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42 Cards in this Set

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Why a BBB?
The CNS is a “privileged” area which needs to be protected at all costs!! - Sensitive to ions, receptors, etc.

Large molecules and even small charged molecules are generally excluded from passing from the vascular lumen to the CNS tissue.
Brain Capillary - Tight Junctions
Tight junctions of overlapping capillary endothelial cells provide protection.
General VS Brain Capillary
There are no clefts or fenestras in the brain capillary. The brain capillary has many mitochondria due to energy needed for transport processes.
CNS- Vascular Endothelial
have little transcytotic activity – lack both fluid-phase (pinocytosis) and receptor-mediated endocytosis.

Contain specific transporters for glucose, amino acids, vitamins, metals, nucleosides.

Catabolic enzymes – neurotransmitters and peptidases.
Transporters of the BBB
Glucose, Amino Acids, NA-K ATPase, L-DOPA, Multiple Drug Resistance
Glucose transporter of BBB
GLUT-1

glucose transporter isotype-1
Glucose transported down its concentration gradient
Amino Acids as transporters of BBB
3 carrier systems:

A System
ASC System
L System
A System
Glycine and neutral AA with short linear side chains
Alanine or serine
Energy dependent, Na+dependent
ASC System
ASC system is energy-dependent and Na+-dependent
Transports alanine, serine and cysteine
Located at the abluminal endothelial cell surface
L System
L system is Na+-independent
large neutral AA with branched or ringed side chains (leucine and valine)
AA are transported down their concentration gradient
L-DOPA as transporter of BBB
The precursor for dopamine
Systemically administered
Treat Parkinson disease
Na,K-ATPase
Removal of K+ that accumulate in brain in response to intense neuronal activity
Multiple Drug Resistant - MDR
Protects brain from circulating neurotoxins
Cancer chemotherapy delivery
Other therapeutic purposes
Experimental Inhibitors of Transporters
L system:
2-aminobicycloheptane-2-carboxylic acid (BCH)

A system:
a-methylaminoisobutyric acid (MeAIB)
BBB - Disruption
Tumors – lack BBB

Hypertension – opens BBB

Ischemic events (stroke)

Head injury - must be very serious
BBB - Circumvent
Direct injection – emergent needs

Injection of hypertonic solutions (glucose, mannose, sucrose, urea, etc) – shrink cells

Bradykinin analogues – pulls cells apart
Enhanced lipid solubility – pro drug approach

Chemical delivery systems
Circumventricular Organs
Areas within the CNS that lack a BBB

Median eminence – hormone/ANS regulation
Organum vasculosum of the lamina terminalis – BP
Subfornical organ –water balance/BP
Subcommissural organ – BP
Area postrema – Ralph!
BLOOD/CSF BARRIER
The lining of the ventricles and central canal of the spinal cord is called the ependyma.

The ependyma lining have special cells called tanycytes that form tight junction.

These tight junctions prevent the entry of molecules from the blood supply of the circumventricular organs from entering the CSF.
Absorption of CSF
arachnoid villi functions as a one-way valve and blood/CSF barrier

Special cells on arachnoid villi to protect the CSF from blood in the dura venous sinuses
4 barriers
BBB

Blood /CSF barrier
Choroid plexus
Circumventricular organs
Arachnoid villi
Meninges
Connective tissue sheaths
Comprised of three membraneous layers from the inner surface of the skull and vertebral column

1. Dura Mater
2. Arachnoid Mater
3. Pia Mater

Brain and spinal cord tissue
Dura mater
Dense firm layer consisting of collagenous connective tissue

The internal surfaces of the bones enclosing the cranial cavity are clothed by periosteum

The cranial dura mater is attached to the periosteum where it receives blood supply

The veins draining the brain empty into the venous sinuses of the dura mater and then into the internal jugular veins.
Arachnoid Mater
collagenous and elastic fibers

both sides covered in squamous epithelial cells

avascular
Pia Mater
connective tissue- collagenous and elastic fibers

external surface covered in squamous epithelial cells

contains fine blood vessels

covers all surfaces of the brain and spinal cord
Meninges - Function
Protective - these three layers protect the soft delicate underlying neural tissue from the hard surfaces of the skull and vertebral column
Brain Ventricles
The ventricles are "fluid-filled" spaces in the brain where the cerebrospinal fluid (CSF) is produced and circulates.
CSF - function
Cushioning of CNS structures.

Dispersion of nutrients/mode of communication between various brain regions.

Removal of CNS metabolic wastes.
CSF - production
CSF is produced by the Choroid Plexus –
specialized highly vascularized epithelial structures found on the inner lining of all brain cerebral ventricles.

Enriched with Na,K-ATPase and other transporters
CSF – production rate
Ventricular/Arachnoid Volume: 100-150mL

Production Rate: 400-500mL/day

Turnover rate: 3-4 times
Absorption of CSF
Pressure dependent
normal pressure of 80 mm H2O – 150 mm H2O

arachnoid villi
functions as a one-way valve projecting into the dura venous sinuses
into the venous blood
CSF vs. Plasma
Water %, osmolarity, and pH are very similiar. Plasma has much, much higher amounts of protein, and has higher levels of glucose.
Meningitis
Inflammation of the meningeal layers -
Pial and arachnoid layers most often affected

Two types: viral and bacterial

Route of entry: ears or nasal sinuses or vascular system
Meningitis - Symptoms
headache
neck stiffness
fever
nausea/vomiting
photophobia
lethargy
Viral meningitis
CSF
Lymphocytes
increase in protein (moderate)
sugar content (normal)

presents following other viral disorders (mumps, West Nile, Epstein-Barr etc).

prognosis is good… let it run its course.

antiviral therapy minimizes symptoms in some patients
Bacterial meningitis
Poorer prognosis than viral meningitis

20% mortality that is helped by rapid antibiotic therapy
Penicillins and cephalosporins are current therapeutic choices

Incidence is lower than viral meningitis
3 types of bacterial meningitis
Neisseria meningitidis – (meningococcal meningitis)
Most infectious form

Haemophilus influenzae – (type b)

Streptococcus pneumoniae – (pneumococcal meningitis)
CSF- pathology indicator
Any elevation in CSF protein concentration is also an indication of possible pathological conditions.

alteration in vascular permeability
meningeal or ventricular compression via tumor


obstruction of the CSF flow and in intracranial pressure
Hydrocephalus
Increase Ventricular volume of CSF
3 causes:

decreased absorption
overproduction
obstruction

usually associated with an increase in intracranial pressure.
Oversecretion of CSF
Choroid Plexus tumor

Rare event… treatable… tricky… but treatable!
Communicating Hydrocephalus
Impaired Absorption of CSF – “clogged” arachnoid villi

any increase in venous pressure
subarachnoid hemorrhage
post-meningitis state

Each state can be characterized by causing an increase in CSF protein content which would subsequently block or
clog the major route of CSF absorption – arachnoid villi
Communicating Hydrocephalus
Normal Pressure Hydrocephalus –

increase in ventricular volume, normal ICP
unknown etiology
difficult to diagnose – dementia, incontinence, motor errors

treat with ventricular shunts (atrial or peritoneal)
Noncommunicating Hydrocephalus
Obstruction of CSF Flow:

obstruction in ventricular system, brain tumors, congenital malformations

Malformations in children.

Aqueduct of Silvius/cerebral aqueduct… most likely area of tumor location.

narrowing of ventricular/subarachnoid interface. (Dandy-Walker Syndrome)