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 SAM-induced delayed cerebral vasospasm. This vasospasm pro bably results from an imbalance among vasoactive factors released from both the clot formed by extravasated blood and adjacent tissues, and in particu lar from a decrease in the endothelium-derived relaxing factor nitric oxide (NO). Brain ischemia is also known to elevate brain production and deposit ion 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 isof orm, phenomena that may secondarily contribute to SAM-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 re mained in a direct contact with the clot, (ii) formation of the beta-amyloi d precursor protein (beta-APP), (iii) total brain NOS activity, and (iv) ne urological 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 a ttenuated post-SAM neurological deficit. It also reduced the SAM-related in creases in hippocampal and cortical beta-APP immunoreactivities and hippoca mpal NOS activity measured 24 h after commencement of the treatment. These results indicate that intracellular NO donors that yield NO through the act ion of widely distributed enzymes in brain cells (cytochromes, catalase) ca n attenuate detrimental effects of SAH. (C) 1999 Elsevier Science B.V. All rights reserved.