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.