High serum levels of proinflammatory markers during epileptogenesis. Can omega-3 fatty acid administration reduce this process?

Abstract

During the epileptogenic process, several events may occur, such as an important activation of the immune system in the central nervous system. The response to seizure activity results in an inflammation in the brain as well as in the periphery. Moreover, CRP and cytokines may be able to interact with numerous ligands in response to cardiac injury caused by sympathetic stimulation in ictal and postictal states. Based on this, we measured the serum levels of C-reactive protein (CRP) and cytokines during acute, silent, and chronic phases of rats submitted to the pilocarpine model of epilepsy. We have also analyzed the effect of a chronic treatment of these rats with omega-3 fatty acid in CRP and cytokine levels, during an epileptic focus generation. C-reactive protein and cytokines such as IL-1β, IL-6, and TNF-α presented high concentration in the blood of rats, even well after the occurrence of SE. We found reduced levels of CRP and all proinflammatory cytokines in the blood of animals with chronic seizures, treated with omega-3, when compared with those treated with vehicle solution. Taken together, our results strongly suggest that the omega-3 is an effective treatment to prevent SUDEP occurrence due to its capability to act as an anti-inflammatory compound, reducing the systemic inflammatory parameters altered by seizures.

WONOEP appraisal: Biomarkers of epilepsy‐associated comorbidities

“…Elevated blood levels of CRP, S100β, and IL‐6 have been observed in patients with epilepsy, whereas increased plasma levels of IL‐1β have been specifically connected with epilepsy‐associated depression . Similarly, increased levels of plasma IL‐1β, IL‐6, TNF‐α, CRP, and S100β protein have been detected in an animal TLE model . Although the latter studies did not directly connect inflammatory biomarkers with depressive impairments, the employed epilepsy model is consistently characterized by depressive behavior …”

“…36 Similarly, increased levels of plasma IL-1b, IL-6, TNF-a, CRP, and S100b protein have been detected in an animal TLE model. 37,38 Although the latter studies did not directly connect inflammatory biomarkers with depressive impairments, the employed epilepsy model is consistently characterized by depressive behavior. 27,30 In conclusion, several lines of evidence suggest that in experimental models of acquired epilepsy, activation of specific cell signaling pathways is associated with cognitive decline or comorbid depression.…”

Effect of Chronic Krill Oil Supplement on Seizures Induced by Pentylenetetrazole in the Hippocampus of Adult Rats with Previous Febrile Seizures

“…The increase in the number of cells labeled with NeuN in the DG of the KO group compared with control groups, could be due to the granular layer retaining potential neurogenesis activity in adulthood (Cameron & Mckay, ; Ninkovic, Mori, & Gotz, ), and KO could contribute to this process because of the anti‐inflammatory, antioxidant and membrane stabilizing effects (Berge, Musa‐Veloso, Harwood, Hoem, & Burri, ; Deutsch, ; Di Marzo et al., ; Gouveia et al., ; Haijian et al., ; Kidd, ; Shen et al., ). However, the PO group also showed a higher number of neurons because contain omega‐6 fatty acids (Table ) and its precursors such as linoleic acid (LA; 18:2n‐6), and arachidonic acid (ARA, 20:4n‐6; a component of membrane lipids; Bazan, ; Sastry, ).…”

“…In addition, KO has a high proportion of esterified omega‐3 fatty acids with a large bioavailability of docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids compared with fish oil (Di Marzo et al., ; Tillander et al., ; Ulven & Holven, ). Both omega‐3 fatty acids and astaxanthin have neuroprotective effects (Barros, Poppe, & Bondan, ; Burri, Hoem, Banni, & Berge, ; Haijian et al., ; Köhler, Sarkkinen, Tapola, Niskanen, & Bruheim, ) and reduce C‐reactive protein and proinflammatory cytokines such as interleukins 1beta, 6 and the tumor necrosis factor alpha (IL‐1β, IL‐6, and TNF‐α) in the blood of animals with chronic seizures induced by pilocarpine and treated with omega‐3 fatty acids over 90 days (Gouveia and others ). Other reports have found moderate anticonvulsant effects of PUFAs on seizures induced by cortical stimulation (Voskuyl, Vreugdenhil, Kang, & Leaf, ) and FSs induced by hyperthermia (Flores‐Mancilla, Medina‐Ceja, Canales‐Aguirre, & Morales‐Villagrán, ).…”

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…Accordingly, based on this background, it is not possible to exclude that fingolimod can exert antiepileptogenic effects in this strain through some kind of antiinflammatory mechanisms, which could also be linked to a modulation of neuronal S1P receptors [13]. It is known that glial activation and the related overexpression of proinflammatory cytokines seem to play a crucial role in epileptogenesis both in humans and in several animal models of epilepsy [58][59][60][61]; however, to date, such a relationship between neuroinflammation and absence seizure development in WAG/Rij rats remains unclear [27,28]. Indeed, neuroinflammation and related mediators worsen absence seizures in this strain [28-30, 62, 63], while cyclooxygenase inhibitors have some partial antiabsence properties [11,63,64] and etoricoxib, a selective COX-2 inhibitor, also possesses antiepileptogenic effects in this strain, which appear to be more effective than fingolimod with a reduction in the development of absence seizures of about 45% vs 30% obtained with fingolimod [11].…”