The role of inflammation in epileptogenesis.

Laboratory Experimental Neurology, Department of Neuroscience, Mario Negri Institute for Pharmacological Research, Via G. La Masa 19, 20156 Milano, Italy.
Neuropharmacology (Impact Factor: 4.82). 04/2012; DOI: 10.1016/j.neuropharm.2012.04.004
Source: PubMed

ABSTRACT One compelling challenge in the therapy of epilepsy is to develop anti-epileptogenic drugs with an impact on the disease progression. The search for novel targets has focused recently on brain inflammation since this phenomenon appears to be an integral part of the diseased hyperexcitable brain tissue from which spontaneous and recurrent seizures originate. Although the contribution of specific proinflammatory pathways to the mechanism of ictogenesis in epileptic tissue has been demonstrated in experimental models, the role of these pathways in epileptogenesis is still under evaluation. We review the evidence conceptually supporting the involvement of brain inflammation and the associated blood-brain barrier damage in epileptogenesis, and describe the available pharmacological evidence where post-injury intervention with anti-inflammatory drugs has been attempted. Our review will focus on three main inflammatory pathways, namely the IL-1 receptor/Toll-like receptor signaling, COX-2 and the TGF-β signaling. The mechanisms underlying neuronal-glia network dysfunctions induced by brain inflammation are also discussed, highlighting novel neuromodulatory effects of classical inflammatory mediators such as cytokines and prostaglandins. The increase in knowledge about a role of inflammation in disease progression, may prompt the use of specific anti-inflammatory drugs for developing disease-modifying treatments. This article is part of a Special issue entitled 'Epilepsy'.


Available from: Alon Friedman, Mar 16, 2014
1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Post-traumatic epilepsy (PTE) remains one of the most intractable consequences of traumatic brain injury (TBI) and its incidence and characteristics have remained relatively constant through the past century, in spite of significant advances in medical management. Survivors of military penetrating head injury (PHI) suffer by far the highest incidence of (PTE), ranging from 32% to 55%, and they are a particularly valuable group in which to study this complication. Clues to the high incidence of PTE in PHI survivors are likely related to dural penetration with free intracerebral blood, and perhaps to retained ferric metal fragments. The failure of well-reasoned and well-conducted trials evaluating conventional anticonvulsants for prevention of PTE also offers important clues and has forced us to reconsider our approach to management. Here we briefly review the clinical characteristics of PHI patients with PTE, with an emphasis on clues to pathogenesis that can generalize to other types of head injury; followed by a discussion of the pathogenetic mechanisms common to epilepsy, PHI, and TBI in general, with an eye to future neuroprotection and PTE prophylaxis. Future studies that more directly target the basic pathogenesis of TBI, including neuroinflammation and lipid peroxidation with their consequent excitotoxic mechanisms and aberrant regeneration, may ultimately prove to be more fruitful in the struggle to understand and control this especially stubborn complication of head injury. © 2015 Elsevier B.V. All rights reserved.
    Handbook of Clinical Neurology 01/2015; 128:525-38. DOI:10.1016/B978-0-444-63521-1.00033-9
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mounting evidence suggests that brain inflammation mediated by glial cells may contribute to epileptogenesis. Minocycline is a second-generation tetracycline and has potent antiinflammatory effects independent of its antimicrobial action. The present study aimed to investigate whether minocycline could exert antiepileptogenic effects in a rat lithium-pilocarpine model of temporal lobe epilepsy. The temporal patterns of microglial and astrocytic activation were examined in the hippocampal CA1 and the adjacent cortex following pilocarpine-induced status epilepticus (SE). These findings displayed that SE caused acute and persistent activation of microglia and astrocytes. Based on these findings, Minocycline was administered once daily at 45 mg/kg for 14 days following SE. Six weeks after termination of minocycline treatment, spontaneous recurrent seizures were recorded by continuous video monitoring. Minocycline inhibited the SE-induced microglial activation and the increased production of interleukin-1β and tumor necrosis factor-α in the hippocampal CA1 and the adjacent cortex, without affecting astrocytic activation. In addition, Minocycline prevented the SE-induced neuronal loss in the brain regions examined. Moreover, minocycline significantly reduced the frequency, duration, and severity of spontaneous recurrent seizures during the two weeks monitoring period. These results demonstrated that minocycline could mitigate SE-induced brain inflammation and might exert disease-modifying effects in an animal model of temporal lobe epilepsy. These findings offer new insights into deciphering the molecular mechanisms of epileptogenesis and exploring a novel therapeutic strategy for prevention of epilepsy. Copyright © 2014. Published by Elsevier Ltd.
    Neuroscience 12/2014; 287. DOI:10.1016/j.neuroscience.2014.12.021 · 3.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although leukotrienes have been implicated in seizures, no study has systematically investigated whether the blockade of CysLT1 receptors synergistically increases the anticonvulsant action of classic antiepileptics. In this study, behavioral and electroencephalographic methods, as well as isobolographic analysis, are used to show that the CysLT1 inverse agonist montelukast synergistically increases the anticonvulsant action of phenobarbital against pentylenetetrazole-induced seizures. Moreover, it is shown that LTD4 reverses the effect of montelukast. The experimentally derived ED50mix value for a fixed-ratio combination (1:1 proportion) of montelukast plus phenobarbital was 0.06±0.02μmol, whereas the additively calculated ED50add value was 0.49±0.03μmol. The calculated interaction index was 0.12, indicating a synergistic interaction. The association of montelukast significantly decreased the antiseizure ED50 for phenobarbital (0.74 and 0.04μmol in the absence and presence of montelukast, respectively) and, consequently, phenobarbital-induced sedation at equieffective doses. The demonstration of a strong synergism between montelukast and phenobarbital is particularly relevant because both drugs are already used in the clinics, foreseeing an immediate translational application for epileptic patients who have drug-resistant seizures. Copyright © 2015. Published by Elsevier Ltd.
    Pharmacological Research 02/2015; 94. DOI:10.1016/j.phrs.2015.02.001 · 3.98 Impact Factor