Experimental Studies in Epilepsy: Immunologic and Inflammatory Mechanisms

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In this article, we review the literature based on experimental studies lending credence to a relationship between epilepsy and immune-mediated mechanisms linked to central nervous system innate immunity. The brain innate immunity responses to neuronal injury or excessive neuronal activity are mediated by resident microglia and astroglia, but also neurons play an immunomodulatory role. Antigens or antibodies applied to the brain trigger an epileptogenic and inflammatory response. Furthermore, seizure activity and status epilepticus elicit the production and release of proinflammatory cytokines and chemokines. The immune pathogenesis of epilepsy involves complex cell-to-cell interactions including a cross talk between astrocytes and neurons, between astrocytes and brain microvascular endothelial cells, as well as reciprocal leukocyte-endothelial interactions in the context of disruption of the blood-brain barrier. There is a large body of literature from experimental studies showing that seizures can initiate a cascade of innate and adaptive immune responses from various cellular sources and perpetuate neuroinflammation through mechanisms involving transcription of inflammatory genes or posttranslational changes in cytokine release machinery. These inflammatory processes could also possibly contribute to the pathogenesis of comorbidities often associated with epilepsy. This opens exciting possibilities for the development of disease-modifying drugs aimed at mitigating neuroinflammation as a means of ameliorating epileptogenesis and lessening or preventing postictal brain injury.

Introduction

The association between immune-mediated inflammation and excitatory activity in the brain was already suspected at the beginning of the 20th century with the experiments performed by the French physician and biologist Camille Delezenne.1 He injected, into the anterior brain of dogs, serum containing antibodies obtained in rabbits and ducks by administering emulsions of canine liver and brain. The animals developed epileptic discharges, with most of them becoming paralyzed and some showing epileptic salivation and clonic-tonic convulsions.

Since these early discoveries, progress on basic research methodologies and molecular biology discoveries has advanced this area of neurology, and now the hypothesis of an association between epilepsy, immune system, and inflammation is a field of strong research and clinical interest.

In this article, we review the experimental studies and basic science mechanisms of immune-mediated inflammation as they relate to epilepsy. We first describe the immunologic characteristics of the brain with the potential of causing an inflammatory response. This review is followed by a historical perspective of the scientific experiments that have supported such pathogenic relationship.

Section snippets

Neuroinflammation

The central nervous system (CNS) was regarded as an immune-privileged site in the presence of an intact blood-brain barrier (BBB). However, in recent years, this time-honored concept has been the subject of critical reappraisal given the emerging role of CNS-resident cells as innate immune-competent cells.2, 3, 4, 5, 6 A large body of literature has come to light lending credence to the concept of neuroinflammation as an intricate and specialized immune response system triggered by a variety of

Induction of Epileptic Seizures with Cerebral Application of Antigens or Antibodies

Following the pioneer experiments of Delezene1 previously referred to, throughout the 20th century many investigators used different animal models to demonstrate the epileptogenic effect of antigens or antibodies applied to the brain. In 1947, Kopeloff et al42 produced experimental epileptic seizures with the application of aluminum hydroxide and other foreign antigens to the cortex of monkeys.

In 1961, Mihailovic and Jankovic43 administered to cats intraventricular anti–caudate nucleus

Blood Brain Barrier Disruption and Leukocyte Migration

Nitsch and Klatzo79 showed how electrographic seizures cause a regional change with breakdown of the BBB. They investigated the permeability to macromolecules using Evans Blue as indicator. Pentylenetetrazol-induced seizures caused bilateral leakage mainly in the hypothalamus, with exception of the mammillary bodies, and the preoptic area. In contrast, seizures due to the GABA receptor blocker bicuculline brought about a penetration of the dye in the region of the pallidum, whereas the GABA

Conclusions

The information reviewed here demonstrates that since the beginning of the 20th century, experimental models of epilepsy have demonstrated that the brain is an immunologically active organ. The brain innate immunity responds to excessive neuronal injury or to excessive neuronal activity, which is mediated by its resident microglia and astroglia, but neurons also play a role. Thus, prostaglandins produced by neuronal COX-2 regulate signaling pathways normally involved in synaptic activity, but

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