Title

 

Authors

E. Russo¹, R. Citraro¹, F. Scicchitano¹, I. Perrotta², G. Donato¹, P. De Fazio¹, De Sarro G¹.
 
¹Dept of Experimental and Clinical Medicine, School of Medicine, University of Catanzaro, Catanzaro, Italy. ²Ecology Dept, University of Calabria, Cosenza, Italy. 

 

Abstract

 
Psychiatric comorbidities in epilepsy have been considered to reflect a ‘‘consequence or complication’’ of the seizure disorder. Yet, in recent years, a bidirectional relationship between depressive disorders (DDs) and epilepsy has been demonstrated, as not only are people with epilepsy at greater risk of developing a DD, but patients with DD have a three- to seven-fold higher risk of developing epilepsy¹. These data may be explained by the existence of common pathogenic mechanisms operant in both conditions². WAG/Rij rats (WGr) represent a validated model of absence epilepsy with depressive symptoms also validated for mild depression, i.e. dysthymia³. We have demonstrated that epilepsy in WGr results from epileptogenic processes, and pharmacological intervention can prevent absence seizure development⁴. We wanted to determine if an early treatment with anticonvulsants (AEDs) or Antidepressant drugs (ADs) might alter seizures development and which correlation with depressive symptoms exists, furthermore, an histological study on the hippocampus has been performed. Rats were treated with AEDs (Ethosuximide, Levetiracetam, Carbamazepine and Zonisamide) or ADs (Fluoxetine and Duloxetine) following our previously validated protocol⁴. For epilepsy assessment, animals were EEG monitored⁴, for depressive behaviour the Forced swimming test (FST) was performed⁴. Wistar rats (WSr) served as a control. Ethosuximide (ETH), Levetiracetam (LEV), Zonisamide (ZNS), Fluoxetine (FLX; 30mg/kg) and Duloxetine (DLX; 30mg/kg) showed antiepileptogenic properties whereas Carbamazepine (CBZ), FLX or DLX (both at 10mg/kg) were ineffective. The FST revealed that: 1) all AEDs tested have no effects in WSr whereas both ADs used are effective in reducing immobility times (IT). 2) ETH reduced IT in WGr both at 4 and 6 months of age. LEV increased IT in WGr at 6 months. CBZ and ZNS have no effects. 3) At 4 months of age in WGr, FLX at both doses was ineffective whereas, DLX reduced IT. 4) At 6 months of age in WGr, DLX at both doses and FLX 30 mg/kg had no effects on ITs, while the latter at the dose of 10mg/kg increased IT. Brains were collected from animals of every group of treated and untreated animals and processed by standard protocols for later analysis in light and electron microscopy. From sample analysis, the main results obtained were: 1) Only some untreated WGr show ischemic damage at 6 months of age in CA1 and dentate gyrus, and therefore, further studies are needed in order to validate this alteration. 2) Electron microscopy showed that all untreated WGr have an unspecific ultrastructural alteration of synaptic connections indicating a synaptic dysfunction in some hippocampal areas. 3) The latter damage was prevented only by the drugs able to prevent epileptogenesis, however, LEV and FLX 10mg/kg (increasing ITs at 6 months of age) seem to increase synaptic damage and this might be related to IT increase at 6 months of age. In conclusion, a complex relation between epilepsy, epileptogenesis and depression exists indicating that a proper pharmacological treatment can improve efficacy and modulate pathogenic processes. A prominent role in the depressive symptoms of this animal model is very likely played by the noradrenergic system since DLX was effective whereas FLX had only antiepileptogenic properties. This difference indicates and confirms a role for serotonin in this animal model and epileptogenesis⁵. The ultrustructural alteration observed in the hippocampus with electron microscopy deserves further investigation in order to define if it is dependent on depressive or epileptic symptoms even if both phenomena might contribute to altered hippocampal neuronal connections.
 
¹Kanner (2011). Epilepsia. 52, 21-27.
²Kanner (2009). Neurologic Clin. 27:865-880.
³Sarkisova & van Luijtelaar (2010). Prog Neuropsychopharmacol Biol Psychiatry. In press. 
⁴Russo et al. (2011). Epilepsia. In press.
⁵Bagdy et al. (2007). J. Neurochem. 100, 857-873.