血脑屏障(英文版)-课件

Structure and function of the bloodbrain barrierNeurobiology of Disease 2017.9.20ABSTRACTNeural signalling requires a highly controlled microenvironment Cells at three key interfaces form barriers BBB major site of bloodCNS exchange bloodCSF barrier the arachnoid barrier the physical barrier the endothelial tight junctions the transport barrier membrane transporters and vesicular mechanisms.astrocytic glial cells endfeet The associated cells pericytes microglia The embryonic development of the BBB,and changes in pathology Any programme for drug discovery or delivery,to target or avoid the CNS,needs to consider the special features of the BBB.1.Introduction 2.BBB tight junctions3.Transport across the BBB4.Development of the bloodbrain 5.Bloodbrain barrier in pathology6.Bloodbrain barrier regulation 1.Introduction 1.1 Signalling in the central nervous system chemical Neurons Communication electrical signals local ioni Barrier layers play a major role in this regulation 1.2 CNS barriers microvessels the blood cerebrospinal fluid barrier the avascular arachnoid epithelium the largest interface for bloodbrain exchange the seal between the extracellular fluids of the central nervous system and that of the rest of the body the epithelial cells of the choroid plexus1.3.Functions of CNS barriers 1.3.1 Ion regulation The BBB provide a combination of specific ion channels and transporterskeeps the ionic composition optimal for synaptic signalling function Ca2+Mg2+and pH are actively regulated at the BBB and BCSFB 1.3.2 NeurotransmittersBBB helps to keep the central and peripheral transmitter pools separate and communicate with each other.Glutamate released in an uncontrolled manner stroke considerable and permanent neurischemic otoxic/neuroexcitatory damage 1.3.3 Macromolecules prevents macromolecules from entering the brain Neuroproteceive Plasma proteins damaging to nervous tissue lead to apoptosis a higher concentration in CSF than in plasma may be a protective measure against micro-leaks prevent allow plasma components to seep into the brain1.3.4 NeurotoxinsThe BBB shields the CNS from neurotoxic substances *endogenous metabolites *Proteins *xenobiotics ingested in the diet or from the environment 1.3.5 Brain nutrition The BBB has low passive permeability Specific transport systems therefore are expressed in the BBB to ensure an adequate supply of these substances essential watersoluble nutrients metabolites2.BBB tight junctions tight junctions(a key feature of the BBB)reduce permeation of polar solutes through paracellular diffusional pathways The junctional complexesadherens junctions(AJs)TJsAjs holding the cells together giving the tissue structural support disruption barrier a further complex of proteins(occludin and claudins)and junctional adhesion molecules(JAMs)disruptionThe tight junctionsTJs In EAE and GBM selective of claudin-3 loss of BBB integrity permeability are associated with inflammatory events at the BBB lack claudin-5 a severely compromised and leaky bloodbrain barrier die shortly after birth TJs is not solely related to the expression and presence of claudins and occludin,but is also influenced by the way these proteins are organized and interact The tight junctions are responsible for the severe restriction of the paracellular diffusional pathway between the endothelial cells to ions and other polar solutes,and effectively block penetration of macromolecules Induction and maintenance of bloodbrain barrier properties astrocytes Tight junction can be induced barrier induction involves multiple agents and cell typesinduction by pericytes,neurons and cells of monocyte lineage has also been described 3.Transport across the BBB 3.1 Passive partitioning into brain A wide range of lipid-soluble molecules can diffuse though the BBB and enter the brain passively.Factors restrict the entry of compounds into theCNS*polar surface area(PSA)*rotatable bonds in the molecule and a molecular weight in excess of 450 Da*A high affinity of binding to plasma proteins with a low off-rate These factors are not always an absolute indication These factors are not always an absolute indication3.2 Solute carriers in the BBB The barrier isolates the brain from many essential polar nutrients the BBB endothelium must contain a number of specific solute carrier to supply the CNS with these substances.Most polar molecules cannot diffuse through cell membranes express SLCs in the cell membrane 3.3 ATP-binding cassette transporters a large number of solutes and drugs have a much lower CNS entry rate than might be expected from their logD increasing the lipid solubility of a drug to make it more brain penetrant may sometimes be counter-productive increase the likelihood of the molecule becoming a substrate for ABC efflux transporters The major function of the ABC transporters in the BBB pumps consuming ATP transporting a diverse range of lipid-soluble compounds removing from the brain potentially neurotoxic endogenous or xenobiotic molecule neuroprotective and detoxifying function 3.4 BBB transport of macromolecules specific and some non-specific transcytoticmechanisms transport large molecules and complexes across the BBB.These vesicular mechanisms receptor-mediated transcytosis(RMT)adsorptive-mediated transcytosis(AMT).RMT receptors and their bound ligand cluster caveolus Internalised Dissociation of the ligand/receptor presumably occurs during cellular transit or during the exocytotic event AMT requires an excess positive charge interaction with cell surface binding sites induces endocytosis and subsequent transcytosis 3.5 Cell movement across the BBB*Cells from the bone-marrow derived monocyte lineage enter the brain during embryonic development and become resident immunologically-competent microglia *In inflammation and pathological states Perivascular macrophages and microglia activated the tight junctions opened cytokines and other agents,and mononuclear cells enter 4.Development of the bloodbrain barrier The BBB develops(fetal life and is well formed by birth)In the mouse identifiable tight junctions are present(E11 E17)ion regulation may continue to mature and only become fully expressed and functional in the peri-or post-natal period Wnt/beta-catenin signalling controls development ofthe bloodbrain barrier The high electrical resistance,characteristic of the bloodbrain barrier exhibited in the BBB of rats by E21 an effective barrier to the movement of ions Tight junction formation appears to be a very early feature of BBB development and be initiated by signals from neurons and progenitor cells rather than from differentiated glia in the first instance.5.Bloodbrain barrier in pathology *BBB dysfunction a growing list of CNS pathologies changes in transport systems and enzymescan *Microglial activation an early sign of CNS inflammation *In most cases it is not possible to determine whether barrier compromise is causal in disease onset,but developing pathology barrier disturbance can often be seen to contribute to and exacerbat developing pathology 6.Bloodbrain barrier regulation BBB is a dynamic system capable of responding to local changes and requirements,and able to be regulated via a number of mechanisms and cell types,in both physiologyand pathological conditions.Such regulation includes changes in tight junction function,and in expression and activity of many transporters and enzymes.Thank You！