The Blood-Brain Barrier Breakdown During Acute Phase of the Pilocarpine Model of Epilepsy Is Dynamic and Time-Dependent

Abstract

The maintenance of blood-brain barrier (BBB) integrity is essential for providing a suitable environment for nervous tissue function. BBB disruption is involved in many central nervous system diseases, including epilepsy. Evidence demonstrates that BBB breakdown may induce epileptic seizures, and conversely, seizure-induced BBB disruption may cause further epileptic episodes. This study was conducted based on the premise that the impairment of brain tissue during the triggering event may determine the organization and functioning of the brain during epileptogenesis, and that BBB may have a key role in this process. Our purpose was to investigate in rats the relationship between pilocarpine-induced status epilepticus (SE), and BBB integrity by determining the time course of the BBB opening and its subsequent recovery during the acute phase of the pilocarpine model. BBB integrity was assessed by quantitative and morphological methods, using sodium fluorescein and Evans blue (EB) dyes as markers of the increased permeability to micromolecules and macromolecules, respectively. Different time-points of the pilocarpine model were analyzed: 30 min after pilocarpine injection and then 1, 5, and 24 h after the SE onset. Our results show that BBB breakdown is a dynamic phenomenon and time-dependent, i.e., it happens at specific time-points of the acute phase of pilocarpine model of epilepsy, recovering in part its integrity afterwards. Pilocarpine-induced changes on brain tissue initially increases the BBB permeability to micromolecules, and subsequently, around 5 h after SE, the BBB breakdown to macromolecules occurs. After BBB breakdown, EB dye is captured by damaged cells, especially neurons, astrocytes, and oligodendrocytes. Although the BBB permeability to macromolecules is restored 24 h after the start of SE, the leakage of micromolecules persists and the consequences of BBB degradation are widely disseminated in the brain. Our findings reveal the existence of a temporal window of BBB dysfunction in the acute phase of the pilocarpine model that is important for the development of therapeutic strategies that could prevent the epileptogenesis.

Effects of centrifugation and whole-body vibrations on blood–brain barrier permeability in mice

“…We hypothesize that at least 30 min to a couple of hours are required to induce the BBB leakage. 25 Shorter durations as those used in take-off and landing experiments were not sufficient to induce BBB leakage even at high gravity intensity. This mechanism could be related to: (1) impairments of the vestibular and/or sympathetic regulations of cerebral blood flow and cerebrospinal fluid that can alter the tight junctions and their regulations in endothelial cells to reduce the resistance of the BBB via the modification of shear stress induced by adaptation to 2 × g, as proposed on endothelial cell lines 31,32 , or (2) a modification of the ratio between local blood pressure and cerebrospinal fluid, inducing pressure-evoked endothelial cell responses.…”

“…Moreover, if we consider that this leakage is also possible just after 24 h of exposure to 2 × g, we confirm that an alteration of the BBB could be a rapid, localized and reversible process, as recently reported during epileptic seizure. 25 Finally, the BBB leakage induced by gravity changes could be temporary and this question should be addressed.…”

Measurement of the Estradiol Concentration in Cerebrospinal Fluid from Infants and Its Correlation with Serum Estradiol and Exosomal MicroRNA-126-5p

“…We and other investigators reported that seizures can cause temporary BBB leakage. 11,12) This change could affect estradiol transport between the peripheral blood and the central nervous system (CNS), although it is difficult to recruit healthy voluntary infants for the collection of CSFs.…”

Imaging biomarkers of posttraumatic epileptogenesis

“…32 Several hypotheses exist that associate cerebrovascular permeability with epileptogenesis, including asymmetric ion and molecule distribution and other changes to neuronal homeostasis (see Dadas et al 33 for review). [34][35][36] In one model, microvascular dysfunction was evaluated on T1-weighted contrast enhanced and T2-weighted images within 2 days of status epilepticus (SE), an epileptogenic injury that precedes epilepsy development in all animals, and BBB dysfunction in the piriform network was found to be a sensitive and specific predictor of epilepsy (area under the curve [AUC] = 0.96, P < .0001). [34][35][36] In one model, microvascular dysfunction was evaluated on T1-weighted contrast enhanced and T2-weighted images within 2 days of status epilepticus (SE), an epileptogenic injury that precedes epilepsy development in all animals, and BBB dysfunction in the piriform network was found to be a sensitive and specific predictor of epilepsy (area under the curve [AUC] = 0.96, P < .0001).…”

“…BBB pathology and its relationship to emergent epilepsy have been demonstrated in experimental models. [34][35][36] In one model, microvascular dysfunction was evaluated on T1-weighted contrast enhanced and T2-weighted images within 2 days of status epilepticus (SE), an epileptogenic injury that precedes epilepsy development in all animals, and BBB dysfunction in the piriform network was found to be a sensitive and specific predictor of epilepsy (area under the curve [AUC] = 0.96, P < .0001). 20 In addition, structural alterations have been found in hippocampal subfields in a study of lateral fluid percussion injury (LFP): Ipsilateral hippocampal deformation 1 week postinjury acquired from MRI-based large-deformation high-dimensional mapping showed increased lateral regions in rats that developed PTE compared with reduced medial and ventral regions in nonepileptic rats.…”