Ž . Brain Research 850 1999 225–233 www.elsevier.comrlocaterbres Research report Hydroxylamine attenuates the effects of simulated subarachnoid hemorrhage in the rat brain and improves neurological outcome Miroslaw S. Ryba a , Wanda Gordon-Krajcer b , Michal Walski c , Malgorzata Chalimoniuk d , Stanislaw J. Chrapusta a, ) a Laboratory of Experimental Pharmacology, Polish Academy of Sciences Medical Research Centre, 5 Pawinskiego St., 02-106 Warsaw, Poland ´ b Department of Neurochemistry, Polish Academy of Sciences Medical Research Centre, 5 Pawinskiego St., 02-106 Warsaw, Poland ´ c Laboratory of Ultrastructure of the NerÕous System, Polish Academy of Sciences Medical Research Centre, 5 Pawinskiego St., 02-106 Warsaw, Poland ´ d Department of Cellular Signalling, Polish Academy of Sciences Medical Research Centre, 5 Pawinskiego St., 02-106 Warsaw, Poland ´ Accepted 21 September 1999 Abstract Ž . 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 Ž . in the endothelium-derived relaxing factor nitric oxide NO . Brain ischemia is also known to elevate brain production and deposition of Ž . b-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 Ž. Ž. treatment with the intracellular NO donor hydroxylamine on: i basilar arterial wall that remained in a direct contact with the clot, ii Ž . Ž . Ž . formation of the b-amyloid precursor protein b-APP , iii total brain NOS activity, and iv neurological outcome in a ‘two-hemor- Ž . Ž . rhage’ rat SAH model. Intraperitoneal i.p. administration of 0.18 mmolrkg hydroxylamine hydrochloride 12.5 mgrkg twice daily for Ž . 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 b-APP immunoreactivi- ties and hippocampal NOS activity measured 24 h after commencement of the treatment. These results indicate that intracellular NO Ž . donors that yield NO through the action of widely distributed enzymes in brain cells cytochromes, catalase can attenuate detrimental effects of SAH. q 1999 Elsevier Science B.V. All rights reserved. Keywords: Subarachnoid hemorrhage; Cerebral vasospasm; Amyloid precursor protein; Nitric oxide; Neurological deficit; Animal model 1. Introduction Ž . Aneurysmal subarachnoid hemorrhage SAH is a rela- tively frequent cause of death or sustained neurological deficits in human clinical setting. Development of these deficits involves a loss in the endothelium-derived relaxing Ž . w x factor nitric oxide NO 38 due to both NO scavenging Ž w x. by hemoglobin catabolites for references, see Ref. 42 Ž . w x and declines in certain NO synthase NOS isoforms 41 . On the other hand, SAH is known to cause the release of Ž many proinflammatory and vasoconstricting factors e.g., ) Corresponding author. Fax: q48-22-60-86-527; e-mail: chrapuss@ibb.waw.pl w x. endothelin, see Ref. 70 from the perivascular clot, adja- cent tissues, and infiltrating leukocytes. The resulting im- balance between various vasoactive agents probably plays a key role in the emergence of delayed chronic vasospasm Ž of large cerebral arteries delayed cerebral vasospasm, . DCV that is the main cause of post-SAH ischemic brain w x damage and poor outcome 12,48 . There is also evidence for DCV spreading into small vessels in brain regions w x remote from the site of bleeding 45 , and for a diffuse microangiopathy developing in patients with aneurysmal w x SAH 32 . An important factor in the development of SAH-in- duced delayed ischemic neurological deficits likely is an w x increased formation of free radicals 48 . A major source of these radicals may be NOS, which show complex 0006-8993r99r$ - see front matter q 1999 Elsevier Science B.V. All rights reserved. Ž . PII: S0006-8993 99 02161-7