spd-502 and Disease-Models--Animal

Topics: Acetamides; Animals; Anticonvulsants; Carbamates; Disease Models, Animal; Fructose; Humans; Lacosamide; Pyrroles; Pyrrolidinones; Rats; Receptors, AMPA; Status Epilepticus; Tetrahydroisoquinolines; Topiramate; Treatment Outcome

The current first line treatment of status epilepticus (SE) is based on the use of compounds that enhance GABAergic transmission or block sodium channels. These treatments discontinue SE in only two-thirds of patients, and therefore new therapeutic approaches are needed. We investigated whether a novel water-soluble AMPA antagonist, NS1209, discontinues SE in adult rats. SE was induced by electrical stimulation of the amygdala or subcutaneous administration of kainic acid. Animals were monitored continuously with video-electroencephalography during SE and drug treatment. We found that NS1209 could be safely administered to rats undergoing electrically induced SE at doses up to 50mg/kg followed by intravenous infusion of 5mg/kg for up to 24h. NS1209 administered as a bolus dose of 10-50mg/kg (i.p. or i.v.) followed by infusion of 4 or 5mg/kg h (i.v.) for 2-24h effectively discontinued electrically induced SE in all animals within 30-60 min, and there was no recurrence of SE after a 24-h infusion. Kainate-induced SE was similarly blocked by 10 or 30 mg/kg NS1209 (i.v.). To compare the efficacy and neuroprotective effects of NS1209 with those of diazepam (DZP), one group of rats received DZP (20mg/kg, i.p. and another dose of 10 mg/kg 6h later). By using the administration protocols described, the anticonvulsant effect of NS1209 was faster and more complete than that of DZP. NS1209 treatment (20 mg/kg bolus followed by 5mg/kg h infusion for 24 h) was neuroprotective against SE-induced hippocampal neurodegeneration, but to a lesser extent than DZP. These findings suggest that AMPA receptor blockade by NS1209 provides a novel and mechanistically complimentary addition to the armamentarium of drugs used to treat SE in humans.

Topics: Amygdala; Animals; Anticonvulsants; Diazepam; Disease Models, Animal; Dose-Response Relationship, Drug; Electric Stimulation; Electroencephalography; Hippocampus; Kainic Acid; Male; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Status Epilepticus; Tetrahydroisoquinolines; Video Recording

The effects of systemic administration of the novel AMPA/GluR5 selective receptor antagonist NS1209 in animal models of experimental pain have been tested and compared with the AMPA receptor antagonist NBQX and the opiate morphine. In the mouse hot plate test, NS1209 (3-30 mg/kg, s.c. and i.p.) and morphine (3-30 mg/kg, s.c.) significantly increased the nociceptive response latency, whereas NBQX (3-30 mg/kg, i.p.) was ineffective. In the rat formalin test, a model of persistent pain, NS1209 (3 and 6 mg/kg, i.p.) and morphine (0.5 and 3 mg/kg, s.c.) produced dose-dependent reductions in second phase nociceptive behaviours, although NBQX (10 and 20 mg/kg, i.p.) was without effect. In the chronic constriction injury model of neuropathic pain, NS1209 (3 and 6 mg/kg, i.p.), NBQX (10 and 20 mg/kg, i.p.) and morphine (3 and 6 mg/kg, s.c.) all reduced mechanical allodynia and hyperalgesia responses to von Frey hair and pin prick stimulation of the injured hindpaw. NS1209 and morphine also reduced cold hypersensitivity in response to ethyl chloride stimulation of the injured hindpaw. At the doses associated with anti-nociceptive actions, no effects on motor performance as determined by the rotarod test were observed for any of the drugs tested. Thus, systemic administration of NS1209 at non-ataxic doses has marked analgesic actions comparable to those of morphine in a range of animal models of experimental pain.

Topics: Animals; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Routes; Excitatory Amino Acid Antagonists; Male; Morphine; Narcotics; Pain; Pain Measurement; Pain Threshold; Peripheral Nervous System Diseases; Pyrroles; Quinoxalines; Rats; Rats, Sprague-Dawley; Reaction Time; Receptors, Kainic Acid; Tetrahydroisoquinolines; Time Factors

Protection of both grey and white matter is important for improvement in stroke outcome. In the present study the ability of a competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist to protect axons, oligodendrocytes, and neuronal perikarya, was examined in a rodent model of transient focal cerebral ischemia. SPD 502 (8-methyl-5-(4-( -dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-o(4-hydroxybutyricacid-2-yl)oxime) was administered as an intravenous bolus (16 mg/kg) 15 minutes before transient (3-hour) middle cerebral artery (MCA) occlusion, followed by an intravenous infusion (16 mg kg(-1) hr(-1)) of the drug for 4 hours. Twenty-one hours after ischemia, axonal damage was reduced by 45% (P = 0.006) in the SPD 502-treated group compared with the vehicle. The anatomic extent of ischemically damaged oligodendrocytes, determined by Tau1 immunoreactivity, was reduced in the cerebral cortex by 53% (P = 0.024) in SPD 502-treated rats compared with vehicle-treated rats, but there was minimal effect in the subcortex. The volume of neuronal perikaryal damage after MCA occlusion was significantly reduced by SPD 502 in the cerebral cortex (by 68%; P = 0.005), but there was minimal change in the subcortex with drug treatment. The AMPA receptor antagonist significantly reduced the anatomic extent of lipid peroxidation (assessed as the volume of 4-hydroxynonenol immunoreactivity), and this may have contributed to its ability to protect multiple cell types in ischemia. The data demonstrate that AMPA blockade protects both grey and white matter from damage induced by transient focal ischemia.

Topics: Aldehydes; Animals; Brain Ischemia; Carotid Artery, External; Carotid Artery, Internal; Disease Models, Animal; Functional Laterality; Growth Inhibitors; Humans; Isoquinolines; Male; Oligodendroglia; Periaqueductal Gray; Pyrroles; Rats; Rats, Sprague-Dawley; Receptors, AMPA; Tetrahydroisoquinolines