Principles 2 Flashcards
what is the function of the BBB
Functions to protect the brain
Maintain homeostasis for the neuronal/glial environment
- CSF: e.g. ion balance, osmolarity etc. for normal neuron function
- facilitate uptake of nutrients (glucose) and hormones (insulin)
- mitigate normal fluctuation in blood (stress hormones, infection)
what is the composition of the BBB
Composition
- Endothelial cells form a wall within the lumen of blood vessels
- Tight junctions connect endothelial cells
-Made of occludins and claudins, contributes to the high electrical
resistance across the BBB.
- Basement membrane made of collagen, laminin, fibronectin
- Prevents the transport of macromolecules
Characteristics of drugs that cross the blood brain barrier?
NOT strictly hydrophilic
- MAY cross if hydrophobic (e.g. nicotine)
- CAN depend on octanol/water partition coefficient
e.g. diphenhydramine (Benadryl or NyQuil) versus loratadine (Claratin)
- NOT subject to efflux transporters like P-Glycoprotein
e.g. Morphine-based opioids versus loperamide (Imodium)
How to get a xenobiotic across the blood brain barrier?
paracellular pathway
transport protein
lipophilic diffusion pathway
receptor medicated transcytosis
adsorptive transcytosis
efflux pumps
How to get a xenobiotic across the blood brain barrier?
(A) Paracellular: temporarily disrupt tight junctions via osmotic shock,
electric fields, focussed ultrasound
(B) Transporter-mediated: mimic endogenous entities like glucose and insulin
(C) Lipophilic diffusion: many brain-penetrant xenobiotics are lipophilic
e.g. ethanol, nicotine, benzodiazepines, opiates
(D) Receptor-mediated transcytosis: receptor-mediated endocytosis from
vascular lumen, transport through the cytoplasm, exocytosis into the brain.
- Target receptors for known molecules (e.g. insulin, low-density lipoprotein)
- Attached xenobiotic to known ligands
(E) Adsorptive-mediated transcytosis: positively-charged substances bind to
negatively-charged endothelial cells membrane
- Involves endocytosis, transport across cytoplasm, and exocytosis.
- Non-specific to the BBB or brain
- Positively-charged cell-penetrating peptides like penetratin and
transportan may be used as xenobiotic carriers
How to get a xenobiotic across the blood brain barrier?
intracerebroventricular
convection enhanced delivery
intracerebral
intranasal
what are the example of GPCRs
Example G-protein coupled receptors (GPCRs)
Glutamate: mGluR1, mGluR5 (Gq)
mGluR2-4, 6-8 (Gi)
GABA: GABAB (Gi)
Muscarinic acetylcholine: m1, m3, m5 (Gq)
m2, m4 (Gi)
Serotonin (5-HT): 5-HT4, 5-HT6, 5-HT7 (Gs)
5-HT 2 (Gq)
5-HT 1, 5-HT5 (Gi)
Dopamine: D 1, D 5 (Gs)
D 2, D 3, D 4 (Gi)
Opiate: 𝞵, 𝞭, 𝞳 (Gi)
explain Ligand-gated ion channels (LGICs)
4-TM family is also known as the Cys-loop receptors
- composed of five subunits
- each subunit has 4 transmembrane domains
- potential for homomeric or heteromeric receptors within each type
- activation opens ion channel; ion selectivity depends on the amino
acid composition within the ion pore
- negative amino acids = selective for cations (Na+, K, Ca2+)
- positive amino acids = selective for anions (Cl- )
4-TM family is also known as ?
4-TM family is also known as the Cys-loop receptors
Example 4-TM LGICs?
Nicotinic acetylcholine: composed of 𝞪 and 𝞫 subunits
homomers and heteromers
excitatory
Serotonin: 5-HT3 receptors: 5-HT3A – 5-HT3E
homomers and heteromers
excitatory
GABA: GABAA: Composed of 𝞪, 𝞫, 𝞬, 𝞭, 𝞮, 𝞹, 𝞱 subunits
heteromers
inhibitory
Glycine: Composed of 𝞪 and 𝞫 subunits
heteromers in brain, homomers in the lab
inhibitory
3-TM family is specific to?
cglutamate
- forms tetramers, usually heteromers, excitatory
examples of 3-TM family
3-TM family is specific to glutamate
- The three types are named for selective agonists
AMPA: - composed of GluA1 – GluA4 subunits
- dimer of dimers: GluA2 plus one of the others
- selective predominantly for Na+ and K+
Kainate: - composed of GluK1 – GluK5 subunits
- may form homomers (GluK1-3) or heteromers
- selective predominantly for Na+ and K+
NMDA: - composed of GluN1, GluN2A-D, and GluN3A-B subunits
- forms heteromers of GluN1 and a GluN2 or GluN3
- selective predominantly for Na+, K+, and Ca2+
