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One of the most important complications of TBI is edema, which occurs more frequently in the pediatric than in the adult population. This is possibly due to the higher water content of the developing brain and also to the mechanism of regulation of water homeostasis. The Badault group has recently evaluated the contribution of the aquaporins to the post-traumatic edema process in juvenile rats and mice Badaut et al. Pups treated with an inhibitor of aquaporin-4, siGLO siAQP4, show acute improvements in motor function 3 days after injury and long-term improvements in spatial memory 60 days after injury when compared with control animals.
These improvements are associated with decreased edema formation, increased microglial activation, decreased BBB disruption, and reduced astrogliosis and neuronal death. Thus, aquaporin's seems to be molecules significantly involved in post-TBI damage, and represent an interesting therapeutic target Fukuda et al. Another study has revealed that the inhibition of a kinase involved in the development of brain edema, myosin light-chain kinase, by the administration of an inhibitor, ML-7, to P24 mice starting 4 h after TBI and every 24 h until sacrifice, significantly reduces BBB breakdown and the development of cerebral edema, and preserves neurological function Rossi et al.
Neuroinflammation is a key pathological factor in most insults to the developing brain Degos et al. Neuroinflammation is induced by the invasion of pathogens or the release of damage-associated proteins by injured and dying cells. There is an increased expression of endothelial adhesion molecules such as vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and the selectins Simi et al.
Inflammatory processes are, moreover, associated with modifications of the molecular composition or functional state of TJs Coisne and Engelhardt, Proinflammatory cytokines also influence the expression of MMPs, which increase BBB permeability by degrading TJs and extracellular matrix components in the endothelial basement membrane Rosenberg, These events lead to barrier leakiness, which in turn allows pathogen and immune cell invasion Labus et al.
Resident microglia are some of the first cells to respond to inflammatory stimuli. In the case of TBI and hypoxia-ischemia, mast cells also produce large quantities of proinflammatory mediators Biran et al. With regard to the BBB, these cytokines lead to increased permeability and facilitate the entry of peripheral macrophages and cytokines from the systemic circulation. In the instance of inflammation following hypoxic-ischemic injury, this has the effect of exacerbating the excitotoxic cascade by further stimulating glutamate release and free radical and NO production McLean and Ferriero, The importance of the mast cell response in causing brain damage after TBI is supported by post-insult treatment with cromoglycate, a mast cell stabilizer that inhibits mast cell degranulation and decreases BBB opening Strbian et al.
Leukocyte migration depends on strict interactions with the vascular endothelium, mediated by 3 groups of adhesion molecules: the selectins, the immunoglobulin superfamily such as intercellular adhesion molecule 1 and the integrins. A comparative study in P7 and adult rats subjected to transient middle cerebral artery occlusion shows that Evans Blue extravasation, a measure of paracellular diffusion, the main method of entry for bulky proteins and leukocytes into the brain, remains low during the 24 h period following reperfusion in neonatal rats but is profoundly increased in adult rats. The largely unaltered paracellular diffusion in neonatal rats is associated with the increased expression of several TJ proteins Vexler and Yenari, rather than with the decrease in their expression seen in adult rats after a similar injury.
In contrast to stroke in adults, in P7 hypoxic-ischemic brains, the transmigration of neutrophils is far lower Hudome et al. This may be related to the greater resistance of the BBB to hypoxia-ischemia-induced leaks at this age but also to the immaturity of both endothelial cells, which express less P-selectin Lorant et al.
The lower extent of leukocyte extravasation after ischemic injury in neonatal rats may contribute to the age difference in the structural and functional changes to the BBB after ischemia. Specific studies have been carried out to examine the effects of inflammation on the functions of the developing BBB and how this influences the development of brain injury. A rather complex and unexpected effect of inflammatory stimuli on BBB integrity and leukocyte transmigration has been reported during the first 3 weeks of life in rats. These data demonstrate that at birth, the BBB is functional, and is in fact more resistant to inflammatory stress than in the juvenile brain.
Stolp et al. They have demonstrated for the first time a possible link between changes in BBB permeability evaluated by permeability to sucrose, inulin and plasma proteins and Cld-5 distribution and behavioral alterations in animals exposed to the inflammatory stimulus early in development, i. LPS treatment resulted in increased permeability only in adulthood, preceded by Cld-5 alterations in a few vessels at an earlier time point. However, due to the normally low permeability of cerebral blood vessels, it is probable that even a few vessels with altered permeability could significantly contribute to the overall properties of the BBB, and that these changes could explain the short-term changes seen in behavioral tests, in particular in the prepulse inhibition paradigm, that were distinguishable in juvenile animals but not in adult animals.
A third study from the same group analyzes, in a similar model using the opossum Monodelphis domestica , the ability of minocycline, a potent anti-inflammatory molecule, to modulate the inflammation-induced changes in BBB permeability and white matter damage following acute and prolonged inflammation during development. Interestingly minocycline significantly reduced this augmentation. Thus, the inclusion of minocycline probably did not prevent barrier permeability changes after a single LPS injection but prevented barrier permeability to proteins and 14 C-sucrose when administered during prolonged inflammation.
We have carried out further studies of the BBB in a model in which inflammation alone induces WMD, by the twice-daily i. We evaluated modifications in the expression of the most important choroid plexus TJ proteins at P2, the second day of injections, and 5 days after the beginning of the injections Favrais et al. Our results demonstrate that there is no significant non-specific disruption of BCSFB integrity, as assessed by paracellular permeability to tracers, and only a modest increase in Cld-3 expression in the choroidal tissue.
In adult animal models of inflammation, the choroid plexus is known to be extremely sensitive to peripheral inflammatory stimuli, as demonstrated by the augmentation of cytokines and other inflammatory markers Quan et al. Thus, studies on the choroid plexus conducted in the context of moderate systemic perinatal inflammation occurring during a period approximating 28—35 weeks of gestation in humans, which alters the developmental program of the white matter, should focus more on the perturbation of specialized functions of the BCSFB, such as neuroimmune regulation, rather than on gross non-specific alterations of barrier integrity.
Inflammation, vascular reactivity and excitotoxicity are the main protagonists of perinatal diseases, and the BBB and NVU are certainly majorly implicated in these processes. As our knowledge of these processes increases, promising new targets for neuroprotection have been found.
However, a lot of questions remain open, especially regarding differences between the behavior of young and adult brains. Funding research on the BBB, both in the pre-clinical and clinical domains, should be encouraged in order to better understand early cerebral development and develop effective therapeutic strategies. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
A special thanks to Dr. S Rasika for her priceless proofreading and critical editing of the manuscript. Aden, U. Brain Behav. Agarwal, R. Potential role of cerebral glutathione in the maintenance of blood-brain barrier integrity in rat.
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