Lecture 6: Function & Dysfunction of the CNS Barriers PDF

Lecture 6: Function & Dysfunction of the CNS Barriers: Introduction: ● Blood brain barrier: controls what’s going in & out the brain as it is an important & sensitive tissue that needs to be protected ● Extensive capillary network 15-20% of CO Brain Circulation: Extensive networks of capillaries: C...

Lecture 6: Function & Dysfunction of the CNS Barriers: Introduction: ● Blood brain barrier: controls what’s going in & out the brain as it is an important & sensitive tissue that needs to be protected ● Extensive capillary network 15-20% of CO Brain Circulation: Extensive networks of capillaries: CSF-ventricular system: ● Supply the neurons & glia with the needed O₂ & nutrients ● Remove CO2 & other waste from the nervous tissue ● Helps provide some nutrients ● Acts as a drainage system for the removal of some waste ● CSF also has a protective function Brain Capillaries: Systemic Capillaries: ● Tight junctions between endothelial cells (CE) = blood-brain barrier (BBB): ○ Separates blood from brain tissue ○ Prevents free exchange between plasma & brain parenchyma = NO starling equilibrium + NO lymphatics ■ Bcz we don’t want the brain to ↑ in size = ↑ ICP ■ CSF replaces lymphatics (provides nutrients + removes wastes) ● RARE pinocytic & transocytic activity ● Gaps in between endothelial cells ● Fenestrations (pores) & starling equilibrium → easy exchange of materials between tissue & plasma ● LOTS of pinocytic & transocytic activity Transport Across BBB: ● There are many transport systems to pass molecules through the BBB, including: ○ Carriers (water soluble molecules; ex: glucose): ■ Lumen of BV ■ Attach to a carrier at Luminal Membrane of endothelial cell (CE) ■ Move across ■ Leave at the Abluminal Membrane of endothelial cell (CE) ○ Channels → small ions & water ○ Membrane transport → lipid soluble molecules ○ Receptor mediated transport → endocytosis/exocytosis; bigger molecules specific to the receptor ○ Adsorption-mediated transcytosis system → attachment due to charge; much bigger molecules ○ Active efflux transporters → to help clean out the environment Tight Junctions as the site of BBB: ● Tight junctions: formed from a branching network of sealing strands; made of proteins (anchor to zona occluding & actin of cytoskeleton of the cell), including: ○ Claudin ○ Occludin ○ Junctional Adhesion Molecules (JAM) Neurovascular Unit (cells functioning together & having cross communication) Endothelial cells: ● Has lots of transporters ● Control gate to entry & exit of substances into and out of NS Astrocytes: ● Have the most abundant glial cells in the NS; found wrapping around the capillaries ● Function: ○ Biochemical support for EC ○ Providing nutrients to nervous tissue (a lot of glucose is stored as glycogen here) ○ Maintenance of extracellular ion balance ○ Role in the repair of damaged CNS ○ Vasodilator (brain function ↑ = ↑ in BF) ○ Cleaning the environment Pericytes: ● Contractile filaments ● Multiple critical functions: ○ Blood flow ■ Actin, myosin, tropomyosin, they can shorten & lengthen → regulating BF ○ BBB permeability ○ Repair of the neurovascular unit Brain Ventricles & CSF: ● Brain has 4 cavities (ventricles) which contain circulating CSF ● Most of CSF is produced by choroid plexus (highly vascularized tissue) ● At the choroid plexus, endothelial cell have gaps between them ● Tight junction is located between choroidal cells, forming the blood-CSF barrier Blood-CSF Barrier: ● Any molecule that gets into the CSF can freely exchange with the brain tissue ● Ependymal layer of ventricle separates CSF from brain tissue ● CSF barrier’s resistance in choroidal epithelial cells is lower than the BBB (Resistance = allowing ions/materials to pass through) CSF Secretion: ● Secretion of any fluid across a membrane needs osmotic effect ● Na movement across the membrane provides the greatest osmotic effect in body fluids ● CSF secretion: ○ First, active energy required ○ Then, gradient of Na & Cl water will follow ● In addition to ionic transporters choroidal membranes also have transporters for glucose, aa, vitamins etc ● Secretion rate ~ 500ml/day ● Total volume ~ 150 ml ● Turnover rate (replacement) = 3.333 times/day (meaning that 3.33 times a day whole CSF is replaced) CSF Composition: ● Component found in the CSF & in plasma have differ concentrations, for example: ○ Osmolality: CSF = plasma → bcz of osmosis (water movement) ○ Proteins: Plasma > CSF → bcz blood-CSF barrier prevents proteins ○ Specific gravity (how heavy it is per gram / same volume): ~ CSF = plasma Brain Barriers Functions: ● BBB & blood-CSF barrier maintain a ↑ controlled constant environment for the brain by restricting: ○ Entry of