Abstracts

Rationale: Wistar Audiogenic Rats (WARs) develop tonic-clonic seizures (SZ) in response to acute stimulus and limbic SZ, known as Audiogenic Kindling (AK), after repeated acoustic stimuli. In addition, WARs are anxious and have a hyperactive hypothalamic-pituitary-adrenal axis. Indeed, when compared to Wistars, WARs have dysplastic adrenal gland, elevated corticosterone release after ACTH injection and increased ACTH release after restraint stress (Umeoka et al., Brain Res. 2011). The aim of this study was to evaluate the role of glucocorticoid receptors on stress modulation of seizure susceptibility in WARs. Methods: Male WARs (n=47) were submitted to AK (acoustic stimuli/twice a day/10 days). The rats were divided according to the treatment that they received before each acoustic stimulation. The control (CTR, n=17) group was only submitted to AK; the stress (STR, n=7) group had 60 minutes of restraint stress before the AK. Antagonist-treated groups were injected with the mineralocorticoid receptor (MR) antagonist spironolactone (50 mg/kg) (SPI, n=6) or glucocorticoid receptor (GR) antagonist mifepristone (25 mg/kg) (MIF, n=7) or both (SPI/MIF, n=10). All drugs were diluted in propylene glycol and injected 30 minutes before the stress (90 minutes before acoustic stimulation). For each SZ it was attributed a severity index for mesencephalic (MSI) and limbic (LSI) SZ. Latencies for wild running (WR) and tonic convulsion (CVT) were also calculated. The MSI and the LSI were determined according to Rossetti et al., 2006 (Epilepsy Res.) and Pinel and Rovner, 1978 (Exp. Neurol.), respectively. ANOVA and Bonferroni post-tests were applied with GrahPad Prism 5. The local Ethics Committee approved this project (012/2011). Results: When submitted to AK CTR group developed SZ with higher MSI observed during the initial stimuli and a decrement with subsequent stimuli. In contrast, no limbic SZ were observed at the beginning of AK, but the LSI increased during its progression, in accordance with previous results from our group (Garcia-Cairasco et al., Epilepsy Res. 1996). The STR group had severe SZs from the beginning until the end of the AK and did not show the MSI decrement as observed in CTRL group. SPI, MIF and SPI/MIF groups presented a significant (p<0.05) reversal of the stress effect on MSI, albeit without difference among them. We did not find any significant alteration on the LSI in any of the groups. The latency for wild running (WR) was increased (p<0.05) only in the SPI/MIF group. Latency for tonic convulsion (TCV) was shorter in STR group when compared with CTR, and longer in MIF and SPI/MIF groups (p<0.05) when compared with and STR group and even longer than CTR groups (p<0.05). Conclusions: Blockade of GR and MR, either alone or in combination, was able to revert the stress modulatory effect on the MSI. GR and MR antagonism also increased the latencies for WR and TCV, showing the crucial role of the glucocorticoids on SZ susceptibility modulation. Acknowledgments: FAPESP, FAPESP-Cinapce, PROEX-CAPES, CNPq, FAEPA.