In the lithium–pilocarpine model of epilepsy, brain lesions are not linked to changes in blood– brain barrier permeability: an autoradiographic study in adult and developing rats Claire Leroy, a, * Catherine Roch, b Estelle Koning, a Izzie J. Namer, b and Astrid Nehlig a a INSERM U.398, Faculty of Medicine, 11 rue Humann, 67085 Strasbourg Cedex, France b Institut de Physique biologique (UMR 7004 ULP/CNRS), Faculty of Medicine, 4 rue Kirschleger, 67085 Strasbourg Cedex, France Received 30 July 2002; revised 25 October 2002; accepted 5 February 2003 Abstract Lithium–pilocarpine-induced status epilepticus (SE) leads to the genesis of massive neuronal loss in adult rats and to a lesser extent in P21 rats. Neuronal damage occurs mainly via a process of necrosis in limbic forebrain, cerebral cortex, thalamus, and substantia nigra. It is not known, however, whether damage is the result of local excitotoxic hyperactivity or if leakage at the blood– brain barrier (BBB) could participate in the damaging process. Therefore, we investigated the permeability of the BBB in adult and P21 rats using [- 14 C]amino- isobutyric acid, which does not cross an intact BBB, at 90 min after the onset of SE. At both ages, BBB opening occurred both in structures that will undergo damage (thalamus, septum, amygdala) and structures that will not be injured (globus pallidus, hypothalamus). In addition, neuronal damage occurs in the absence of increased BBB permeability in hippocampus, entorhinal cortex, and substantia nigra. Moreover, the increase in the intensity and distribution of BBB permeability changes is age-related, suggesting a differential activation of seizure circuits in adult and P21 rats. In summary, there is no clear correlation between the anatomical distribution of BBB opening and the occurrence of neuronal damage which, in this model, appears to rather depend on excitotoxic mechanisms due to major neuronal hyperexcitability. © 2003 Elsevier Science (USA). All rights reserved. Keywords: Lithium–pilocarpine; Blood– brain barrier; [- 14 C]Aminoisobutyric acid; Neuronal damage; Development; Seizures Introduction Numerous reports indicate that extensive electrical and convulsive activity may produce an increase in cerebral capillary permeability and impair function of the blood– brain barrier (BBB) in humans (Horowitz et al., 1992; Nagasaka et al., 2002) and in many experimental models (Nitsch et al., 1986; O ¨ ztas and Kaya, 1991; Padou et al., 1995; Pont et al., 1995; Ruth, 1984). BBB breakdown is transient and occurs rather early during epileptic activity (Pont et al., 1995). The regional pattern of BBB opening varies with the convulsive agent (Nitsch et al., 1986; Padou et al., 1995; Ruth, 1984) and with postnatal age (O ¨ ztas et al., 1990; Ziylan and Ates, 1989, 1992). It has been proposed that local relative hypoxia secondary to increased ictal me- tabolism with an increase in local PCO 2 and lactate and systemic increase in blood pressure and decrease in blood pH changes induce a vasodilation resulting in increased local cerebral blood flow (LCBF) and BBB breakdown (Lee and Goldberg, 1977; Lorenzo et al., 1972). Nevertheless, the possible contribution of vasogenic factors to epileptic dam- age remains to be clarified. In this work, we performed the first study on the po- tential role of BBB opening in cellular damage induced by lithium–pilocarpine (Li-Pilo) seizures in adult and 21-day- old (P21) rats. The pilocarpine model associated or not with lithium is a well-studied model of temporal lobe epilepsy, which reproduces most clinical and neuropathological fea- tures of human temporal lobe epilepsy (Cavalheiro, 1995; Turski et al., 1989). The Li-Pilo injection induces an initial * Corresponding author. Fax: +33-390-24-32-48. E-mail address: leroy@neurochem.u-strasbg.fr (C. Leroy). R Available online at www.sciencedirect.com Experimental Neurology 182 (2003) 361–372 www.elsevier.com/locate/yexnr 0014-4886/$ – see front matter © 2003 Elsevier Science (USA). All rights reserved. doi:10.1016/S0014-4886(03)00122-5