Blood brain barrier presentation for PCII.pptx

Blood brain barrier

1. Cerebral Blood Flow-CBF 1

2. CBF----- The brain is supplied by the carotid artery 70 % and vertebral artery 30%. It is usually 50ml/100g/min, or 14% of normal cardiac output It is described by the Ohm equation,   Q = (P a - P v )   /   R,  where (P a - P v )   is the cerebral perfusion pressure (CPP) R  is the cerebral vascular resistance  2

3. CBF------ Cerebral perfusion pressure = MAP - (ICP or CVP) The higher the ICP (or CVP), the lower the CPP, if the MAP remains stable Cerebral resistance (R)    = (8  l η) / πr 4 ,  where l  = length   of the vessel η  = viscosity of the blood r  = radius of the cerebral vessels, which is the main variable susceptible to regulation 3

4. CBF------- Cerebral autoregulation  is a homeostatic process that regulates and maintains CBF constant and matched to cerebral metabolic demand across a range of blood pressures . It is affected by: PaCO 2 :  increased PaCO 2  leads to increased CBF  PaO 2 :   PaO 2  falling below 50 mmHg leads to exponentially increased CBF MAP:  CBF is stable over a range of MAP between 50 and 150 mmHg The brain is a hungry organ, to the extent that some authors have described it as having an  " avaricious appetite “ . 4

5. Central venous pressure P erfusion pressure (the pressure drop across a vascular bed) should be viewed more as the product of flow and resistance. One should not underestimate the role of pressure in producing flow (flow only exists where there is a pressure difference , so pressure is still pretty important). From this, we can surmise that anything that decreases the pressure difference across the circulation will decrease cerebral blood flow. When CVP is higher than ICP, the CVP becomes the major impedance to blood flow through the brain : CPP = MAP - CVP 5

6. Thus, you can achieve a decreased pressure gradient by either lowering the arterial pressure or by increasing the venous pressure. The effects of increasing the CVP from 0 to 30 mmHg will have the same functional effect as decreasing MAP from 60 to 30 mmHg: In both cases the CPP will drop, and cerebral blood flow will decrease and brain suffers from ischemia .. 6

7. Intracranial pressure=ICP ICP  is what  normally  has the effect of impeding blood flow through the brain, because the CVP is usually much lower than the ICP. The normal version of the formula is: CPP = MAP – ICP Though cerebral perfusion pressure is usually described as the driving gradient for cerebral blood flow, it is probably more logical to discuss pressure as the  result  of flow . Pressure is generated when flow is directed into a conduit which resists flow , making resistance the more important factor . 7

8. Autoregulation of cerebral blood flow The brain, like many other tissues, has the ability to control its own vascular resistance through vasoconstriction and vasodilation, thus modulating its own blood flow. It is a purely local mechanism , as far as anybody can tell. Cerebral metabolic demand is the main regulator of regional cerebral blood flow, and this regulation occurs automatically, probably in response to the abundance or deficit of various local factors   This is mainly metabolic byproducts and  metabolic substrates : 8

9. Autoregulation -------- These metabolic products and substrates include: Carbon dioxide pH of the blood Lactate Potassium Low oxygen 9

10. All of these metabolic factors affect the relationship between systemic blood pressure and cerebral blood flow. In other words, when ↑cerebral metabolic demand → (↓substrate levels, ↑metabolite levels), ↑ CBF at any given perfusion pressure because cerebral vascular resistance will decrease →↑CBF 10

11. Conversely, where cerebral metabolic demand is stable and  perfusion pressure  is changing, the same mechanisms ensure that blood flow remains constant and matched to demand. Thus , CBF autoregulation can be defined as : "A homeostatic process that regulates and maintains CBF constant and matched to cerebral metabolic demand across a range of blood pressures." 11

12. ANS control The autonomic neurogenic theory   is based on the finding that the cerebral vessels have rich autonomic innervation, indicating ANS must play a role in cerebral vascular control. This clearly is not the  only  mechanism, as animals seem to be able to autoregulate their CBF  in spite of total autonomic denervation .  12

