niravoline and Brain-Edema

Niravoline is a selective agonist of kappa-opioid receptors having potent aquaretic activity which may peripherally be mediated in animals. This effect of niravoline is thought to be due to inhibition of arginine vasopressin secretion. Niravoline does not cause an overt excretion of electrolytes that is seen with conventional diuretics, and it is anticipated that niravoline may prove useful in the treatment of oedema. In this study, effect of niravoline on tumour-origin brain oedema was investigated in a brain tumour model created by implantation of C6 glioma cells into the brains of Wistar rats. Five weeks after the tumour cell implantation, niravoline was administered i.v. at 1 mg/kg a total of four times at one-hour intervals. In the control group (i.e., saline or vehicle-treated rats), this brain tumour model was found to result in a statistically significant increase in the water content in selected brain regions remote from the tumour. Administration of niravoline inhibited the increase in the water content in such selected brain regions. Niravoline might be useful on tumour-origin brain oedema clinically.

Topics: Animals; Arginine Vasopressin; Benzeneacetamides; Brain; Brain Edema; Brain Neoplasms; Female; Glioma; Injections, Intravenous; Neoplasm Transplantation; Pyrrolidines; Rats; Rats, Wistar; Tumor Cells, Cultured; Water-Electrolyte Balance

Niravoline is a selective kappa-opioid receptor agonist. Its effect on tumour-origin brain oedema was investigated in a brain tumour model created by implantation of C6 glioma cells into the brain of Wistar rats. Five weeks after the tumour cell implantation, niravoline was administered i.v. at 1 mg/kg, a total of four times at one-hour intervals. In the control group (i.e., saline or vehicle-treated rats), this brain tumour model was found to result in a statistically significant increase in the water content in selected brain regions except for the frontal region, the tumour-containing region and the region surrounding the tumour-containing region. Administration of niravoline inhibited the increase in the water content in the brain regions remote from the tumour.

Topics: Animals; Benzeneacetamides; Body Water; Brain; Brain Edema; Brain Neoplasms; Female; Glioma; Magnetic Resonance Imaging; Neoplasm Transplantation; Pyrrolidines; Rats; Rats, Wistar; Receptors, Opioid, kappa

The effect of niravoline (RU 51599), a kappa opioid receptor agonist with water diuretic properties, was assessed on the resorption of postischemic cerebral edema in the conscious mouse in comparison with U 50488, another kappa opioid receptor agonist, and mannitol. Ischemia was obtained by permanent occlusion of the right middle cerebral artery. Twenty-four hours after occlusion, at a time when brain water content is submaximal, blood samples were collected to measure serum osmolality, and brains were removed to measure the brain water content of two samples of frontoparietal cortical tissue corresponding to the core and the periphery of ischemia. When administered from 3 to 30 mg/kg as a single i.p. injection 20 h after occlusion, niravoline significantly reduced the brain cortical water increase by 27% up to 48% in the periphery of the ischemic tissue. At these same doses, it increased the serum osmolality to the same extent in ischemic as in nonischemic mice: 4 to 10 mOsm/kg. U 50488 generally showed a similar activity. In contrast, mannitol (1 or 2 g/kg i.p. 23 h after occlusion) increased serum osmolality but did not decrease brain water content. In conclusion, kappa opiate agonists could be an alternative to hyperosmotic agents in the treatment of cerebral edema of the focal ischemia type, the use of which is limited to the early phase of cerebral edema.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Arterial Occlusive Diseases; Benzeneacetamides; Brain Edema; Cerebral Arteries; Cerebrovascular Disorders; Male; Mannitol; Mice; Osmolar Concentration; Pyrrolidines; Receptors, Opioid, kappa

RU51599 is an arginine vasopressin (AVP) release inhibitor and a selective kappa opioid agonist which has a pure water diuresis effect without associated electrolyte excretion. The effect of RU51599 on brain oedema following transient forebrain ischaemia in rats was examined. Under microscopy, the visible vertebral arteries at the second vertebra could be easily electrocauterized and completely cut by microscissors to yield complete cessation of circulation of both vertebral arteries. Transient forebrain ischaemia was induced by this improved highly reproducible technique of four-vessel occlusion model. Forty-three male Wistar rats were separated into six groups; saline-treated (1 ml/kg) normal rats (n = 10), RU51599-treated (1 mg/kg) normal rats (n = 4), saline-treated (1 ml/kg) rats with complete occlusion of both vertebral arteries (n = 5), RU51599-treated (1 mg/kg) rats with complete occlusion of both vertebral arteries (n = 5), saline-treated (1 ml/kg) rats with both complete occlusion of both vertebral arteries and carotid occlusion bilaterally during 45 minutes followed by 60 minutes of reperfusion (n = 11), RU51599-treated (1 mg/kg) rats with both complete occlusion of both vertebral arteries and carotid occlusion bilaterally during 45 minutes followed by 60 minutes of reperfusion (n = 8). The brain water content was determined by the dry-wet weight method. Cerebral blood flow was monitored during ischaemia and reperfusion was performed by laser Doppler flowmetry to make sure to obtain reversible forebrain ischaemia. Effects of RU51599 on concentration of glutamate released from the hippocampal CA1 of rats subjected to 5 minutes four-vessel occlusion and 60 minutes of reperfusion were also investigated by the microdialysis method. This modified four-vessel occlusion method produced reversible forebrain ischaemia with a high level of success. Bilateral carotid occlusion followed by 60 minutes reperfusion caused a significant increase in brain water content (P < 0.01), which was significantly attenuated by RU51599 (P < 0.01). These findings indicate that the AVP-release inhibitor RU51599 reduced brain oedema following transient forebrain ischaemia in rats.

Topics: Animals; Arginine Vasopressin; Benzeneacetamides; Brain Chemistry; Brain Edema; Brain Ischemia; Cerebral Cortex; Diuretics; Male; Microdialysis; Prosencephalon; Pyrrolidines; Rats; Rats, Wistar; 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