scale score (p < 0.042), in patients with high intracranial pressure (ICP) readings (p < 0.027) and in those with higher Marshall computed tomography (CT) grading scores (p < 0.026). Simple logistic regression demonstrated that CSF NOx levels were a significant predictor of ICP (b = 0.493, 95%CI: 1.03, 2.58, p = 0.033). A patient with 1 μmol/L increase in NOx level had 1.6 times the odds to have an ICP ≥ 20 mmHg when other confounders were not adjusted. NOx level is also a significant predictor of Marshall CT grading (b = 0.473, 95%CI: 1.02, 2.50, p = 0.037). A patient with 1 μmol/L increase in NOx level had 1.6 times the odds to have a high Marshall grade when other confounders were not adjusted. It can be concluded that CSF NOx levels may serve as a potentially useful biomarker in severe TBI given its significant association with ICP readings as well as Marshall CT grading.

Despite intensive research efforts, by our own team and many others, the molecules responsible for acute neurological damage following subarachnoid hemorrhage (SAH) and contributing to delayed ischemic neurological deficit (DIND) have not yet been elucidated. While there are a number of candidate mechanisms, including nitric oxide (NO) scavenging, endothelin-1, protein kinase C (PKC) activation, and rho kinase activation, to name but a few, that have been investigated using animal models and human trials, we are, it seems, no closer to discovering the true nature of this complex and enigmatic pathology. Efforts in our laboratory have focused on the chemical milieu present in hemorrhagic cerebrospinal fluid (CSF) following SAH and the interaction of the environment with the molecules generated by SAH and subsequent events, including NO scavenging, immune response, and clot breakdown. We have identified and characterized a group of molecules formed by the oxidative degradation of bilirubin (a clot breakdown product) and known as BOXes (bilirubin oxidation products). We present a synopsis of the characterization of BOXes as found in human SAH patients' CSF and the multiple signaling pathways by which BOXes act. In summary, BOXes are likely to play an essential role in the etiology of acute brain injury following SAH, as well as DIND.

Brain injury, like other central nervous system pathologies, causes changes in the composition of the cerebrospinal fluid (CSF). In this study, changes in the concentration of small molecules of the CSF, which are in the minimal micromolar concentration, were observed and monitored using high-resolution proton (NMR) spectroscopy. Twenty-two patients with isolated traumatic brain injuries (TBI) and 15 patients making up the control group were recruited for the study. CSF samples were collected by lumbar puncture from the lumbar subarachnoid space in the patients just before commencement of therapy and on the first, third, seventh and fourteenth days of therapy at the ICU. Forty-four signals of the NMR spectra and NO concentration of the CSF samples were analyzed. The analysis shows that the amino acid and organic acid concentrations change during the therapy and mostly are higher than in the control group. Significant differences in concentration of the analyzed CSF components between the TBI patients and the control group have been noted. The rate of the lactate to pyruvate conversion increased because the L/P ratio showed no significant differences between the TBI group and the control group, while the concentrations of both components were significantly higher in the TBI patients than in the control group. Citrulline, arginine and nitric oxide concentrations were the focus of the analysis. Citrulline concentration changes overlapped NO changes from 0 until 3rd day of therapy, while for the remaining days of observation the NO concentration stabilized at the control level, whereas citrulline concentration significantly decreased.

Hypotension reduces cerebral O(2) supply, which may result in brain cell damage and loss of brain cell function in the near-term neonate. The aim is to elucidate 1) to what extent the functional disturbance of the cerebral cortex, as measured with electrocortical brain activity (ECBA), is related to cerebral cortical tissue damage, as estimated by MAP2; and 2) whether there is a relationship between the glutamate, nitric oxide (NO), cGMP pathway and the development of cerebral cortical tissue damage after hemorrhagic hypotension. Seven lambs were delivered at 131 d of gestation. Hypotension was induced by withdrawal of blood until mean arterial blood pressure was reduced to 30% of normotension. Cerebral O(2) supply, consumption, and ECBA were calculated in normotensive conditions and after 2.5 h of hypotension. Concentrations of glutamate and aspartate in cerebrospinal fluid (CSF), NO(2) and NO(3) (NOx) in plasma, and cGMP in cortical brain tissue were determined in both conditions. CSF and brain tissue from siblings were used to determine normotensive values. Cortical neuronal damage was detected after 2.5 h of hypotension. ECBA was negatively related to the severity of the cortical damage. ECBA was related to respectively glutamate, NOx, and cGMP concentrations. In conclusion, cortical neuronal damage is detected after 2.5 h of hemorrhagic hypotension in the near-term born lamb. The damage is reflected by a reduction of ECBA. The glutamate, NOx, cGMP pathway is likely to be involved in the pathogenesis of cerebral cortical damage.

To investigate the content and dynamics of nitric oxide (NO) in the cerebrospinal fluid (CSF) of patients with acute head injury and to clarify the relationship of NO with clinical features and intracranial pressure (ICP) as well as outcomes, 38 adults with acute head injury were studied. Glasgow Coma Scale (GCS) obtained at admission and Glasgow Outcome Scale (GOS) 3 months after injury was assessed. ICP was surveyed via intraventricular catheter and lumbar puncture and CSF samples were obtained simultaneously. NO was determined with Griess reagents. Results showed that NO peak content in the head injury group was significantly higher than that of the control group. During dynamic research, no peak content of mildly injured cases and severely injured ones appeared in different time windows respectively. The peak value of NO was distinctly higher in the severe group than in the mild group. NO peak value of the raised ICP group was remarkably higher than that of the normal ICP group. The peak value of NO was considerately higher in the poor outcome group than in the good outcome group. When the content of NO was over 6.5 mumol/L, the rate of poor outcome was increased. There existed a correlation between NO and GCS, ICP and GOS. It is concluded that the content of NO was increased in patients with acute head injury and the changes of NO had different time windows in severely injured patients and mildly injured ones. The more sever the injury, the higher the NO content; and the more serious the secondary brain injury and brain edema, the worse the outcomes. When NO is combined with GCS, GOS and ICP, it increases the accuracy of judgement to the degree of head injury and outcome.