Blood brain barrier

blood brain barrier, Anatomy of blood brain barrier, function, Tight junction, Pericytes, Location of BBB, Circumventricular organs, Normal BBB transport, PATHOLOGIC CHANGES IN THE BLOOD-BRAIN BARRIER, BBB and Brain Tumors, Epilepsy and BBB, Pharmacological Measures to Overcome Blood-Brain Barrier Blood, Pharmacological Measures to Overcome Blood-Brain Barrier

1. Blood Brain Barrier DEPARTMENT OF NEUROSURGERY DR. HARDIK PATEL MCH NEUROSURGERY

2. Blood-brain barrier (BBB) is the ability of brain to restrict movement of certain substances into and out of brain. It mediates a complex system of exchange, transport, and clearance. It ensures adequate concentration of essential compounds such as oxygen and glucose and at the same time protects the brain from toxic substances in the peripheral circulation

3. Anatomy of blood brain barrier The blood-brain barrier (BBB), an important component of the neurovascular unit. made of specialized endothelial cells. basement membrane. neuroglial structures: astrocytes, pericytes, and microglia. Neurons.

4. Characteristics of endothelial layer of BBB Structural: • Absence of fenestrations • More extensive tight junctions. Functional: • Impermeable to most substances • Sparse pinocytic vesicular transport • Increased expression of transport and carrier proteins: receptor mediated endocytosis • No gap junctions, only tight junctions • Limited paracellular and transcellular transport receptors for numerous hormones and neurotransmitters Differentiation of the endothelium into a barrier layer begins during embryonic angiogenesis and in the adult is largely maintained by a close inductive association especially the end feet of astrocytic glial cells.

5. Tight junction Claudins make up the backbone of the tight junction strands, form dimers, and bind homotypically to claudins on adjacent cells to produce the primary seal of the tight junction Occludin functions as a dynamic regulatory protein whose presence at the BBB is correlated with increased transendothelial electrical resistance and decreased paracellular permeability Junctional adhesion molecules (JAMs ) are localized at the tight junction and, in association with platelet endothelial cellular adhesion molecule-1 (PECAM), regulate leukocyte migration across the BBB Adherens junctions are located near the basolateral side of the endothelial cells and are not specific for cerebral endothelial junctions. Several accessory proteins also contribute to its structural support, such as zona occludens-1 (ZO-1) to ZO-3, cingulin, and 7H6.

6. Pericytes Pericytes with smooth muscle- like properties that reside adjacent to capillaries Cover 22-32% of endothelium regulation of endothelium proliferation , angiogenesis & inflammatory processes Regulate BBB specific gene expression patterns in endothelial cells Induce polarisation of astrocyte end feet surrounding CNS blood vessels In the absence of pericytes, There will be abnormal vasculogenesis , endothelial hyperplasia and INCREASED permeability in the brain

7. Characteristics of Astrocytic foot processes the star shaped astrocytic foot processes Ensheath >95% of the abluminal vessel surface Do not directly produce a permeability barrier, they may provide the signals which induce the endothelial cells to form the BBB work cooperatively with the endothelial cells to regulate the cerebrospinal fluid (CSF) potassium concentration

8. Location of BBB All over CNS including brain, spinal cord and peripheral nerves, except Circumventricular organs:- Posterior pituitary, median eminence, organum vasculosum of the lamina terminalis (OVLT), subfornical organs, area postrema and pineal gland. the CVO permeable capillaries are the point of bidirectional blood–brain communication for neuroendocrine function In these areas the capillary endothelial cells are fenestrated and have incomplete tight junctions, permitting molecules to pass

9. Sensory CVOs enable rapid detection of circulating signals in systemic blood Area postrema "Vomiting center ": when a toxic substance enters the bloodstream it will get to the area postrema and may induce vomiting. Subfornical organ chemoreceptive area monitoring blood angiotensin II level Important for the regulation of body fluids. Vascular organ of the lamina terminalis A chemosensory area that detects peptides and other molecules.

10.  Secretory CVOs facilitate transport of brain-derived signals into the circulating blood. Pineal body Secretes melatonin and neuroactive peptides. Associated with circadian rhythms. Neurohypophysis (posterior pituitary) Releases neurohormones like oxytocin and vasopressin Median eminence Regulates anterior pituitary through release of neurohormones.

