Abstracts

RATIONALE: Lithium-pilocarpine induced status epilepticus (SE) leads to extended neuronal injury in adult rats. Neuronal damage is mainly necrotic and occurs in limbic forebrain, cerebral cortex, thalamus and substantia nigra. Anatomical MRI shows that neuronal injury appears at 24 h after SE in piriform and entorhinal cortex, amygdala and thalamus and is somewhat delayed in hippocampus. It is not known, however, whether damage is the result of the local excitotoxic neuronal hyperactivity or if a leakage in blood-brain barrier (BBB) could participate in the damaging process. Therefore, we investigated both with MRI and autoradiography the permeability of the BBB during SE in adult rats.
METHODS: BBB opening was studied in adult rats undergoing lithium-pilocarpine SE. Rats subjected to the MRI procedure were anesthetized and examined using T1-weighted images in the presence of gadolinium at 2 and 6 h after the onset of SE. For the autoradiographic procedure, rats were catheterized in the femoral artery and vein on the day before SE. Permeability of BBB was assessed at 90 min after onset of SE by injection of [14C]alpha-aminoisobutyric acid (AIB) which does not cross an intact BBB. Blood samples were regularly taken and rats were sacrificed at 10 min after injection. Brains were dissected out and underwent classical autoradiographic procedure followed by quantification of optical density in 45 areas.
RESULTS: The MRI study showed a hypersignal indicative of increased permeability to gadolinium at 2 h after onset of SE in thalamus and globus pallidus. This signal disappeared by 6 h. A preliminary study using an i.v. injection of blue Evans dye showed that BBB permeability increased at 30 min and spread to a larger number of regions by 60 min. There was no further change up to 150 min. The permeability to [14C]AIB measured at 90 min after onset of SE increased compared to control rats in numerous hypothalamic (+80-330%) and thalamic (+63-420%) nuclei, amygdala (+65-110%), globus pallidus (+620%), medial septum (+170%) and medial geniculate body (+196%).
CONCLUSIONS: As in other seizure models, increase in BBB permeability linked to lithium-pilocarpine SE is transient. Opening of the BBB occurs in both structures that undergo damage (thalamus, septum, amygdala) and structures that are not injured (globus pallidus, hypothalamus). Moreover, neuronal damage occurs in many regions (hippocampus, entorhinal and piriform cortex, substantia nigra) in absence of increased permeability at the BBB. Thus, in this model, neuronal damage appears to rather depend on major neuronal hyperexcitability. The opening of BBB in hypothalamus (a normally more permeable area) or globus pallidus may reflect specific roles during SE such as maintaining vital functions for hypothalamus or control of seizures for globus pallidus.
Support: INSERM U 398 and CNRS UPRES-A 7004.