Role of Brain Inflammation and Angiogenesis in Epileptogenesis

Annamaria Vezzani, Ph.D.

Mario Negri - Istituto Di Ricerche Famacologiche

Funded in September, 2006: $100000 for 3 years
LAY SUMMARY . ABSTRACT . BIOGRAPHY .

LAY SUMMARY

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Can Inflammation in the Immature Brain Lead to Chronic Epilepsy?

This study, in laboratory animal brain tissue, will lay the groundwork for determining whether the degree of inflammation resulting from an initial neonatal seizure determines whether new blood vessels with a weakened blood-brain-barrier (BBB) function are formed and if these phenomena are important for chronic epilepsy to occur.  Ultimately the findings could lead to methods to prevent epilepsy, rather than solely treat seizures.

Clinical and experimental evidence indicates that the immature brain is highly susceptible to seizure activity during early post-natal development.  Seizure results are highly varied.  Some children develop no further problems.  Others progress to chronic epilepsy and thus develop spontaneous recurrent seizures.  These different outcomes suggest that the development of “epileptogenesis” (the transformation of a non-epileptic neural network to a seizure-generating network) depends on the nature and extent of the initial inciting event.  Recent evidence indicates that inflammatory reactions are a common element in people with various types of epileptic disorders from different causes.  Can inflammation be a common factor involved in the development of seizure-generating neural networks? 

Prior studies in laboratory animals have shown that brain inflammation and impaired permeability of the normally protective BBB contribute to hyperexcitability of brain cells.  The researchers hypothesize that conversion of brain cell circuits from normal to seizure-generating depends upon the extent of inflammatory reactions in the brain following an inciting event and on development of new blood vessels in the brain with a weakened BBB function, thus being more permeable to blood components usually excluded from the brain.

The researchers will explore the first part of this hypothesis.  They will determine in laboratory animal tissue whether brain tissue inflammation alters neuronal excitability, and promotes conversion of neural circuits to seizure-generating networks.  Subsequent studies would then focus on determining whether an inflammation-related “cytokine” (called IL-1beta) triggers formation of new, more permeable blood vessels which weaken the BBB and promote brain cells’ excitability and vulnerability to damage. 

Significance:  This study is the first step in understanding whether inflammatory processes in the brain trigger a cascade of events that lead to epilepsy. If so, this area of research ultimately could lead to therapies that prevent epilepsy, rather than current therapies that solely try to control seizures.

ABSTRACT

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Role of Brain Inflammation and Angiogenesis in Epileptogenesis

Clinical and experimental evidence indicates that the immature brain is highly susceptible to seizure activity during early post-natal development. Although neonatal seizures in humans are a common event, they are heterogenous in terms of prognosis. Some classes of early-life seizures such as symptomatic neonatal seizures or complex and recurrent febrile seizures may result in long-term epilepsy, suggesting that development of epileptogenesis (the transformation of a non-epileptic to a seizure-generating neuronal circuit) depends on the nature and context of the initial inciting event.

Transient over-expression of glutamate receptors and  changes in their subunit composition, as well as changes in GABAergic inhibitory transmission, ion channel expression, and homeostasis, increase the excitatory drive that is likely to be critical for normal brain development. Disregulation of these factors, which are important for proper brain maturation, has been suggested to be involved in the enhanced propensity of the immature brain to experience seizures. However, the critical factors that promote epileptogenesis and the related long-term maladaptive functional plasticity are largely unknown. Recent evidence showed that inflammatory reactions occur in the brain in various epileptic disorders with different etiologies, raising the possibility that inflammation may be a common etiological factor involved in the development of epileptogenesis and the occurrence of spontaneous seizures. Brain inflammation and impaired permeability function of the blood-brain barrier in rodents significantly contribute to  the establishment of neuronal hyperexcitability.

Our novel hypothesis is that epileptogenesis in the immature brain depends on the extent of brain inflammatory reactions induced by the inciting event and the consequent changes in brain vascularization and permeability properties of the blood-brain barrier. We will investigate in developing rats, whether inflammation in the brain (as exemplified by induction of the IL-1beta system and glial cells activation), triggered by an initial precipitating event (status epilepticus), promotes angiogenesis and disrupts the BBB and the role of these phenomena in epileptogenesis.

To accomplish our aims, we will use in vivo models of seizures induced by systemic administration of chemoconvulsant drugs in rats during post-natal development. We will focus our studies on 9 and 15 day-old rats, which are highly responsive to acute seizures but do not develop epileptogenesis; thus, in these rats, spontaneous seizures do not occur as a result of status epilepticus. We will compare these rats with 21 day-old rats which develop epileptogenesis and spontaneous recurrent seizures after status epilepticus.

The extent of brain inflammation, angiogenesis and BBB damage will be evaluated using immunohistochemistry coupled to confocal microscopy. Spontaneous recurrent seizures will be evaluated and quantified by video-EEG monitoring in freely moving rats. Novel and selective pharmacological tools will be used in vivo for studying the involvement of Src/Neutral sphingomyelinase, PI3K/Akt and NfkB pathways in the effects of IL-1beta on neuronal excitability and in the long-lasting inflammation-related events that may play a role in the development of epileptogenesis.

These findings may help to identify novel targets for developing antiepileptogenic strategies that are presently unavailable. Thus, only symptomatic drugs are currently used, and these have no effects on the progression of the disease. Additionally, by targeting non-conventional pathways, new drugs may be developed that possibly escape the mechanisms of pharmacoresistance observed in ~30% of epilepsy cases.

INVESTIGATOR BIOGRAPHIES

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Annamaria Vezzani, Ph.D.

Annamaria Vezzani obtained her Ph.D. in Neuropharmacology at the Mario Negri Institute for Pharmacological Research (IRFMN) in Milano (Italy). She spent a post-doctoral period at the University of Maryland in Baltimore, studying basic mechanisms of seizure occurrence in experimental models. She was visiting scientist at the Department of Neurochemistry and Neurotoxicology at Stockholm University, and at the Albert Einstein College of Medicine in 2002 in the laboratory of Developmental Epilepsy. Since 1997, she has been Head of the Experimental Neurology Section at the Department of Neuroscience (IRFMN). She studies the molecular mechanisms involved in the etiopathogenesis of seizures disorders, using experimental models of epilepsy that focus on the role of neuroactive peptides and inflammatory mediators in neuronal excitability and seizure-related neurodegeneration.

Tamas Bartfai obtained his Ph.D. in Biochemistry at Stockholm University. He was former Chairman of the Department of Neurochemistry and Neurotoxicology at Stockholm University, and Professor of Medical Biochemistry and Biophysics at Karolinska Institutet in Stockholm; Adjunct Professor at the Rockefeller University in New York; Adjunct Professor at Stanford University, Palo Alto, CA; Head of Central Nervous System Research, Hoffmann-La Roche, Basel, Switzerland.

Since 2005, he directs the Harold L. Dorris Neurological Research Center at the Scripps Research Institute, which investigates neurological disorders (including schizophrenia and Alzheimer's disease) and seeks to advance knowledge of the brain's aging process. Specifically, Bartfai focuses on three main areas: the neuropeptide galanin, fever and thermoregulation, and uncoupling protein 2.