11. Normal BBB transport 1.Paracellular aqueous diffusion . Small water-soluble molecules are able to pass through this extracellular pathway, which is regulated by TJs. 2. Transcellular lipophilic diffusion. Substances cross the BBB at a rate proportional to their molecular weight and lipid solubility.

12. 3. Adsorptive transcytosis. This endocytotic process is mediated by clathrin -coated pits and, to a lesser extent, caveolae. It is generally selective for cationic molecules and is the predominant mechanism for passage of HIV-1 into the brain. This process is being investigated as a possible pathway for therapeutic drug delivery to the CNS. 4. Saturable transport A Receptor-mediated transcytosis is the transport of solutes through receptor-binding and subsequent endocytosis. This can occur against a concentration gradient but requires energy. B. Channel-mediated transport is a saturable mode of transit that mediates influx and efflux via transport proteins. Eflux pupms P- gycoprotien

13. FUNCTIONS OF BBB Ion regulation Stable environment for neural function combination of specific ion channels and transporters keeps the ionic composition optimal for synaptic signalling function. concentration of [K+] in plasma is approximately 4.5 mM, but in CSF and brain ISF –> ∼2.5–2.9 mM, in spite of changes that can occur in plasma [K+] following exercise or a meal, imposed experimentally, or resulting from pathology Ca2+, Mg2+ and pH are also actively regulated at the BBB Water traverses the plasma membranes by facilitated diffusion through water channels called aquaporins The primary water channel in the CNS is AQP4 , which is predominately expressed by astrocyte

14. Neurotransmitters Blood plasma contains high levels of the neuroexcitatory amino acid glutamate which fluctuate significantly after the ingestion of food. If glutamate is released into the brain ISF in an uncontrolled manner, as for example from hypoxic neurons during ischemic stroke, considerable and permanent neurotoxic/neuroexcitatory damage can occur to neural tissue. Since the central and peripheral nervous systems use many of the same neurotransmitters, the BBB also helps to keep the central and peripheral transmitter pools separate.

15. Macromolecules BBB prevents many macromolecules from entering the brain. The protein content of CSF is much lower than that of plasma Plasma proteins such as albumin, pro-thrombin and plasminogen are damaging to nervous tissue, causing cellular activation which can lead to apoptosis Thrombin and plasmin if present in brain ISF can initiate cascades resulting in seizures, glial activation, glial cell division and scarring, and cell death Leakage of these large molecular weight serum proteins into brain across a damaged BBB can have serious pathological consequences.

16. Neurotoxins Protective barrier which shields the CNS from neurotoxic substances circulating in the blood. Neurotoxins may be endogenous metabolites or proteins, ingested in the diet or otherwise acquired from the environment. A number of Energy-dependent efflux transporters (ATP-binding cassette transporters) actively pump many of these agents out of the brain .

17. Brain nutrition low passive permeability to many essential water- soluble nutrients and metabolites required by nervous tissue. Glucose GLUT-1(glucose transpoter 1) is a 45- to 55-kD protein, depending on its glycosylation state. It is present in high concentration in the ECs of arterioles, venules, and capillaries and facilitates movement of glucose from the peripheral circulation to the brain Function of GLUT-1altered with processes such as hypoglycemia , diabetes, epilepsy, trauma, and tumors

18. PATHOLOGIC CHANGES IN THE BLOOD-BRAIN BARRIER Many factors that regulate permeability under normal conditions are altered during pathologic conditions and result in enhanced vascular permeability and edema formation Trauma Following traumatic brain injury, the BBB is known to disrupt, leading to focal edema and altered extracellular composition. Within 6–48 hours post injury, microglial activation within injured location. Diffuse axonal injury, identified within the neocortex, hippocampus, and thalamus, suggests immune cell responses within diffusely injured brain loci uncomplicated by contusion. It has been suggested that BBB disruption following brain injury increases the risk for long term disability, development of brain dysfunction, epileptic seizures and neuroanatomical alterations Neuroinflammation after TBI has been shown to induce autoantibodies against CNS proteins

19. BBB and Brain Tumors Affect BBB permeability in at least two ways: directly, through invasion or mechanical interference, indirectly, by the production of diffusible molecules that are able to act at a distance from tumor cells. Meningiomas and brain metastases do not contain the astrocytes and do not have a true BBB. The capillary endothelium within brain tumors has sometimes been named the “blood-brain tumor barrier”. The tumor capillaries are surrounded by large collagen-filled extracellular spaces with gaps in the basal lamina and absence of glial processes. In primary brain tumors , the abnormal capillaries are found in the more malignant tumors and have cellular fenestrations, wide junctions, pinocytotic vesicles and infolding of luminal surfaces.