13. Endothelial mechanisms T hese mechanisms are mainly related to the effects of pressure stretch or shear on cerebrovascular endothelium. The endothelial cells, when harassed in some way, respond by secreting paracrine mediators , thereby producing vasodilation in response to mechanical stress.   E xperiments reveal that removing the endothelium from arteries has the effect of attenuating the vasodilatory response to flow. 13

14. The paracrine signaling molecules responsible for these effects are: Nitric oxide Endothelium-dependent hyperpolarization factor (EDHF ) Eicosanoids Endothelins 14

15. The Blood Brain Barrier (BBB) The BBB is the barrier between the cerebral capillary blood and the interstitial fluid of the brain. It is made up of: Capillary endothelial cells Basement membrane Neuroglial membrane Glial podocytes, i.e., projections of astrocytes. These components work in synchronicity with one another to limit the entry of various substances into T he cerebral blood flow and S ubsequently the brain parenchyma.  15

16. BBB…….. CNS organs are highly unique in structure and function Therefore require a stable environment with a composition that differs from that of the peripheral circulation. For this reason, the BBB exists to maintain a homeostatic environment in which CNS structures can function without disruption from other bodily functions 16

17. Blood–brain barrier------ The brain has a large network of arterial and venous vessels taking  blood  to and from (respectively) brain tissue. However , most of the action occurs at the level of the capillaries . Both the luminal and abluminal (outer surface of the vessel) sides are lined by key structures that contribute to the integrity of the cells. Firstly , squamous  epithelial cells  form the endothelial wall of the capillaries; the luminal surface of these cells comes into contact with circulating blood and its constituents. The abluminal surface is in contact with a circumferentially continuous basement membrane. 17

18. Blood Brain Barrier structure 18

19. Structure of BBB……. Squamous epithelium and basement membrane (simple squamous epithelium in green ) The endothelial cells are anchored to each other by zonula occludens  or tight junctions, as well as zonulae adherens . The former provide structural support to the endothelial wall, while the latter physically connects adjacent cells. Additionally , the tight junctions circumscribe the cells and provide a seal with all adjacent cells. 19

20. Structure of BBB…… Studies conducted on other mammals have implicated   pericytes  as integral components in the formation of the blood-brain barrier. The pericytes encircle endothelial cells of capillaries and are able to contract in order to regulate capillary blood flow. Consequently , the contractility also regulates the amount of blood flowing through the capillaries This enhances the blood-brain barrier. Furthermore , some theories suggest that pericytes not only promote the formation of tight junctions, but they also inhibit the production of chemicals that promote vascular permeability . 20

21. BBB……. Tight junctions exist between the endothelial cells of the BBB, which permit the passage of only a select few types of substances between the cells. O nly substances that are lipid-soluble such as oxygen , carbon dioxide can easily diffuse . Hydrophilic substances, for example, hydrogen and bicarbonate, are not permitted to pass through cells and across the blood-brain barrier. 21

22. BBB……. The capillaries in the CNS are continuous capillaries that lack fenestrations and have a continuous basal lamina . They contain only a few pinocytic vesicles , which distinguishes them from other continuous capillaries of the body This makes them well-suited to make up a selective barrier such as the BBB. The BBB also prevents the entry of toxins and foreign substances from entering the CNS . Transporter Protein Pathway allows glucose , ions , and other special molecules to cross the BBB. Most large molecules and proteins are precluded from entering the barrier. 22

23. Embryology The development of the blood-brain barrier begins with angiogenesis Preexisting vessels, guided by vascular endothelial growth factor (VEGF), It invades a developing neuroectoderm and gives rise to new vessels. 23

24. These new vessels form: Neuroectoderm begin to exhibit many properties of the blood-brain barrier even at early stages As well as expression of tight junctions and nutrient transporters that will later play a role in the selectivity of this physiologic barrier. The early vessels also contain high levels of transcytotic vesicles and exhibit high expression of leukocyte adhesion molecules. 24

25. The barrier properties of the BBB mature as endothelial cells of the perinuclear vascular plexus and Develop tight junctions and associate themselves with endothelial cells in utero between days 11 to 13 of gestation. 25

