perampanel and 2-3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline

An itch is defined as an unpleasant sensation that evokes a desire to scratch. Glutamate is a major excitatory neurotransmitter in the mammalian central nervous system and has a crucial role in pruriceptive processing in the spinal dorsal horn. It is well known that glutamate exerts its effects by binding to various glutamate receptors including α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and that AMPA/kainate receptors play a crucial role in pruriceptive processing; however, the precise role of AMPA receptors remains uncertain. Perampanel, an antiepileptic drug, is an antagonist of AMPA receptors. Pretreatment with perampanel dose-dependently attenuated the induction of scratching, a behavior typically associated with pruritus, by intradermal administration of the pruritogen chloroquine. In addition, the induction of scratching in mice painted with diphenylcyclopropenone and NC/Nga mice treated with Biostir AD, animal models of contact dermatitis and atopic dermatitis, respectively, was dose-dependently alleviated by administration of perampanel. These findings indicate that AMPA receptors play a crucial role in pruriceptive processing in mice with acute or chronic pruritus.

Topics: Animals; Behavior, Animal; Chloroquine; Cyclopropanes; Disease Models, Animal; Histamine; Hypodermoclysis; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Nitriles; Pruritus; Pyridones; Quinoxalines; Receptors, AMPA

Intraventricular hemorrhage (IVH) in preterm infants leads to cerebral inflammation, reduced myelination of the white matter, and neurological deficits. No therapeutic strategy exists against the IVH-induced white matter injury. AMPA-kainate receptor induced excitotoxicity contributes to oligodendrocyte precursor cell (OPC) damage and hypomyelination in both neonatal and adult models of brain injury. Here, we hypothesized that IVH damages white matter via AMPA receptor activation, and that AMPA-kainate receptor inhibition suppresses inflammation and restores OPC maturation, myelination, and neurologic recovery in preterm newborns with IVH. We tested these hypotheses in a rabbit model of glycerol-induced IVH and evaluated the expression of AMPA receptors in autopsy samples from human preterm infants. GluR1-GluR4 expressions were comparable between preterm humans and rabbits with and without IVH. However, GluR1 and GluR2 levels were significantly lower in the embryonic white matter and germinal matrix relative to the neocortex in both infants with and without IVH. Pharmacological blockade of AMPA-kainate receptors with systemic NBQX, or selective AMPA receptor inhibition by intramuscular perampanel restored myelination and neurologic recovery in rabbits with IVH. NBQX administration also reduced the population of apoptotic OPCs, levels of several cytokines (TNFα, IL-β, IL-6, LIF), and the density of Iba1(+) microglia in pups with IVH. Additionally, NBQX treatment inhibited STAT-3 phosphorylation, but not astrogliosis or transcription factors regulating gliosis. Our data suggest that AMPA-kainate receptor inhibition alleviates OPC loss and IVH-induced inflammation and restores myelination and neurologic recovery in preterm rabbits with IVH. Therapeutic use of FDA-approved perampanel treatment might enhance neurologic outcome in premature infants with IVH.. Intraventricular hemorrhage (IVH) is a major complication of prematurity and a large number of survivors with IVH develop cerebral palsy and cognitive deficits. The development of IVH leads to inflammation of the periventricular white matter, apoptosis and arrested maturation of oligodendrocyte precursor cells, and hypomyelination. Here, we show that AMPA-kainate receptor inhibition by NBQX suppresses inflammation, attenuates apoptosis of oligodendrocyte precursor cells, and promotes myelination as well as clinical recovery in preterm rabbits with IVH. Importantly, AMPA-specific inhibition by the FDA-approved perampanel, which unlike NBQX has a low side-effect profile, also enhances myelination and neurological recovery in rabbits with IVH. Hence, the present study highlights the role of AMPA-kainate receptor in IVH-induced white matter injury and identifies a novel strategy of neuroprotection, which might improve the neurological outcome for premature infants with IVH.

Topics: Animals; Animals, Newborn; Apoptosis; Brain; Calcium Signaling; Cerebral Ventricles; Cytokines; Disease Models, Animal; Excitatory Amino Acid Antagonists; Female; Glycerol; Hemorrhage; Humans; Leukoencephalopathies; Male; Nervous System Diseases; Nitriles; Pregnancy; Pyridones; Quinoxalines; Rabbits; Receptors, AMPA; Recovery of Function

The AMPA receptor subtype of glutamate receptors, which mediates fast synaptic excitation, is of primary importance in initiating epileptiform discharges, so that AMPA receptor antagonists exert anti-seizure activity in diverse animal models of partial and generalized seizures. Recently, the first AMPA receptor antagonist, perampanel, was approved for use as adjunctive therapy for the treatment of resistant partial seizures in patients. Interestingly, the competitive AMPA receptor antagonist NBQX has recently been reported to prevent development of spontaneous recurrent seizures (SRS) in a neonatal seizure model in rats, indicating the AMPA antagonists may exert also antiepileptogenic effects. This prompted us to evaluate competitive (NBQX) and noncompetitive (perampanel) AMPA receptor antagonists in an adult mouse model of mesial temporal lobe epilepsy. In this model, SRS develop after status epilepticus (SE) induced by intrahippocampal injection of kainate. Focal electrographic seizures in this model are resistant to several major antiepileptic drugs. In line with previous studies, phenytoin was not capable of blocking such seizures in the present experiments, while they were markedly suppressed by NBQX and perampanel. However, perampanel was less tolerable than NBQX in epileptic mice, so that only NBQX was subsequently tested for antiepileptogenic potential. When mice were treated over three days after kainate-induced SE with NBQX (20 mg/kg t.i.d.), no effect on development or frequency of seizures was found in comparison to vehicle controls. These results suggest that AMPA receptor antagonists, while being effective in suppressing resistant focal seizures, are not exerting antiepileptogenic effects in an adult mouse model of partial epilepsy.

Topics: Animals; Anticonvulsants; Chronic Disease; Disease Models, Animal; Electroencephalography; Epilepsy, Temporal Lobe; Female; Hippocampus; Kainic Acid; Mice; Nitriles; Phenytoin; Pyridones; Quinoxalines; Receptors, AMPA; Seizures; Status Epilepticus