oxadiazoles and Brain-Edema

Fingolimod, a sphingosine-1-phosphate receptor (S1PR) agonist, is clinically available to treat multiple sclerosis and is showing promise in treating stroke. We investigated if fingolimod provides long-term protection from experimental neonatal germinal matrix hemorrhage (GMH), aiming to support a potential mechanism of acute fingolimod-induced protection. GMH was induced in P7 rats by infusion of collagenase (0.3 U) into the right ganglionic eminence. Animals killed at 4 weeks post-GMH received low- or high-dose fingolimod (0.25 or 1.0 mg/kg) or vehicle, and underwent neurocognitive testing before histopathological evaluation. Subsequently, a cohort of animals killed at 72 h post-GMH received 1.0 mg/kg fingolimod; the specific S1PR1 agonist, SEW2871; or fingolimod co-administered with the S1PR1/3/4 inhibitor, VPC23019, or the Rac1 inhibitor, EHT1864. All drugs were injected intraperitoneally 1, 24, and 48 h post-surgery. At 72 h post-GMH, brain water content, extravasated Evans blue dye, and hemoglobin were measured as well as the expression levels of phospho-Akt, Akt, GTP-Rac1, Total-Rac1, ZO1, occludin, and claudin-3 determined. Fingolimod significantly improved long-term neurocognitive performance and ameliorated brain tissue loss. At 72 h post-GMH, fingolimod reduced brain water content and Evans blue dye extravasation as well as reversed GMH-induced loss of tight junctional proteins. S1PR1 agonism showed similar protection, whereas S1PR or Rac1 inhibition abolished the protective effect of fingolimod. Fingolimod treatment improved functional and morphological outcomes after GMH, in part, by tempering acute post-hemorrhagic blood-brain barrier disruption via the activation of the S1PR1/Akt/Rac1 pathway.

Topics: Animals; Body Water; Brain; Brain Chemistry; Brain Edema; Cognition; Female; Fingolimod Hydrochloride; Intracranial Hemorrhages; Leukocyte Count; Male; Neuroprotective Agents; Oxadiazoles; Phosphoserine; Pregnancy; Pyrones; Quinolines; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Thiophenes; Tight Junction Proteins

In the present study, we have investigated the effects of glycogen synthase kinase-3 (GSK-3) inhibition on infarct volume and neurobehavioral functions in a focal cerebral ischemia model. To achieve our goals, GSK-3 inhibitor II or VIII was injected at several time points and in varing dosages. GSK-3 inhibitor VIII was more effective than inhibitor II, and infarct volume and water content in the VIII group were significantly decreased 24h after the onset of ischemic stroke, as compared with the control group. These protective effects were associated with reductions of TUNEL-positive cells, neutrophil infiltration, glucose levels after ischemia, and GSK-3 enzyme activity. In addition, expressions of death and inflammation-related signals decreased and those of survival-related signals increased. Lastly, neurobehavioral functions were restored to a greater extent in the VIII group than in the control group. Together, these results suggest that GSK-3 inhibition reduces infarct volume and restores neurobehavioral functions.

Topics: Animals; Behavior, Animal; Blood Glucose; Brain Edema; Calcium-Binding Proteins; Caspase 3; Cerebral Infarction; Cyclooxygenase 2; Disease Models, Animal; Glial Fibrillary Acidic Protein; Glycogen Synthase Kinase 3; Microfilament Proteins; Oxadiazoles; Poly(ADP-ribose) Polymerases; Protein Kinase Inhibitors; Pyridines; Rats; Rats, Sprague-Dawley; Thiazoles; Urea

