BLOOD BRAIN BARRIER PHYSIOLOGY

About 500 mL

Amount of CSF formed per day by the cells of the choroid plexus

. Lateral, third, and fourth ventricles

Locations of the choroid plexus where CSF is formed

. Ventricles and the subarachnoid space

Locations CSF flows into after formation

. Aquaporin-4 water channels in the astrocytic foot processes

Structures via which CSF disperses in the brain parenchyma

. Interstitial fluid

Substance CSF mixes with after dispersion

. Radical oxygen species

Substance collected by CSF mixing with interstitial fluid

. Perivenous spaces

Location where CSF accumulates after mixing with interstitial fluid

. Cervical and meningeal lymphatics

Structures via which CSF is drained out

. Increase in fluid dispersion via perivenous spaces

Observation about fluid dynamics during sleep

. Cleanses the brain and repairs damages

Proposed functions of CSF during sleep

. Sleep is essential for the maintenance of the brain’s integrity

Notion supported by findings of increased glymphatic activity during sleep

. Brain glymphatic system

Name for the lymphatic system in the brain, anchored on the perivenous spaces

. Increased fluid dispersion

Characteristic of the active phase of the glymphatic system

. Decreased fluid dispersion and decreased cleansing of the interstitial space

Effect observed if astrocytes are damaged by stroke, aging, or Alzheimer's disease

. Maintenance of the homeostasis of the brain parenchyma

Main function of the blood-brain barrier

. Brain nutrition (in regulating glucose and oxygen)

A function of the BBB in maintaining brain homeostasis

. Maintenance of ionic homeostasis

A function of the BBB in maintaining brain homeostasis

. Regulate the levels of neurotransmitters

A function of the BBB in maintaining brain homeostasis

. Limit the leak of plasma macromolecules into the brain

A function of the BBB in maintaining brain homeostasis

. Protect the brain against neurotoxins

A function of the BBB in maintaining brain homeostasis

. Passive Diffusion

Mechanism by which small lipophilic molecules can enter the brain across the luminal and abluminal cell membranes

. Molecular weight, Molecular charge, Lipid Solubility

Three main factors affecting cell membrane permeability for passive diffusion

. 400 Daltons

Molecular weight limit for passive diffusion across the BBB

. 8 H+ Ions

Limit for molecular charge; molecules with more than this cannot easily cross the BBB

. Increase in free energy of hydrogen ions

Reason why molecules with more than 8 H+ ions cannot easily cross the BBB

. Oil-water partition coefficient

Factor that blood brain barrier permeability is dependent on for lipid solubility

. Diazepam, Nicotine, Ethanol, Heroin

Examples of highly lipid-soluble drugs/chemicals that can easily cross the BBB

. Methotrexate, Sodium, Mannitol, Penicillin, Dopamine, Morphine

Examples of drugs/chemicals that cannot pass through the BBB

. Ion (water) channels

Structures through which water molecules can easily cross the BBB

. Largely impermeable

Characteristic of the BBB regarding most ions like calcium and magnesium

. Na/H exchanger

Ion/water transporter found on the luminal membrane

. Cl/HCO3 exchanger

Ion/water transporter found on both the luminal and abluminal membranes

. Na/K ATPase pump

ATP needing ion/water transporter found on the abluminal side

. GLUT1 Transporter

Protein that transports glucose molecules to the brain for metabolism

. Monocarboxylic (MCT) Transporter

Protein that transports ketone bodies to the brain when in a fasting state

. L-System

Protein transporter for leucine

. A-System

Protein transporter for alanine

. ASC-System

Protein transporter for other proteins besides leucine and alanine

. P-glycoprotein

An ATP-dependent efflux transporter located at the BBB that helps in drug delivery and protects brain parenchyma

. Active

State of P-glycoprotein where drugs are maintained inside the vascular space, protecting brain meninges and decreasing permeability

. Inactive/Off

State of P-glycoprotein where the brain parenchyma is exposed to chemicals, increasing permeability

. MDR transporter

An efflux pump system that acts as a barrier by pumping out chemicals that crossed the BBB

. Chemotherapeutic agents

Example of substances pumped out by MDR transporters

. Double edged sword

Description of the BBB, as it protects the brain but also prevents delivery of some drugs

. Meningitis, brain tumors, Parkinson’s, and Alzheimer’s disease

Examples of diseases that are difficult to treat due to the BBB

. Become more prone to other diseases

Consequence of not having the BBB

. COVID-19

Pathogen mentioned as having been shown to cross or disrupt the blood-brain barrier

. Drug delivery

Clinical application impacted by the BBB, as it can impede the delivery of important drugs

. Dementia and Parkinson’s disease

Examples of diseases for which chemotherapeutics have delivery issues due to the BBB

. Dexamethasone

Anti-inflammatory drug that decreases vascular resistance, thereby increasing BBB permeability

. Ultrasound

Method used to open tight junctions to facilitate transport of medications across the BBB

. Transporters or proteins (e.g., Insulin and transferrin)

Methods utilizing biological mechanisms to transport needed medications to the brain

. High lipid solubility

Characteristic of first-generation antihistamines that allows them to easily cross the BBB, causing sedation

. Diphenhydramine

Example of a first-generation antihistamine

. Lower lipid solubility

Characteristic of second-generation antihistamines that prevents them from crossing the BBB as easily, resulting in less/non-sedation

. Immature neurovascular unit

Result often seen in brain tumors

. Tight junctions between endothelial cells become less effective

Effect of an immature neurovascular unit in brain tumors

. Increased permeability ("leaky" blood-brain barrier)

Consequence of less effective tight junctions in brain tumors

. Fluids and substances from the tumor can leak into the brain parenchyma

Result of increased permeability in brain tumors

. Finger-like projections

Appearance created by tumor leakage into the brain parenchyma

. Bypassing the BBB

Strategy often involved in medication delivery for brain tumors

. Intraventricular drug delivery

Method of administering drugs directly into the ventricular system to bypass the BBB

. Lumbar puncture to subarachnoid space

Example of how to reach the ventricular system for intraventricular drug delivery

. Utilize proteins as transporters

Strategy used by new dementia drugs to overcome the BBB

. Choroid plexus

Structure that produces CSF by filtering blood plasma

. Area postrema

Circumventricular organ that detects toxins and triggers vomiting

. Astrocytic foot processes

Structure that regulates blood flow according to neuronal needs, and damage here compromises neurovascular coupling

. Cerebral aqueduct

Most likely site of obstruction causing hydrocephalus when CSF flow is blocked between the third and fourth ventricles

. Blood-brain barrier becomes more permeable

Reason drug delivery is often enhanced in brain tumors

. Diencephalon

Embryologic origin of the third ventricle

. Aquaporin-4

Channel necessary for glymphatic clearance, a deficiency in which would impair this cleaning function

.