DEFECTS IN THE EXPRESSION OF GENES ASSOCIATED WITH REFRACTORY EPILEPSY IN THE GASH/SAL MODEL

LAURA ZEBALLOS FERNÁNDEZ; ELENA DÍAZ CASADO; ALBERTO LAZAROWSKI; JERÓNIMO AUZMENDI; DOLORES E. LÓPEZ

Santiago de Compostela

Congreso; 18th National Meeting of the Spanish Society of Neuroscience; 2019

Spanish Society of Neuroscience

The ATP-binding cassettes (ABC) are a family of membrane proteins that mediate ATP-driven transports of different substrates across the membrane. In spite of these beneficial effect, they have also been associated to drug resistance. The ABCB1 or P-glycoprotein (P-gp) is the most expressed drug efflux transporter at the blood-brain barrier. High P-gp levels have been detected at the epileptogenic nucleus in epilepsy-refractory patients and different experimental models of epilepsy. This correlates with the drug transporter hypothesis, which suggests that the inefficiency of the antiepileptic drugs might be explained by the overexpression of ABC transporters at the epileptogenic tissue. Here, we used the genetic audiogenic seizure hamster from Salamanca (GASH/Sal) to assess changes in the mRNA expression levels of genes associated with resistance to antiepileptic drugs.Objectives. Studying the possible changes in the glycoprotein-P expression (Abcb1a and Abcb1b genes) and other members of the ABC superfamily, Abcg1, Abcc1 and Abcc4 in the hamster model of audiogenic epilepsy GASH/Sal. Moreover, we assessed the expression changes of Hif1α, Epo-R, Trpa1 and Trpc5.Results. At basal conditions, the audiogenic epileptic model GASH/Sal shows several genic expression changes in the epileptogenic nucleus. Some of these genes are related to the neural hyperexcitability (Trpc5), pharmacorresistance (Hif-1α and Abcb1b) and different ABC transporters (Abcc1 and Abcc4). These results could explain the susceptibility of GASH/Sal hamsters to epilepsy. After repetitive crisis, GASH/Sal animals show lower levels of Hif-1α, what points out to and adaptative response to hypoxia and stress. Moreover, these animals also present and overexpression of the Trpc5 gene. This fact perfectly correlates with the development of repetitive crisis in this strain.Conclusion. After the kindling protocol, the Abcb1a gene expression decreases in the epileptogenic nucleus of GASH/Sal animals. GASH/Sal animals after repetitive stimulation show an increase of the Trpc5 gene. This gen encodes a channel associated with the maintenance of the neural hyperexcitability that characterized the strokes, and might be participate in the susceptibility to seizures in this strain. The repetitive audiogenic stimulation in the GASH/Sal animals induce a decrease in the expression of the hypoxia inducible factor in the epileptogenic nucleus. This points out to an adaptive response in order to decrease hypoxia and its effects.