26. These barrier properties include: The formation of tight junctions Decreased transcytosis Downregulation of leukocyte adhesion molecules Increased expression of efflux transporters in the cellular membrane. The final step in the maturation of the blood-brain barrier is the sealing of inter-endothelial tight junctions 26

27. Physiologic Variants The blood-brain barrier is considered to be weaker in some areas, and thus these areas are more susceptible to changes in levels of metabolites in the blood . Such areas include : The pineal gland that secretes melatonin Neurohypophysis Area postrema , also called the "emetic center" Median eminence of the hypothalamus Subfornical organ Commissural organ Supraoptic nuclei The choroid plexus OVLT (organum vasculosum of the lamina terminalis) 27

28. BBB  regulates the passage of a multitude of large and small molecules into the microenvironment of the brain via : Amino acid transporters G lucose transporter 1 (GLUT1 ) Nucleoside & nucleotide transporters M onocarboxylate transporters (MCT1 and MCT2 ) I on transporters (Na+/K+-ATPase pumps ) 28

29. BBB Function: Summary BBB is a physiological process responsible for modifying the permeability of cerebral capillaries That prevents some materials, such as some drugs, from entering brain tissue Allowing free access of other necessary materials to the brain. The major role of the BBB is to protect the brain from alterations in the concentrations of blood ions, amino acids, peptides, and other elements. 29

30. Summary……. The BBB has an important role in this mechanism, by restricting the unrestricted flow of water and salts from the bloodstream into the cerebral extracellular fluid . The ECF in other bodily tissues is produced by leakage from the capillary, but the BBB secretes brain extracellular fluid at a regulated rate, which is important for maintaining appropriate brain volume. 30

31. Summary……. When the BBB is becoming leaky due to an injury or infection, water and salts enter the brain tissue, causing swelling and thus high pressure inside the skull; this can be fatal. Thus , the BBB is an essential element for the normal working of the brain and protects it from troubles in fluid formation in the rest of the body. 31

32. Materials Transmission across BBB There are several various pathways that exist for transmitting peptides and other molecules to keep brain homeostasis. These include: P aracellular Transcellular diffusion T ransporter protein mediated transcytosis Receptor-mediated transcytosis A dsorptive mediated transcytosis Cell-mediated transcytosis   32

33. Fig. Mechanism of Transport across the BBB 33

34. Paracellular transport Paracellular transport is the transmit of dissolved molecules through an area between two neighboring endothelial cells Just small water-soluble molecules can cross through the paracellular area. Tight junction modifications have been shown to promote paracellular diffusion There are enzymes lining the brain vessels that can degrade undesirable peptides and other tiny substances in the bloodstream as it passes through the cerebral tissue 34

35. Transcellular transport Transcellular transport is the movement of solute substances across the endothelial cell. The small lipid-soluble agents, such as: Oxygen Carbon dioxide Anesthetics Alcohol , are able to be across the BBB through this way. 35

36. Transcellular--- In addition, lipid-soluble substances can cross freely by dissolving themselves in the lipids of the plasma membrane of microvascular endothelial cells. At the same time, there are additional barrier systems to keep the brain against lipid-soluble compounds that are potentially harmful and can permeate directly out of the vascular walls . These barriers are called efflux pumps which attach to molecules and carry them into the bloodstream out of the cerebral tissue 36

37. Transporter Protein Pathway For nutrients to get to the brain, molecules must pass through the BBB such as glucose for energy generation and amino acids for protein production. To make this transportation possible, brain capillaries have native transporter proteins (carriers), which carry these agents from the bloodstream to the cerebral tissue through an active transport mechanism . Moreover , the drug materials also can ride on the transporter proteins in the brain capillaries, and so be more focused on the brain, or use drugs that open the BBB. However , drugs must be altered to suit the structural binding characteristics of the transporter proteins 37

38. Another significant method for delivering drugs over the BBB is to employ cell surface receptors, which is known as receptor-mediated transcytosis (RMT) In this a substance attaches to a receptor and then both combine to create an intracellular vesicle by membrane invagination. These vesicles are separated from the membrane and transported to distinct destinations. Some vesicles return to the apical membrane, while others are guided to the basolateral side, where they join and expel their contents. 38

