topiramate and Hypoxia

Because antiepileptic drug therapy is usually given chronically with resulting concerns about long-term neurotoxicity, and because short-term topiramate (TPM) therapy has been reported to be neuroprotective against the effects of acute hypoxia, we investigated the long-term effects of continuous TPM therapy during early stages of development. Four groups of rat pups were studied: two sham manipulated normoxia groups and two acute hypoxia groups (at postnatal day [P] 10 down to 4% O(2)), each injected intraperitoneally daily with either vehicle or TPM (30 mg/kg) from P0 to P21. TPM therapy prevented hypoxia-induced long-term (P81) memory impairment (Morris water maze) as well as aggressivity (handling test). The hypoxia group receiving TPM also showed a trend toward reduced CA1 hippocampal cell loss. The aforementioned TPM therapy had no long-term deleterious effects on memory, hyperactivity, or CA1 cell counts in the TPM normoxia group as compared with normal controls.

Topics: Age Factors; Analysis of Variance; Animals; Animals, Newborn; Brain; Disease Models, Animal; Exploratory Behavior; Female; Fructose; Hypoxia; Longitudinal Studies; Male; Maze Learning; Memory Disorders; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Topiramate

The highest incidence of seizures during lifetime is found in the neonatal period and neonatal seizures lead to a propensity for epilepsy and long-term cognitive deficits. Here, we identify potential mechanisms that elucidate a critical role for AMPA receptors (AMPARs) in epileptogenesis during this critical period in the developing brain. In a rodent model of neonatal seizures, we have shown previously that administration of antagonists of the AMPARs during the 48 h after seizures prevents long-term increases in seizure susceptibility and seizure-induced neuronal injury. Hypoxia-induced seizures in postnatal day 10 rats induce rapid and reversible alterations in AMPAR signaling resembling changes implicated previously in models of synaptic potentiation in vitro. Hippocampal slices removed after hypoxic seizures exhibited potentiation of AMPAR-mediated synaptic currents, including an increase in the amplitude and frequency of spontaneous and miniature EPSCs as well as increased synaptic potency. This increased excitability was temporally associated with a rapid increase in phosphorylation at GluR1 S845/S831 and GluR2 S880 sites and increased activity of the protein kinases CaMKII (calcium/calmodulin-dependent protein kinase II), PKA, and PKC, which mediate the phosphorylation of these AMPAR subunits. Postseizure administration of AMPAR antagonists NBQX (2,3-dihydroxy-6-nitro-7-sulfonyl-benzo[f]quinoxaline), topiramate, or GYKI-53773 [(1)-1-(4-aminophenyl)-3-acetyl-4-methyl-7,8-methylenedioxy-3,4-dihydro-5H-2,3-benzodiazepine] attenuated the AMPAR potentiation, phosphorylation, and kinase activation and prevented the concurrent increase in in vivo seizure susceptibility. Thus, the potentiation of AMPAR-containing synapses is a reversible, early step in epileptogenesis that offers a novel therapeutic target in the highly seizure-prone developing brain.

Topics: Animals; Animals, Newborn; Anticonvulsants; Benzodiazepines; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Cyclic AMP-Dependent Protein Kinases; Disease Susceptibility; Enzyme Activation; Epilepsy; Excitatory Postsynaptic Potentials; Fructose; Hypoxia; Male; Phosphorylation; Protein Kinase C; Quinoxalines; Rats; Rats, Long-Evans; Receptors, AMPA; Synapses; Topiramate