Hydroxylamine attenuates the effects of simulated subarachnoid hemorrhage in the rat brain and improves neurological outcome.

Some of the neurological deficits that emerge after aneurysmal subarachnoid hemorrhage (SAH) in humans are presumably caused by ischemic brain damage consequential to SAH-induced delayed cerebral vasospasm. This vasospasm probably results from an imbalance among vasoactive factors released from both the clot formed by extravasated blood and adjacent tissues, and in particular from a decrease in the endothelium-derived relaxing factor nitric oxide (NO). Brain ischemia is also known to elevate brain production and deposition of beta-amyloid, and to induce a delayed increase in total NO synthase (NOS) activity due to induction of expression of so-called induced NOS isoform, phenomena that may secondarily contribute to SAH-related brain damage. The aim of this study was to investigate the effects of treatment with the intracellular NO donor hydroxylamine on: (i) basilar arterial wall that remained in a direct contact with the clot, (ii) formation of the beta-amyloid precursor protein (beta-APP), (iii) total brain NOS activity, and (iv) neurological outcome in a 'two-hemorrhage' rat SAH model. Intraperitoneal (i.p.) administration of 0.18 mmol/kg hydroxylamine hydrochloride (12.5 mg/kg) twice daily for 7 days beginning immediately after the first 'hemorrhage' (intracisternal blood injection) reduced basilar arterial wall damage and attenuated post-SAH neurological deficit. It also reduced the SAH-related increases in hippocampal and cortical beta-APP immunoreactivities and hippocampal NOS activity measured 24 h after commencement of the treatment. These results indicate that intracellular NO donors that yield NO through the action of widely distributed enzymes in brain cells (cytochromes, catalase) can attenuate detrimental effects of SAH.

Changes in oxidative stress in the rat brain during post-cardiac arrest reperfusion, and the effect of treatment with the free radical scavenger idebenone.

The study was designed to determine the effect of idebenone, an electron-trapping agent and free radical scavenger capable of crossing the blood-brain barrier, on cardiac arrest-induced oxidative brain stress. Stress indices used were the brain contents of thiobarbituric acid-reactive material (TBAR), conjugated dienes and protein and non-protein thiols. Twenty-four hours after receiving one oral dose of placebo or 100 mg kg(-1) idebenone, the rats were anaesthetized with diethyl ether and either decapitated immediately, or subjected to 7.5 min cardiac arrest induced by compression of the heart vessel bundle. The next groups of rats were sacrificed at the end of the cardiac arrest session, or resuscitated by external chest compression and artificial ventilation with air and sacrificed 15 min, 60 min, 24 h, and 72 h later while re-anesthetized with diethyl ether. Subsequent placebo or idebenone (100 mg kg(-1)) doses were given to the appropriate surviving rats once daily, beginning 8-10 min after the end of cardiac arrest session. Compared to pre-arrest values, TBAR and conjugated dienes' contents increased, respectively, by 339 and 286%, and protein and non-protein thiol contents decreased, respectively, by 69 and 85% within 60 min after the resuscitation in placebo-treated rats. Normalization of all oxidative stress indices in these rats was slow and incomplete even at 72 h. Idebenone treated rats showed no increase in TBAR contents, and a marked attenuation of changes in the other indices. These results show that oral idebenone greatly reduces oxidative brain stress following transient circulatory arrest in the rat. This effect could not be explained by simple stoichiometric scavenging of free radicals. Possible mechanisms of idebenone action are discussed.

Oral coenzyme Q10 administration prevents the development of ischemic brain lesions in a rabbit model of symptomatic vasospasm.

Treatment with oral coenzyme Q10 (CoQ10, 10 mg/kg per day for 6 days) was compared with no treatment in a previously described rabbit model of symptomatic cerebral vasospasm [Endo et al. (1988) Stroke 19: 1420-1425]. The treatment was initiated within 1-2 h after injection of autologous blood into the subarachnoid space. In CoQ10-untreated rabbits, moderate to severe neurological deficits developed, and multiple focal ischemic lesions were found in the brain regions with compromised blood supply, i.e., in the regions normally supplied by common carotid arteries which are subject to ligation in this model. CoQ10 treatment prevented the development of both the neurological deficits and histologically detectable brain tissue damage. In both CoQ10-treated and -untreated rabbits, infiltration of mononuclear cells was evident in the brain stem, although this region did not show signs of ischemic damage. The findings indicate that the histological and neurological correlates of brain tissue damage in this rabbit model of symptomatic cerebral vasospasm develop via mechanism(s) involving free radical-mediated oxidation of plasma lipoproteins. Similar mechanisms may play a role in the development of brain damage attributed to cerebral atherosclerosis.

Immune abnormalities in aneurysmal subarachnoid haemorrhage patients: relation to delayed cerebral vasospasm.

Peripheral blood CD3+, CD19+, CD4+, CD8+ and CD45RO+ mononuclear cell subsets, T-cell proliferative responses to combinations of coimmobilized OKT3 antibody and an ECM protein (collagen I, collagen IV, fibronectin or elastin), and T-cell adhesion to collagen IV, fibronectin and elastin were studied in patients with aneurysmal subarachnoid haemorrhage. No significant difference was found in the major lymphocyte subsets between subarachnoid haemorrhage patients receiving no dexamethasone for brain oedema treatment and healthy blood donors. Compared with the latter, both the dexamethasone-untreated and -treated subarachnoid haemorrhage patients showed decreased relative proliferative responses of circulating T cells to OKT3 combinations with collagen IV and fibronectin, and an increased PHA-activated T-cell adhesion to elastin. CD45RO+, CD4+ and CD19+ peripheral blood cell subsets, CD4+/CD8+ cell ratio, PHA-activated T-cell adhesion to fibronectin and collagen IV, and OKT3-triggered T-cell costimulatory responses to elastin, collagen IV and fibronectin were significantly higher in subarachnoid haemorrhage patients presenting with delayed cerebral vasospasm (DCV) than in their DCV-free counterparts. The DCV-related differences in circulating lymphocyte subsets showed no apparent relationship to the glucocorticoid treatment, whereas the differences in the other indices were confined to the dexamethasone-untreated subarachnoid haemorrhage patients. The above results suggest that the CD4+/CD8+ ratio and T cell-ECM interactions play a role in the emergence of subarachnoid haemorrhage/DCV and may represent potential targets for subarachnoid haemorrhage therapy.

Serum cholesterol in cerebral malignancies.

Reduced blood cholesterol levels were reported in patients with a variety of malignant peripheral tumors. This fact is likely related to increased cholesterol demand by proliferating tumor cells. The question arises whether this 'tumor-associated hypocholesterolemia' occurs also in patients with brain tumors, and--if it does not--whether its absence can be related to the location of the tumors. We have compared fasting serum total cholesterol levels among three groups of patients: 52 patients with gliomas, 56 patients with symptomatic metastatic brain tumors, and 50 patients harboring malignant tumors of peripheral location but showing no clinical signs of brain metastases. Patients in the last group, despite being--on an average--more age-advanced, had lower total serum cholesterol levels than either the patients with gliomas, or the patients with brain metastases. No difference in the cholesterol levels was found between the two latter groups, and a majority of these patients had borderline or elevated cholesterol levels. This apparent absence of 'tumor-associated hypocholesterolemia' in brain tumor patients may be related to either brain tumors' ability to synthesize cholesterol de novo and their reduced dependence on peripheral cholesterol supply, the existence of brain tumor-blood barrier, effect of medications used to counteract brain edema and seizures, or a combination of these factors.