niravoline and Brain-Injuries

It has recently been reported that kappa-opioid receptor agonists inhibit antidiuretic hormone secretion and promote water excretion in humans and animals. We investigated the effect of niravoline (RU 51599), a selective kappa-opioid receptor agonist in the treatment of intracranial hypertension. Acute intracranial hypertension was induced in cats by continuous inflation of an extradural balloon with physiological saline at the constant rate of 0.5 ml/h for 3 h. At this point, inflation was discontinued and the balloon remained expanded for an additional hour after which it was deflated. In the post-deflation period, monitoring continued for 1 h. The control group (n = 8) received ringer's lactate solution only, while the treatment group (n = 8) received an intravenous (IV) injection of 1.0 mg/kg of niravoline, every hour at the beginning of balloon inflation, during balloon inflation, in post-inflation, and at deflation time (5 doses). Changes in intracranial pressure (ICP), mean arterial blood pressure (MAP), cerebral perfusion pressure (CPP), electroencephalogram (EEG), blood gases, pupil size, serum electrolytes, and osmolality were measured in both groups. Brain water content was determined in a separate group of cats at the end of a 3-h extradural brain compression. Compared to the untreated group, the niravoline-treated group had a significantly lower ICP and higher CPP at the 2 and 3 h during balloon inflation, in post-inflation, and in post-deflation periods. Brain water content was significantly reduced in niravoline-treated animals. No significant change was observed in serum osmolality throughout the experiment. Our results indicate that the mechanism by which niravoline reduces ICP is partly via a reduction in brain water content. Also, the current findings suggest that in clinical situations in which ICP is elevated due to the pressure of an extradural mass, niravoline may effectively reduce ICP while maintaining adequate CPP until the mass is removed.

Topics: Animals; Benzeneacetamides; Blood Pressure; Brain Injuries; Cats; Cerebrovascular Circulation; Electroencephalography; Female; Intracranial Pressure; Male; Pyrrolidines; Receptors, Opioid, kappa

Centrally released arginine vasopressin (AVP) has been implicated in the regulation of the brain water content and is elevated in the cerebrospinal fluid of patients with ischaemic and traumatic brain injuries. The protective effect of RU51599, which is a selective kappa opioid agonist as an AVP release inhibitor, on brain oedema was examined. Male Wistar rats, weighing 300 to 400 g each, were used. The cortical cryogenic injury was produced by application of a previously prepared metal probe cooled with dry ice to the dura of the right patietal region. Animals were separated into three groups. Group 1: sham operated rats without lesion production. Group 2: saline-treated rats with lesion production. Group 3: RU51599-treated rats with lesion production. In Group 3, rats were treated with RU51599 (0.1-3 mg/kg) at 30 minutes before lesion production, 1 hour, 2 hours, and 4 hours after lesion production. After 6 hours, animals were decapitated and brain water contents were measured using the dry-wet weight method. The extent of blood brain barrier (BBB) disruption was determined by assessment of Evans blue uptake based on extraction from tissue using dimethylformamide. The primary injured infarcted area was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining. Sodium and potassium contents in serum and brain tissue were measured using atomic absorption spectrophotometry. The antagonism of naloxone against protective effects of RU51599 on cryogenic induced brain oedema and on antinociceptive effects in acetic-acid treated animals was examined. Statistical analysis was performed using Dunnett-test and U-test following Kruskal-Wallis test. RU51599 significantly reduced the brain water contents on the injured side and the contralateral non-injured side (p < 0.01) after 4 administration of 1 and 3 mg/kg. RU51599 neither significantly inhibited BBB disruption nor reduced the primary injured infarcted area. RU51559 significantly increased brain sodium and potassium contents in the injured brain and also increased serum sodium levels (p < 0.01). Naloxone antagonized the anti-oedema effects and anti-nociceptive effects of RU51599. These findings indicate that the AVP release inhibitor, RU51599 possibly mediated by opioid receptors, has a potential protective effect on cryogenic-induced brain oedema and that centrally released AVP plays an important role in the progression of vasogenic brain oedema.

Topics: Animals; Arginine Vasopressin; Benzeneacetamides; Blood-Brain Barrier; Brain Chemistry; Brain Edema; Brain Injuries; Cold Temperature; Diuretics; Evans Blue; Male; Naloxone; Potassium; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa; Sodium; Spectrophotometry, Atomic