The non-indole 5-HT receptor agonist, alniditan (R 91274), was tested and compared to sumatriptan in an in vivo model of neurogenic inflammation within the meninges of rats and in rat basilar artery in a Mulvany-Halpern chamber in vitro. Alniditan dose dependently attenuated the neurogenic inflammation and was more potent than sumatriptan. The alniditan response was blocked by the 5-HT(1B/D) receptor antagonist, GR 127935 (2'-methyl-4'-(5-methyl-[1,2, 4]oxadiazol-3-yl)-biphenyl-4-carboxylic acid [4-methoxy-3-(4-methyl-piperazin-1-yl)-phenyl]-amide), but not by ketanserin, indicating that the effect is mediated through 5-HT(1B/D) receptors. Alniditan did not attenuate substance P-induced inflammation, suggesting that the mediating receptors are located prejunctionally. In vitro alniditan exhibited less vasoconstrictive effects on the rat basilar artery than did sumatriptan, although at a very high concentration (1 mM), alniditan caused intensive constriction, most likely through a mechanism independent from 5-HT receptor activation.

Topics: Animals; Basilar Artery; Benzopyrans; Brain Edema; Capillary Permeability; Dose-Response Relationship, Drug; Dura Mater; Extravasation of Diagnostic and Therapeutic Materials; In Vitro Techniques; Ketanserin; Male; Oxadiazoles; Piperazines; Propylamines; Pyrimidines; Rats; Rats, Sprague-Dawley; Serotonin; Serotonin Agents; Serotonin Antagonists; Substance P; Sumatriptan; Vasoconstriction; Vasoconstrictor Agents

SM-6586 (SM) is a new derivative of dihydropyridine with potent calcium blocking activity and inhibitory activity of the Na+/H+ and Na+/Ca++ exchange transport. The effect of SM on survival rate, brain edema and metabolites was evaluated using two different models in spontaneously hypertensive rat (SHR). Global ischemia was induced by bilateral common carotid artery ligation (BLCL) and focal ischemia was induced by middle cerebral artery occlusion. The survival rate after BLCL was higher in the SM-treated group. The brain water content was lower, the ATP level was higher and lactate level was lower in the SM-treated group compared to the control group. In focal ischemia models, the SM-treated group showed a reduction of T1 relaxation time. The brain water content was significantly decreased in the SM-treated group. These results indicate that SM was effective in ameliorating the ischemic insult in global and focal cerebral ischemia models.

Topics: Animals; Blood-Brain Barrier; Brain Damage, Chronic; Brain Edema; Brain Ischemia; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Energy Metabolism; Male; Oxadiazoles; Rats; Rats, Inbred SHR; Water-Electrolyte Balance

Glutamate (2.5 mg) was administered after the blood-brain barrier had been opened by a unilateral intracarotid infusion of 5 mg protamine sulfate in rats. Whereas the brain specific gravity, measured 24 h later, did not differ between the injected and non-injected side after protamine alone, glutamate significantly reduced the specific gravity in the right hemisphere indicating brain edema (P less than 0.01). NBQX, a potent AMPA receptor antagonist, significantly reduced the edema (P less than 0.01) and completely inhibited the glutamate mediated increase in albumin content in cerebrospinal fluid (P less than 0.01).

Topics: Animals; Blood Pressure; Blood-Brain Barrier; Brain; Brain Edema; Glutamates; Glutamic Acid; Hematocrit; Male; Oxadiazoles; Protamines; Quinoxalines; Rats; Rats, Inbred Strains; Receptors, AMPA; Receptors, Neurotransmitter; Serum Albumin

The effect of PN200-110, a novel calcium antagonist, on the formation of brain edema was examined with rats using a middle cerebral artery (MCA) occlusion model. PN200-110 was effective in preventing the formation of brain edema in 6-h ischemia and in 3-h reperfusion following 3-h ischemia, which were cases in which great accumulations of calcium were autoradiographically observed. Furthermore, PN200-110 diminished the excessive accumulation of calcium in the MCA area involved. These results indicate that an inhibition of the massive influx of calcium into brain cells by PN200-110 may partially ameliorate cell damage, resulting in prevention of brain edema.

Topics: Animals; Autoradiography; Brain Edema; Brain Ischemia; Calcium; Calcium Channel Blockers; Isradipine; Oxadiazoles