Blood Brain Barrier= Neuroscience and Pharmacology Flashcards
Major subdivisions of nervous system operate in
different chemical environments
bran and spinal cord chemical environment
-under protect of blood brain barrier which separates CNS from rest of body
Peripheral nervous system chemical environment
- PNS outside blood brain barrier
- activity modulated in pt by fluctuations of chemical environment
Chemical environment ANS and ENS
- changing chemical environment of ANS and ENS contribute to sensory input to CNS
Blood brain barrier limits access of what to CNS
- nutrients, ions, drugs, other chemicals
Choroid plexsus epithelial cells provide
- another barrier and secrete CSF acting as liquid fusion for brain
What gets delivered to brain and taken away from brain by circulatory system
Oxygen, glucose, essential amino acids delivered; CO2 removed
blood to brain
heart -> internal carotid
OR
heart -> vertebral -> basilar artery
-> circle of willis -> larger arteries branch to follow sulci and fissures -> dip into brain tissue
blood draining form brain
collects in sinuses (largest = dorsal sagittal sinus) drains via maxillary vein
Needs of brain
- Oxygen
- Special nutrient needs
- Glucose
- Water
- Gas exchange
- Circulation of blood
brain need for oxygen
brain ischemia of less than 1 min = unconscious; ischemia for a few min= fatal
brain special nutrient needs
- 50kg mammal brain uses equivalent of total energy typical stored in liver as glycogen
- brain glial cells limited capacity to store glycogen
brain under starvation conditions
will slowly adapt to use ketone bodies for energy
what does brain use energy for
maintain active transport of ions (including Na+ and K+ and also H+?) to maintain ionic gradients that allow:
- neurons firing action potentials
- facilitated diffusion for uptake essential amino acids
- facilitated reuptake NT and precursors from synapse
Glucose exchange brain
- uncharged D-glucose enters brain via facilitated diffusion
- CSF glucose level always less than systemic glucose concentration
brain metabolism
-brain has > 90% aerobic nutrient metabolism facilitated by constant perfusion oxygenated blood containing glucose
H20, O2, and CO2 exchange brain
freely diffuse between blood and brain following individual concentration gradient
- H20 uses aquaporin 4 to cross btwn
circulation of blood in brain
- brain 1-2% body mass and gets 15% resting cardiac output
how does brain get rapid delivery of nutrients and drugs
- high perfusion rate and high vascularization contribute to rapid delivery of nutrients and drugs to brain
- perfusion rate maintained near constant 50ml/min/ 100gm tissue when systemic BP varies over lg range
mechanisms playing role in brain perfusion
- Brain metabolism
- Potassium ions and glutamate released from activated neurons
- Neural (ANS) control via symp nerves
brain metabolism role in brain perfision
brain metabolism -> lower pH -> drop PO2 -> vasodilation
potassium ions and glutamate released form activated neurons
stimulate astrocytes to release vasoactive substances -> capillary endothelial cells increasing in luminal diameter
Atrocyte role in capillary diameter
- Glutamatergic neurons release glutamate
- stimulate astrocytes to release vasodilatory factors
- vasodilatory factors secreted by astrocytic end-feet
CNS (brain and spinal cord) contained in what
dura/ meningeal sac
Layers of meningeies forming protective sheath around CNS
- Dura
- Arachnoid layer
- Pia cell layer
Dura mater
Two cell layer around brain:
-fibrous periosteal dura (collagen and elastin) (adheres to cranial bones) is outer layer
- inner menial layer ensheath cr nerves as they pass from skull
- Septa= formed by sheets dura= separate major subdivisions of brain
Spinal Dura Matter:
- Only meningeal layer
Arachnoid layer
Delicate membrane between dura and pia layer
subdural space
between dura and arachnoid membranes (potential space?)
