IC4 Introduction to Neuropharmacology

Question 1

What is the function of Astrocytes?

Answer 1

• Protective
• Provides tropic support
• Electrolyte balance
  Astrocytes have their own membrane potential

Question 2

What is the difference in function between Oligodendrocytes & Schwann cells?

Answer 2

Oligodendrocytes form the myelin sheath of brain neurons while Schwann cells form them for PNS neurons

Question 3

Why is the RMP -70 mV?

Answer 3

1. Selective permeability where K+ > Cl-&raquo_space;> Na+
2. Sodium potassium pump

Question 4

How does active conduction of action potential occur in unmyelinated vs myelinated neurons?

Answer 4

Unmyelinated
Multiple Na+ channels in close proximity (slower)

Myelinated
Saltatory conduction using myelin sheath and Nodes of Ranvier (faster)

Question 5

How are neurotransmitters released for synaptic transmission?

Answer 5

• Neurotransmitter-containing vesicles are normally anchored to the cytoskeleton away from presynaptic membrane (active zone) by Ca2+ sensitive vesicle membrane proteins (VAMPs)
• When action potential reaches the terminal, voltage-gated Ca2+ channels open, allowing Ca2+ influx
• Ca2+ influx acts on VAMPS to release the vesicles from cytoskeleton & facilitates vesicle docking to presynapse, fusion with presynaptic membrane & exocytosis

Question 6

How is neurotransmitter release regulated?

Answer 6

Presynaptic autoreceptors (e.g. M2 muscarinic receptors) are activated together with postsynaptic receptors → inhibit further transmitter release via feedback inhibition

Question 7

How is a signal propagated & terminated?

Answer 7

• Neurotransmitters in the synaptic cleft activates postsynaptic receptors (GPCRs & ion channels) → signal reaches the receiving neuron)
• Signal is terminated by catalytic enzymes &/or reuptake transporters

Question 8

List 4 common neurotransmitters

Answer 8

1. Glutamate
2. GABA
3. Acetylcholine
4. Dopamine

Question 9

_____ is a major transmitter in excitatory synapses & are found in ______. They are implicated in ______

Answer 9

Glutamate
Pyramidal neurons in the neocortex
Learning & memory

Question 10

_____ is a major transmitter in inhibitory synapses & its receptors are important drug targets for ______. Give an example of such a drug

Answer 10

GABA
Sedatives
Benzodiazepines

Question 11

Where are Acetylcholines from & what are they implicated in?

Answer 11

Arise from nucleus basalis of Meynert
Involved in learning, arousal & reward

Question 12

A major source of Dopamine is ______ & are involved in?

Answer 12

Substantia nigra (in midbrain)
Motor system & reward

Dopamine is a member of monoamine family which includes noradrenaline, adrenaline, serotonin

Question 13

What is the difference in excitatory vs inhibitory synapse in terms of their relation with postsynaptic depolarisation / signalling?

Answer 13

Excitatory
Presynaptic neurotransmitter release e.g. glutamate directly correlates with postsynaptic depolarisation/signalling

Inhibitory
Presynaptic neurotransmitter release e.g. GABA inversely correlates with postsynaptic depolarisation/signalling

Question 14

What is the blood-brain barrier?

Answer 14

• Isolates nervous system from the blood, providing it with a stable & chemically optimal environment for neuronal function
• Neurons & neuroglia are bathed in brain extracellular fluid (ECF), which accounts for15% of total brain volume

Question 15

What are the functions of the blood-brain barrier?

Answer 15

Modulates entry of metabolic substrates
Glucose is a fundamental source of energy for neurons
Glucose levels in the brain ECF is more stable than that of the blood

Controls ion movements
Na+–K+ ATPase in the barrier cells pumps sodium into the CSF & potassium out of the CSF into the blood

Prevents CNS access to toxins, & peripheral neurotransmitters from escaping into the bloodstream from autonomic nerve endings

Question 16

Transmembrane diffusion across BBB is the mechanism of transport for most drugs with (A) & (B)

However, what happens when (B) is too high?

Answer 16

A: Low MW
B: High lipid solubility

However, when lipid solubility is too high, they will be sequestered in the capillary bed or be taken up by peripheral tissues

Question 17

What affects BBB penetration by transmembrane diffusion?

Answer 17

1. MW (inversely related to BBB penetration → <500 Da according to Lipinski’s Rule of Five)
2. Charge
3. Tertiary structure
4. Degree of protein binding
5. P-glycoprotein (efflux transporters ie ↓uptake of drugs)
   “Overexpressors” vs. “under-expressors” limit the rate of uptake by BBB

Question 18

Which method of transport across BBB is saturable, & which is non-saturable?

Answer 18

Saturable
Transporter systems

Non-saturable
Transmembrane diffusion

Question 19

How does the rate of uptake across BBB via transporter systems compare to transmembrane diffusion?

Answer 19

10x more than transmembrane diffusion

Question 20

What regulates the rate of uptake by transporter systems across BBB?

Answer 20

1. Cerebral blood flow
2. Co-factors
3. Hormones / peptide modulators

Question 21

State 3 general drug strategies for transport across BBB & briefly explain what the strategy entails

Answer 21

Target transporters
(Trojan Horse strategy by coupling a substance which does not cross the BBB to one which does) 🐴

Analogs of Transported ligands
Designing analogs that retain affinity to BOTH BBB transporters & CNS target receptor, while improving peripheral PK (but development of such drugs have been slow)

BBB itself as a therapeutic target
(ie taking advantage of BBB)
1. Stimulate luminal receptors of endothelial cells to synthesize desired CNS substances (e.g. neurotransmitters, cytokines)
2. Bypass BBB in disease states like infection (During breakdown, porous capillary walls will allow entry of non–lipid-soluble antibiotics)

Question 22

What are the advantages & disadvantages of the Target Transporters strategy used for drug transport across BBB?

Answer 22

Advantage
Improved peripheral PK due to avoidance of peripheral catalytic enzymes & clearance mechanisms

Disadvantage
Hybrid molecule may not be recognized by original transporter & ends up being routed to lysosome