u-50488 and Brain-Edema

To meet the challenge of identification of new treatments for stroke, this study was designed to evaluate a potent, nonselective opioid receptor (OR) agonist, biphalin, in comparison to subtype selective OR agonists, as a potential neuroprotective drug candidate using in vitro and in vivo models of ischemic stroke. Our in vitro approach included mouse primary neuronal cells that were challenged with glutamate and hypoxic/aglycemic (H/A) conditions. We observed that 10nM biphalin, exerted a statistically significant neuroprotective effect after glutamate challenge, compared to all selective opioid agonists, according to lactate dehydrogenase (LDH) and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays. Moreover, 10nM biphalin provided superior neuroprotection after H/A-reoxygenation compared to selective opioid agonists in all cases. Our in vitro investigations were supported by in vivo studies which indicate that the nonselective opioid agonist, biphalin, achieves enhanced neuroprotective potency compared to any of the selective opioid agonists, evidenced by reduced edema and infarct ratios. Reduction of edema and infarction was accompanied by neurological improvement of the animals in two independent behavioral tests. Collectively these data strongly suggest that concurrent agonist stimulation of mu, kappa and delta ORs with biphalin is neuroprotective and superior to neuroprotection by activation of any single OR subtype.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Brain Edema; Brain Infarction; Brain Ischemia; Cells, Cultured; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Enkephalins; Glutamic Acid; Ischemia; Motor Activity; Neurons; Neuroprotective Agents; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Reperfusion Injury; Severity of Illness Index; Stroke

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

U-50488 is a specific kappa opioid agonist which produces in rats water diuresis resulting in an elevation of plasma osmolarity. Pretreatment with U-50488H (the methanesulfonate salt) in Fisher rats prior to 4 h of bilateral carotid occlusion prevented the development of edema in the forebrain, and the effect was greater than that from pentobarbital anesthesia. An additional injection of an antidiuretic hormone which prevented the plasma hyperosmolarity also significantly reduced the anticerebral edemic effects of U-50488H. The plasma osmotic effect, however, may not completely account for the ischemic protection produced by U-50488H.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Animals; Body Water; Brain Chemistry; Brain Edema; Brain Ischemia; Diuresis; Male; Osmolar Concentration; Potassium; Pyrrolidines; Rats; Rats, Inbred F344; Receptors, Opioid; Sodium; Vasopressins