39. The Cerebrospinal Fluid -CSF Cerebrospinal fluid (CSF) is an ultrafiltrate of plasma contained within the ventricles of the brain and the subarachnoid spaces of the cranium and spine It performs vital functions, including providing nourishment, waste removal, and protection to the brain. Adult CSF volume is estimated to be 150 ml, with a distribution of 125 ml within the subarachnoid spaces and 25 ml within the ventricles. CSF is predominantly secreted by the choroid plexus 39

40. CSF……. In the adult population, its secretion varies between individuals, usually ranging from 400 to 600 ml per day. The constant secretion of CSF contributes to complete CSF renewal four to five times per 24-hour period in the average young adult. The reduction of CSF turnover may contribute to the accumulation of metabolites seen in aging and neurodegenerative diseases. The composition of CSF is strictly regulated, and any variation can be useful for diagnostic purposes. 40

41. Cellular Level Seventy to eighty percent of CSF production is via a network of modified ependymal cells known as the choroid plexus (CP ). The CP is a highly specialized, simple, cuboidal epithelium continuous with ependymal cells lining the ventricles of the brain. 41

42. CSF……. This simple cuboidal epithelium surrounds clusters of fenestrated capillaries allowing for the filtration of plasma . CP cells have dense microvilli present on their apical surface. They are interconnected via tight junctions, creating a blood-CSF barrier that helps control the composition of CSF 42

43. CSF……. As there is no appreciable barrier between the CSF and the extracellular space of the brain (ECSB), the blood-CSF barrier also serves to regulate the environment of the brain . Larger substances such as cells, protein, and glucose are not allowed passage, whereas ions and small molecules such as vitamins and nutrients can pass into the CSF relatively easily. 43

44. CSF……. Water is allowed passage through the CP epithelium via epithelial AQP1 channels. Substances that may not pass through the blood-CSF barrier, but are needed by the brain can be actively synthesized by or actively transported through the CP epithelial cells into the CSF. 44

45. CSF……. A 5-mV lumen positive voltage potential is present across CP epithelial cell membranes. This electrical potential difference pulls sodium, chloride, and bicarbonate ions from the plasma into the CSF, creating an osmotic gradient which then drives the movement of water into the CSF. 45

46. CSF…… When compared to plasma, CSF has a higher concentration of sodium, chloride, and magnesium, but a lower concentration of potassium and calcium. Unlike plasma, CSF has only trace amounts of cells, protein, and immunoglobulins .   46

47. CSF……… No cells can pass through the blood-CSF barrier, although small numbers of white blood cells are usually introduced to the CSF. The normal cell count of CSF is generally lower than 5 cells/ml .   Despite changes in blood composition and flow, the composition of CSF is kept constant, which provides a stable intraventricular environment, critical for maintaining normal neuronal function 47

48. Function CSF assists the brain by providing protection, nourishment, and waste removal.  CSF provides hydromechanical protection of the neuroaxis through two mechanisms.  First , CSF acts as a shock absorber, cushioning the brain against the skull. Second , CSF allows the brain and spinal cord to become buoyant, reducing the effective weight of the brain from its normal 1,500 grams to a much lesser 50 grams. 48

49. Function…….. The reduction in weight lessens the force applied to the brain parenchyma and cerebral vessels during mechanical injury.  Another function of CSF is to maintain homeostasis of the interstitial fluid of the brain. A stable environment for brain parenchyma is imperative for maintaining normal neuronal function.  49

50. Function ……. The major conduit of nutrient supply to the brain is the CP-CSF-ECSB nexus. Substrates needed by the brain are transported from the blood, through the CP, into the CSF, and then diffuse into the ECSB for transportation to their sites of action within the brain.  50

51. Function……. CSF also assists in the removal of: Brain metabolism waste products, such as: Peroxidation products Glycosylated proteins Excess neurotransmitters Debris from the lining of the ventricles Bacteria Viruses Otherwise unnecessary molecules.  51

52. Function….. Accumulation of such unnecessary molecules, seen in aging and some neurodegenerative diseases, interferes with neuronal functioning of the brain. The disruption of cerebral physiology experienced with the disruption of the hydrodynamics or composition of CSF suggests the importance of CSF functioning 52