Antiepileptic drug resistant rats differ from drug responsive rats in GABAA receptor subunit expression in a model of temporal lobe epilepsy

Jun 20, 2008Neurobiology of disease

Differences in GABA A receptor subunits between drug-resistant and drug-responsive rats in a temporal lobe epilepsy model

AI simplified

Circadian Biology on OpenScience ↗PubMed ↗DOI ↗

Abstract

Histological examination revealed neurodegeneration in 5 of 6 AED-resistant rats compared to only 1 of 8 AED-responsive rats (P=0.0256).

20-40% of epilepsy patients do not respond to antiepileptic drugs.
Potential mechanisms for AED resistance include changes in drug target sensitivity and the overexpression of drug transporters in the brain.
AED-resistant rats exhibited significant neurodegeneration in specific brain regions compared to AED-responsive rats.
In nonresponders, decreased levels of several GABA(A) receptor subunits were detected in multiple areas of the hippocampus.
Increased expression of the alpha 4-subunit of GABA(A) receptors was observed specifically in the CA1 region of nonresponders.
These findings suggest that changes in GABA(A) receptor subtypes may play a role in resistance to antiepileptic drugs.

AI simplified

Epidemiological data indicate that 20-40% of the patients with epilepsy are refractory to treatment with antiepileptic drugs (AEDs). The mechanisms underlying pharmacoresistance in epilepsy are unclear, but several plausible hypotheses have emerged, including loss of AED target sensitivity in the epileptic brain, decreased AED concentrations at brain targets because of localized overexpression of drug efflux transporters in epileptogenic brain tissue, and network alterations in response to brain damage associated with epilepsy. Rat models of epilepsy in which part of the animals are resistant to treatment with AEDs offer a means to investigate the mechanisms underlying AED resistance. In the present study, AED-responsive and AED-resistant rats were selected from a model in which spontaneous recurrent seizures develop after a status epilepticus induced by electrical stimulation of the basolateral amygdala. For selection into responders and nonresponders, epileptic rats were treated over two weeks by phenobarbital. Subsequent histological examination showed neurodegeneration of the CA1, CA3 and dentate hilus in only one of eight responders but five of six nonresponders (P=0.0256). Based on previous studies in AED-resistant rats of this model, we hypothesized that changes in the structure and function of inhibitory GABA(A) receptors may contribute to drug resistance. We therefore analyzed the distribution and expression of several GABA(A) receptor subunits (alpha1, alpha2, alpha 3, alpha 4, alpha 5, beta2/3, and gamma 2) immunohistochemically with specific antibodies in the hippocampal formation of responders, nonresponders and nonepileptic controls. In nonresponders, decreased subunit staining was observed in CA1, CA2, CA3, and dentate gyrus, whereas much less widespread alterations were determined in responders. Furthermore, upregulation of the alpha 4-subunit was observed in the CA1 of nonresponders. Our data suggest that alterations in GABA(A) receptor subtypes may be involved in resistance to AEDs.

Full Text

Full text is available at the source.

View full text (XML) ↗View full text ↗

Antiepileptic drug resistant rats differ from drug responsive rats in GABAA receptor subunit expression in a model of temporal lobe epilepsy

Abstract

Full Text

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief

Abstract

Full Text

Related papers

You found one interesting study. We’ll send the next 7.

what lands in your inbox each week:

Recent issues from the circadian biology brief