The mortality rate in people with epilepsy is substantially higher than that observed in the general population, which is a matter of concern among specialists (1). In this scenario, sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature mortality directly related to epilepsy (2).

Sudden unexpected death in epilepsy is defined as “sudden, unexpected, witnessed or unwitnessed, non-traumatic and non-drowning death in patients with epilepsy, with or without evidence for a seizure, and excludes documented Status epilepticus (SE), in which postmortem examination does not reveal a toxicological or anatomic cause for death” (3). The fatal event is most likely provoked by functional disturbance, and researchers have proposed cardiac arrhythmia as a potential cause of SUDEP (2). Recently, clinically relevant genetic variants in cardiac arrhythmia and epilepsy have been found in a considerable number of SUDEP cases (4). Inflammation has been implicated in the pathophysiological events of both epilepsy and life-threatening ventricular arrhythmia (5, 6), in which the central role of the interleukin-6 (IL-6) is well recognized.

Our group was the first to describe increased levels of IL-6 in the hearts of rats with chronic epilepsy (7). Omega-3 polyunsaturated fatty acids, which are abundant in fish oil, have been described as potent anti-inflammatory agents (8). Thus, in the search for complementary therapy for epilepsy, this study was conducted to examine the potential anti-inflammatory effects of fish oil supplementation on the levels of the pro-inflammatory cytokine IL-6 in the heart of rats with chronic epilepsy.

The results of Western blot analysis showed that IL-6 levels in the heart of rats with epilepsy were substantially increased when compared with control rats [F(1;12) = 54.78; p < 0.0001]. Animals with epilepsy that were treated with fish oil for an extended time exhibited a marked reduction in IL-6 levels, since an interaction effect was observed between epilepsy and fish oil treatment [F(1;12) = 5.34; p = 0.039], as shown in Figure 1.

In Figure 2, the ELISA results corroborated the results obtained with immunoblotting analysis as increased levels of IL-6 were found in the hearts of animals with epilepsy compared with those in control rats [F(1;16) = 10.26; p = 0.0059]. Furthermore, the ELISA results show the effectiveness of the fish oil treatment, which reduced IL-6 levels in both control and epileptic rats [F(1;16) = 6.05; p = 0.0264]. There was no interaction effect between epilepsy and fish oil treatment [F(1;16) = 1.06; p = 0.3178].

In this rodent pilocarpine model of seizures, fish oil supplementation reduced cardiac levels of IL-6, indicating an anti-inflammatory effect of fish oil.

Consistent preclinical and clinical findings support the presence of a persistent inflammatory condition in the brain and plasma of subjects with epilepsy (4, 6, 11). Epileptic seizures often affect heart rate and rhythm, and poor seizure control is by far the major clinical risk factor for SUDEP (2). However, despite the available therapeutic arsenal, 30–40% of individuals with epilepsy have uncontrolled seizures. Studies focused on the pathological basis of epilepsy have focused on the role of inflammatory events (6). Basic and clinical studies has been described that chronic inflammatory state contribute to the pathogenesis of seizures and maintance of epilepsy (6, 11, 12). Previously, we demonstrated chronically elevated levels of the pro-inflammatory cytokine IL-6 in the ventricles of rats with seizures (7). Here, our findings support the existence of persistent inflammation in the ventricles of rats with epilepsy, which exhibited elevated levels of IL-6. Elevated circulating levels of IL-6 have been described in patients with heart failure, and these higher levels are positively correlated with the presence and duration of cardiac arrhythmias and with the severity of disease and mortality risk (5, 13). Taken together, there is compelling evidence that increased levels of IL-6 are deeply involved in the pathophysiological mechanisms underlying both epilepsy and cardiac diseases.

Using the pilocarpine model of epilepsy, Ferrari and colleagues in our group demonstrated that chronic treatment with fish oil promoted neuroprotection and positive plastic changes in the brain of rats with epilepsy (14). The beneficial anti-inflammatory effects of omega-3 fatty acids in chronic inflammatory diseases have been consistently documented (8). Fish oil dietary consumption is suggested as a good source of omega-3 polyunsaturated fatty acids for consumers. This study suggests that chronic oil fish supplementation has a protective anti-inflammatory effect against elevated levels of IL-6 in the heart of rats with epilepsy, but the underlying mechanisms of these effects remain unknown.

Our findings report the beneficial anti-inflammatory effects of long-term oil fish intake in the hearts of rats with chronic inflammation associated with epilepsy. Our results suggest the potential therapeutic value of dietary supplementation with oil fish in patients with epilepsy.

All animals were treated according to protocols for animal care, and this study was carried out in accordance with the recommendations established by the Federal University of Sao Paulo. All efforts were made to minimize animal suffering (Comissão de Ética no Uso de Animais—CEUA).

MN: conducted the experiments, acquired data, analyzed data, critically discussed the manuscript, and wrote the manuscript. AAH: conducted the experiments, acquired data, analyzed data, and critically discussed the manuscript. AEH, LO, A-CA, and RC: analyzed data and critically discussed the manuscript. EC: conceived the work and wrote the manuscript. CS: critically discussed the manuscript and wrote the manuscript. FS: conceived the work, critically discussed the manuscript, and wrote the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.