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.