Experimental Studies in Epilepsy: Immunologic and Inflammatory Mechanisms
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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