neurotransmitters ○ Plasma proteins ○ Preventing entry of endogenous & exogenous toxins ● BBB also prevents the escape of nts from their functional sites in the CNS into the general circulation ● Barrier function: ○ Paracellular barrier: Endothelial tight junctions restrict free movement of water soluble compounds ○ Transcellular barrier: ↓ level of endocytosis & transcytosis ○ Enzymatic barrier: Complex set of enzymes degrade diff compounds (so that it doesn’t reach brain) ○ Efflux transporters: Cerebral endothelium express large number of efflux transporters (transport out of the brain) (To regulate the environment of the brain) ● Carrier function: Specific transporters carry water soluble compounds in & out across the barriers BBB vs Peripheral Capillaries: ● 3 main factors when comparing brain & systemic capillaries: ○ Tight junctions as opposed to gaps ○ Lots of transporters very active endothelium as opposed to separating compartments ○ Scarcity of transcytotic activity Functions of CSF: ● Protection/Cushioning of the brain in the cranium: ○ CSF have similar specific gravity as brain tissue so the brain floats in the CSF ○ The weight of the brain is ↓ 30x ● Supply brain tissue with some nutrients (ex: vitamins) ○ Some substances are delivered into CSF from blood, they gain access into brain tissue via CSF ● Sink action of CSF: ○ Acts as a “sink” for various extracellular materials in brain tissue ○ Waste material in interstitial fluid enters CSF into the ventricles & enters venous circulation ● Provide a route for movement of substances from brain to blood: ○ CSF drainage into sinus blood through the arachnoid villi (pressure of CSF > sinuses) CSF Production and Drainage: ● Produced mainly by choroidal cells ● CSF production creates a gradient of Na & Cl → produces an osmotic effect resulting in H2O secretion into the ventricles. ● CSF circulates around the ventricles & drains into venous blood via arachnoid villi ● Villi acts like a one way valve which allows CSF movement into blood only ● CSF moves into venous blood when CSF pressure is 1.5 mmHg or > venous blood pressure CSF Flow: ● Pressure difference makes CSF circulate ● Pressure is made by production of CSF (↑ production = ↑ flow) ○ Ventricles don’t expand when production ↑ → pressure ↑ → CSF circulates ● Lateral ventricle makes the most CSF Glymphatic System (relatively new): ● System of bv that carry wastes that clump together & turn toxic if left in place ● Protein fragments (b-amyloid peptides) present in Alzheimer’s disease are cleared through this drainage system mostly during sleep (to help clean/renew the interstitial fluid) ● Incoming fluid: ○ CSF (from subarachnoid space) travels through periarterial space propelled by pulsating artery (provides pressure to move fluid) → enters through tiny channels into astrocytes → then out of astrocytes & into brain tissue ● Outgoing waste: ○ Fluid picks up waste moves to perivenous space then moves to larger & larger veins until enters lymphatics in the neck & eventually into circulation BBB Disruption: ● BBB disruption causes edema & excess fluid in the brain parenchyma ● BBB can be broken by: ○ HTN ○ Hyperosmolarity ○ Radiation ○ Infection ○ Trauma ○ Ischemia ○ Inflammation ● Vasogenic edema: Breakdown of BBB permits the movement of plasma proteins into the brain tissue, so water is obligated to follow & accumulates within the extracellular space → ↑ brain volume → ↑ ICP Drug Delivery to the CNS ● Drugs penetrate the BBB to varying degrees, ex: nonionized (lipid-soluble) drugs cross more readily than ionized (water-soluble) drugs ○ Inflammation, irradiation & tumors may destroy the BBB & permit entry into the brain of substances that are usually excluded (ex: antibiotics, radiolabeled markers) Invasive (very effective): Non-invasive: ● Intracerebral ● Intrathecal → in SC (usually for chronic pain) ● BBB opening → by using hyperosmolar mannitol (usually mannitol doesn’t pass thru but high concentration can shrink (?) cells & open BBB →§ leaves the brain very susceptible) ● ● ● ● ● ● ● Drug conjugates Nanoparticles Exosomes Liposomes Peptide carriers Receptor mediated Others: ○ Intranasal (through olfactory & trigeminal nerve) Hydrocephalus: ● Excess water in the cranial vault ● Results from blockage of CSF flow ● 2 types: Communicating hydrocephalus ● Ventricles are still communicating: blockage is at the level of subarachnoid space or at the arachnoid villi. Non-communicating hydrocephalus: ● Blockage is at the ducts communicating between the ventricles ● Such as the blockage of the aqueduct of Sylvius. Lumbar Puncture ● Very invasive and a last resort ● CSF sample provides a lot of info ● The position in which lumbar puncture is usually performed in a subject