20. Capillary permeability in gliomas is regionally variable, and can be 10–30 times that of the normal brain. Malignant gliomas, actively degrade tight junctions by secreting soluble factors, eventually leading to BBB disruption within invaded brain tissue. Vascular endothelial growth factor (VEGF) appears to be involved in tumorigenesis, neovascularization, and edema production. VEGF is a mitogen for endothelial cells and has extremely potent effects on microvascular permeability. vasogenic cerebral edema of tumor effects on brain metabolism and functions is primarily due to alterations in the neuronal environment, collapse of microvessels by edema fluid, tissue hypoxia and the cellular effect of the extravasating serum proteins. The metastatic tumors have capillary properties similar to that of the derivative tissue. These changes form the basis of higher uptake of isotopes and contrast media. Radiotherapy can also alter BBB; changes may be seen many years after exposure.

21. BBB in CNS infection The integrity BBB is compromised and leukocyte infiltration occurs in infection. The leukocytes pass through BBB and there is some derangement of the glucose transport. Contrast enhancement in CT and MRI scans is due to BBB breakdown. When treatment becomes effective, BBB returns to normal.

22. Epilepsy and BBB Acute rise in blood pressure and blood flow that follows a seizure is associated with increase in the number and volume of pinocytic vesicles of the brain capillaries with deranged tight cell junctions are responsible for increased movement of normally excluded substances. BBB is restored in about 1 hour. Reduction of blood pressure, steroids and pentobarbitones appear to protect and restore BBB. Delayed neurodegeneration and functional impairment occur following the development of the epileptic focus in the BBB permeable cerebral cortex

23. Other factor and BBB Like hypertension, hypoxic ischemia, hypercapnia or increased serum osmolarity alters BBB. GLUT1 deficiency syndrome is a rare condition caused by inadequate transport of glucose across the barrier, resulting in mental retardation and other neurological problems.

24. Clinical applications Restoration of Blood-Brain Barrier Corticosteroids are thought to decrease the permeability of CNS capillaries, thereby protecting BBB function, and reversing the effect of influences acting to disrupt the BBB in brain tumors . Antioxidants such as lipoic acid may be able to stabilize a weakening BBB. Lipoic acid affects cellular migration into the CNS and stabilizes BBB integrity.

25. Pharmacological Measures to Overcome Blood-Brain Barrier Blood brain barrier is the single most important obstacle for effective dose delivery of chemotherapeutic agents when given by intravenous route. Pharmacologically, the drugs are administered in solvents such as ethanol or dimethyl sulfoxide (DMSO) the dose of solvent is such that the BBB obstacle may be overcome by administration of the drug/solvent mixture

26. Disruption of Blood-Brain Barrier and therapeutic implications blood- tumor barrier limits adequate delivery of antitumor agents to tumor and the immediately adjacent brain Systemic toxicity has usually been the dose limiting factor in brain tumor chemotherapy. Goal of BBB disruption is maximizing delivery of agents to the brain while preserving neurocognitive function and quality of life, and minimizing systemic toxicity.

27. Osmotic shock by injecting a hyperosmotic agent (mannitol) to the brain to deliver therapeutics. involves administering hyperosmolar mannitol intra-arterially in the carotid or the vertebral arteries. The infusion of mannitol causes osmotic shrinkage of capillary endothelial cells, with resultant separation of the tight junctions between the cells. There is only a 25% increase in permeability within the actual tumor tissue Circumventing the Blood-Brain Barrier Intrathecal therapy is invasive and confined to only three agents: methotrexate, cytosine arabinoside, thiotepa . Side effects include aseptic meningitis, chemotherapy-related leukoencephalopathy.

28. Convection-Enhanced Delivery chemotherapy is infused into the brain tumor under constant pressure to deliver drug by bulk flow through catheters placed into the tumor bed Local Delivery of Polymer-Infused Chemotherapy A craniotomy must be performed to implant the drug wafers into the tumor resection cavity.

29. BBB properties that shield the brain from deleterious agents are the same properties that prevent drugs from treating disease. Thank you.