CSF and the BBB 1/04/10

Blood Brain Barrier
Structure = endothelial cells (most important) and underlying basal lamina, astrocytes, and pericytes. + endothelial cells: brain capillaries have tight junctions and a lack of fenestrations, which limits/prevents bulk movement of fluids into the brain parenchyma (also says lack of pinocytotic vesicles in endo cells contributes, but I’m not sure how). The endothelial cells are what is responsible for the “barrier”. Substances must move across endothelial cell itself to get into brain parenchyma. + Astrocytes have “end feet” that cover the basal lamina, and signal/induce the capillaries (via PDGF) to form the tight junctions (so astrocytes themselves do not fxn as part of the barrier). + Pericytes control growth and repair of endothelial cells, regulate vascular tone, and secrete components of basal lamina. They are also located outside the basal lamina, between astrocyte foot processes and basal lamina. Can also be phagocytic after injury. Function = homeostatic barrier that protects neurons (by restricting access of microorganisms, proteins, cells, drugs/toxins etc, and protects against fluctuations in plasma ion concentrations/serum-borne factors and against unregulated exposure to circulating) neurotransmitters. How/what things get through: in general, the more hydrophobic the easier things pass, the more hydrophilic the harder to get through. Most things fall right along the S-curve (see graph below, work of William Oldendorf experiments) – those that don’t are b/c of transporters, bound to plasma proteins, etc (see examples of specific substances below) :: Substances cross barrier via diffusion, selective transport, or ion channels. + diffusion: O2 and CO2 are lipid soluble and readily diffuse across the BBB + selective transport: glucose, aa’s, vit K & D are water soluble, but have selective transporters that let them cross + ion channels: Na & K pass via ion channels :: specific substances covered during lecture: + Heroin v. Morphine: heroin is slightly more hydrophobic than morphine (morphine has partial dipole, 2 hydroxyl groups), so heroin gets into the brain faster. (Note, while it gets into the brain faster, it has to be reconverted into morphine before it has bio activity) + Dopamine v. L-Dopa: dopamine is more hydrophobic than L-Dopa, but L-Dopa crosses easier b/c it has an aa, and uses a large neutral aa transporter to get in. + Glucose v. Mannitol: glucose crosses the barrier much better than mannitol, despite having similar hydrophobicity. This is b/c glucose has specific transporters (GLUTs) + Phenytoin (dilantin) and phenobarbital: don’t get in quite as well, b/c they are bound to serum albumin (is holding them back) Areas that lack the BBB = Circumventricular organs (are mostly around the 3rd/4th ventricles) = “windows of the brain” 1. Median eminence: where hypothalamic hormones are secreted and enter hypothalamic-pit portal system (on their way to ant. pit) 2. Neurohypophysis (post. pit): where hypothalmic neurons release oxytocin and vasopressin into the systemic circulation 3. Pineal gland: secretes melatonin which is highly charged – wouldn’t be able to get through the BBB 4. Area postrema (near Obex): detects circulating toxins in order to initiate a vomit response (if detects toxins, BBB around would be bad) 5. OVLT (Organum Vasculosum of the Lamina Terminalis): senses bl glucose (and other sugar) levels, acts in controlling hunger and allows more sensitive sensing of sugar levels. Clinical: can utilize BBB for both imaging and therapeutic purposes :: Some pathologies (e.g., cancers) disrupt the BBB. This can be seen on MRI by injecting gadolinium salts, which shows up as a bright image :: Can disrupt the barrier long enough to get hydrophilic molecules (eg methotrexate) across using high concentrations of mannitol injected into the brain arteries

Rather it is the choroid epi cells that form the blood-CSF barrier. which carry the CSF in pinocytic vesicles to the sup sag sinus – the arachnoid villi essentially act as one-way valves for the return of CSF to venous blood + enters the superior sagittal sinus (venous system) :: CSF turns over completely 4-5x/day! Clinical :: what can CSF tell us? Clinically there are 4 features looked for in CSF: 1. Production/Blood-CSF Barrier :: choroid plexus produces CSF. tumor. protecting from concussive (bruise that produces neuro effect) injury :: buffers pH and concentration of ions :: occupies space w/in the cranial vault (so limited expansion of brain tissue). Allows for just a little swelling of brain. vascular space. Normal CSF should have only ~2-5 RBC’s/mm3. so they can’t reabsorb the CSF and it backs up. Usually caused by blood “gumming up” the arachnoid villi. Protein – should NOT cross BBB at all. so obstruction of interventricular foramen of Monro or the cerebral aqueduct. increases in volume of one of these 3 comes at the expense of the others.) + abnormally high WBC’s may indicate immune or autoimmune problem 2. normal level = 2/3 that of serum + abnormally low glucose may indicate bacterial infxn (bacteria metabolize the glucose) 4. Flow :: CSF starts in the choroid plexus :: flows through the system unidirectionally to eventually enter venous blood: + from the lateral ventricles through the interventricular foramen of Monro to the 3rd ventricle + then through the cerebral aqueduct to the 4th ventricle + leaves ventricular system through three foramina: 2 lateral foramina of Luschka (lateral) and 1 foramen of Magendie (medial) + enters subarachnoid space around brain and spinal cord. In general. tumor) which can produce local disruption of BBB) *cytotoxic (ie swelling of neurons (eg rxn to ischemia) + obstruction of CSF flow = hydrocephalus or “water on the brain” * Communicating hydrocephalus: refers to the fact that that the ventricles still have CSF flow between them. flows to the region near the superior sagittal sinus + leaves subarachnoid space through the arachnoid villi (aka arachnoid granulations). * non-communicating hydrocephalus: obstruction that stops flow between ventricles. while normal blood has 20-40K cells! (Color of bl gives info on timing of bleed: If red=fresh blood. . are all in “communication” (no blockage between them). which may mean brain infxn or autoimmune problem 3.Eg Dandy-Walker malformation: blockage at foramina of Luschka and Magendie. abscess + edema: *vasogenic (ie fluid in extracell space outside neurons (like inflammation.CSF and the BBB 1/04/10 CSF = fluid w/in the ventricular and sub-arachnoid spaces of the CNS Functions :: reduce effective weight of the brain (keeps brain from smashing up against skull. Monroe-Kellie Principle = limited volume w/in the cranial vault containing brain tissue. Depending on where the blockage is. Pressure – variety of things can cause increased intracranial P + mass effects: bleeding. congenital malformation where the cerebellum is lodged in the foramen magnum = hydrocephalus in all 4 ventricles Embryology of the ventricular system :: ventricles are simply enlargements of the neurocoele of embryogenesis . get the hydrocephalus upstream. brown/metachromatic (stain w/one color looks like another color)=old blood. Glucose = main source of C metabolized by neurons for ATP production. :: choroid plexus is located in each of the 4 ventricles :: Here cap endo cells are leaky (no tight jxns) just like systemic cells – so they do NOT form bl-CSF barrier. the CSF spaces are the first to collapse. Cells + abnormally high RBC’s may indicate a sub-arachnoid bleed. and CSF. so should see 0 protein in CSF + abnormally high protein may indicate altered capillary permeability (tumor. inflammation) + abnormally high IgG’s suggest presence of plasma cells.

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