The blood-brain barrier (BBB) plays a vital role in regulating the trafficking of fluid, solutes and cells at the blood-brain interface and maintaining the homeostatic microenvironment of the CNS. Under pathological conditions, such as ischemic stroke, the BBB can be disrupted, followed by the extravasation of blood components into the brain and compromise of normal neuronal function. This article reviews recent advances in our knowledge of the mechanisms underlying BBB dysfunction and recovery after ischemic stroke. CNS cells in the neurovascular unit, as well as blood-borne peripheral cells constantly modulate the BBB and influence its breakdown and repair after ischemic stroke. The involvement of stroke risk factors and comorbid conditions further complicate the pathogenesis of neurovascular injury by predisposing the BBB to anatomical and functional changes that can exacerbate BBB dysfunction. Emphasis is also given to the process of long-term structural and functional restoration of the BBB after ischemic injury. With the development of novel research tools, future research on the BBB is likely to reveal promising potential therapeutic targets for protecting the BBB and improving patient outcome after ischemic stroke.
The relative impermeability of the blood-brain barrier (BBB) results from tight junctions and efflux transport systems limits drug delivery to the central nervous system (CNS), and thus severely restricts the therapy of many central nervous system diseases. In order to enhance the brain-specific drug delivery, we employed a 12-mer phage display peptide library to isolate peptides that could target the drug delivery system to the brain. A 12-amino-acid-peptide (denoted as Pep TGN) which was displayed by bacteriophage Clone 12-2 was finally selected by rounds of in vivo screening. Pep TGN was covalently conjugated onto the surface of poly (ethyleneglycol)-poly (lactic-co-glycolic acid) (PEG-PLGA) based nanoparticles (NPs). The cellular uptake of Pep TGN decorated nanoparticles was significantly higher than that of unmodified nanoparticles when incubated with bEnd.3 cells. Enhanced brain accumulation efficiency together with lower accumulation in liver and spleen was observed in the nude mice intravenously injected with Pep TGN conjugated nanoparticles compared with those injected with plain nanoparticles, showing powerful brain selectivity of Pep TGN. Coumarin 6 was used as a fluorescent probe for the evaluation of brain delivery properties. The brain Drug Targeting Index (DTI) of coumarin 6 incorporated in targeted nanoparticles was significantly higher than that of coumarin 6 incorporated in plain nanoparticles. In conclusion, the Pep TGN is a motif never been reported before and Pep TGN modified nanoparticles showed great potential in targeted drug delivery across the blood brain barrier.
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