Pial cell layer
- ensheaths brain and spinal cord
- provides some structural support for blood vessels
subarachnoid space
- space between arachnoid membrane and pia
- filled with CSF
- contains larger blood vessels of brain and cistern
what maintain chemical microenvionrment of brain
- blood brain barrier
- near constant CNS microenvionrment
blood brain barrier formed by
- specialized brain capillary endothelial cells
- astrocyte end feet (encircle endothelial cells)
what maintains near constant CNS microenvionrment
choroid plexsus epithelial cells lining brain ventricle
endothelial cells blood brain barrier
- no large fenestrations
- tight junctions
- both in brain capillairies = endothelial cells blood brain barrier?*
Astrocytes blood brain barrier
- glial cells provide second set cell membranes by ensheathing brain capillaries; these = additional cells that must be transferred and second intracellular compartment where cell metabolic process can transform rendering substances
- Glial cells take up and redistribution excess interstitial K+
- Glial cells respond to neurotransmitters released at synapses and communicate local environmental changes to neurons in area of neuropil they envelope
blood brain barrier fx
protect brain from chemical environment of rest of body
Blood brain barrier and transporteres
contains membrane bound transporters to maintain extra cell environment in CNS
- Transporters for essential amino acids and D-glucose
- ATP-dependent active transporters
- Aquaporins to bring water across membrane
ATP-dependent active transporters what does it require and what does it provide
1/5th glucose goes to maintaining activity of ATP-depenedent active transporters:
- Active transport Na+, Ca2+, K+ maintains ion gradient across cell membrane which lets body
- maintain neuronal cell excitability - ATP-dependent H+ ion transporter
- Drive amino acid transport and facilitate re-uptake of neurotransmitters
Glutamate and GABA removal from synaptic cleft and concentration in synaptic vesicles
- removal from synaptic cleft via facilitated diffusion
- concentration in synaptic vesicles via H+ ion gradient established by ATP-dependent H+ ion transported
How do drugs and other substances cross blood brain barrier
common pharmicokinenetic principles and with aid of cellular proteins
what delivers nutrients and drugs to brain
large perfusion area of cerebral vasculature
what easily crosses BBB
- lipophilic drugs
- non-ionized forms drugs
Types cellular protein aids for crossing BBB
Carrier proteins/ ion gradient-dependent facilitated diffusion:
- ex. amino acids and D-glucose
Active transporters
- ex. K+ ions removed from CSF by Na+/K+ ATPase
important factors determining ability of drug to get into CNS
- oil/water partition coefficient (bc high lipophilic cross easily)
- blood pH for some drugs (bc pH governs degree ionization and non-ionized forms drugs cross BBB)
substances that don’t cross blood brain barrier in normal adult mammals
- Albumin
- Globulin
- Transferrin
- IgG
- IgA
- IgM
Where/ When is blood brain barrier more leaky
- Young age (neonates and young animals don’t have fully formed BBB)
- Region of circumventricular organs
- Pathologic BBB leakiness
- Clinician-induced hyperosmotic shock
Region of circumventricular organs
- Hypothalmic region of median eminence and pituitary
2. Area postrema
Area postrema
aka Chemotactic trigger zone or chemoreceptor trigger zone (CTZ or CRTZ)
- this is area where neurons express chemosensory that sample environment of IVth ventricle and transmit info to V+ reflex center in brainstem
pathologic blood brain barrier leakiness occurs with
- infectious dx of meninges
- high fever
- hepatic dxs- high plasma bilirubin
hyperosmotic shock
- clinician induces this to get chemotherapeutic agents to brain by injecting hyper osmotic solution with drug
Cerebrospinal fluid-blood barrier
- choroid plexsus epithelial cells form this and serve barrier and transport fx; these cells= impermeable to plasma proteins and amino acids
- Tight epithelium
Choroid epithelial cells and CSF
regulate fluid volume and ion concentration and allow gas exchange and manufacture CSF
Fxs CSF
- shock-absorber
- provide constant chemical microenvionrment (brain extracellular fluid protects CNS synapses from variable ionic environments of blood)
Choroid plexus tissue
- located in ventricles of brain
- CSF continuously secreted, circulates throughout ventricles and flows along spinal column and throughout spinal canal
- CSF exits ventricles via openings leading to sinuses
CNS pharmacology considerations
- Drugs excluded from BBB bc pharmacokinetics can be used for peripheral nervous system
- Little compartmentalization in brain so drug crossing BBB interacts can interact with all potential receptors
- Neural circuitry complex includes excitatory and inhibitory neurotransmitter signaling in feed-forward and feedback configurations so behavioral responses to CNS drugs hard to predict
