Neurological Disorders Flashcards
What are COMT inhibitors
A class of drug which inhibits the action of COMT, the enzyme involved in the degradation of levodopa.
They can help control symptoms between doses of L-DOPA and reduce the amount of L-DOPA needed.
What are anticholinergics
a class of drug which block the action of acetylcholine
True or false: neurons in the brain secrete their own serotonin.
true
What is the cheng-prusoff equation used for
The IC50 value is converted to an absolute inhibition constant Ki using the Cheng-Prusoff equation
Explain the steps of autophagy
- Cytosolic material is sequestered by an expanding membrane sac, the phagophore,
- Formation of a double-membrane vesicle, an autophagosome
- The outer membrane of the autophagosome subsequently fuses with a lysosome,
- Inner single membrane of the autophagosome exposed to lysosomal hydrolases
- The cargo-containing membrane compartment is then lysed
- Contents are degraded
What is pKi
The negative log of the Ki value (inhibition constant)
symptoms of alzheimer’s
- loss of memory, cognitive ability, communication
- changes in mood and personality
- forgetting recent events, unable to store new information in the temporal lobe
What receptor activation inhibits noradrenaline release
presynaptic adrenergic receptors
where specifically is dopamine most abundant
corpus striatum
what is siRNA
Small interfering RNA, is the most commonly used RNA interference tool for silencing protein coding genes short-term; it induces genetic knock-down, of a variety of cell lines.
What is an IC50
The concentration of competing ligand which displaces 50% of the specific binding of the radioligand
What are the two strands of siRNA
anti-sense guide strand, and a sense strand
True or false: serotonin can cross the blood brain barrier
false
Explain the steps of apoptosis- extrinsic pathways
- Fas ligand binds to death receptors
- Protein recruitment and from death-inducing signalling complex (DISC)
- Activates caspase-8 initiator
- Activates caspase 3/7 executioner
what is the equation for radioligand equilibrium
kon = koff
What are MAO inhibitors
a class of drug which inhibit the activity of one, or both monoamine oxidases; both MAOs deaminate the neurotransmitter dopamine
What is L-DOPA
An anabolite for dopamine.
It can can cross the blood brain barrier and forms dopamine in the presence of DOPA decarboxylase
True or false: Deep brain stimulation destroys small sections of the patient brain, so is not reversible
False
why is L-DOPA used to treat parkinson’s
Dopmaine is hydrophilic so cant cross BBB
L-DOPA is take peripherally and can then cross the BBB where is it converted to dopamine
describe the nigrostriatal pathway
key dopamine pathway
cell body in the substantia nigra, moves up to corpus striatum
Involved in the production of movement, as part of the basal ganglia motor loop
What effect des Gs have
stimulate adenylyl cyclase to produce cAMP, increasing intracellular calcium among other cAMP mediated processes.
What is a radioligand binding assay
used to characterize the binding of a drug to its target receptor.
They can provide information on both the affinity and mode of interaction of the drug with its receptor.
true or false: Ki is an absolute value
true
Describe the tuberohypophyseal pathway
Dopamine release in this pathway is to inhibit prolactin release
How do Selective serotonin reuptake inhibitors work
increase the extracellular level of serotonin available for binding to the post-synaptic receptor
What are present to reduce likelihood of proteopathy
Chaperones- by avoiding the conformational change to beta-sheet structure.
symptoms of huntington’s
cognitive disorders - impulse control, task organisation. flexibilty, learning
movement disorder - involuntary jerking. twitching movements, rigidity, speech
How is dopamine broken down
broken down by homovanillic acid via DOPAC and 3MT
What is deep brain stimulation
A neurostimulator is implanted into the patient’s brain- subthalamic nucleus or Globus pallidus interna.
When switched on, the internal electrodes deliver high frequency stimulation to the targeted area, changing electrical signals which cause symptoms of diseases such as Parkinson’s.
What are anticholinergics used for
help to block involuntary muscle movements associated with disease, or in surgery to maintain body functions under anaesthetic
what is the precursor of noradrenaline
dopamine
What is the precursor of dopamine
tyrosine
what is huntingdons’ disease
progressive neurodegeneration reduces lifespan (15-20yrs)
What are antipsychotic drugs
These utilise the 4 dopaminergic pathways to reduce dopamine levels
How can the availability of dopamine be increased in the brain
L-dopa , and DDC inhibitors that do not pass the BBB, such as carbidopa can increase its avaliability
what type of molecules CAN cross the BBB
hydrophobic/non-lipophilic molecules
What conditions are high dopamine associated with
paranoia or Schizophrenia
Where is most serotonin found
in the raphe region, of the pons and upper brainstem
What is a proteopathy
protein misfolding causing disease
Describe the mesolimbic pathway
VTA –> Limbic system
What neurotransmitter does cocaine modulate
dopamine
what is MAO-B used for
used in the treatment of depression and parkinson’s
prevent the breakdown of dopamine
how does siRNA elicit gene silencing
siRNA are transfected into cells, and the activated protein and nucleic acid complex binds to a single target mRNA sequence.
Transmission of inherited genetic disorders with increased severity is called what
Anticipation
70% of dopamine is found in which of the 4 pathways
Nigro-striatal
What is noradrenaline
A post-ganglionic sympathetic neurotransmitter, and adrenoceptor agonist.
Why are MAO inhibitors used to treat parkinson’s
by specifically targeting MAO-B. This prevents the dopamine catabolism associated with disease.
They can also block mAChR and inhibit glutaminergic NMDA receptors.
true or false: focused ultrasound is non-invasive but irreversible
true
What can tag histone proteins (epigenetic markers)
methyl, acetyl, ubiquitin, phosphate, and other biochemical groups.
What is the cheese reaction
monoamine oxidase (MAO) effectively prevents dietary pressor amines, from entering the tissues.
So a hypertensive response can occur when subjects treated with MAO inhibitors ingest foods or beverages rich in such amines.
What are epigenetic markers
Non-hereditary changes to the histone code or to any molecules other than the DNA itself, which include methylation of DNA and covalent modification of histone proteins
What effect does Gi have
block the activity of adenylyl cyclase.
what is the use of COMT
prevents L-DOPA being broken down into another dopamine precursor
define bradykinesia
suppression of voluntary movement
Which part of the pain control system does serotonin affect
the descending pain-control system
Where is noradrenaline predominantly found in the brain
locus coeruleus, in the pons
What is focused ultrasound
focuses beams of ultrasonic energy on targets deep within the brain, without damaging surrounding normal tissue.
It can temporarily open the blood-brain barrier, to improve delivery of genes, growth factors, stem cells, other drugs
What is radioligand binding
Ligand and receptor remain bound for a length of time, dependent on the affinity of the drug for the receptor.
What is dopamine
catecholaminergic neurotransmitter
True or false: Some toxic mis-folds can interact with other native copies of the same protein and catalyse their conversion into the toxic state
true
What is serotonin
A neurotransmitter derived from tryptophan
What G protein uses D1 and D5
Gs
what happens when misfolded or toxic proteins are identified?
They are tagged with ubiquitin and sent to the proteasome for degradation
What G protein uses D2, 3 and 4
Gi
What is the precursor to serotonin
tryptophan
what proteins are proteopathies most likely to occur in
proteins containing repetitive amino acid motifs such as poly-glutamine (in Huntingdon Disease).
What conditions are low dopamine associated with
Parkinson’s
Explain the steps of apoptosis- intrinsic pathways
- Cytotoxic stress
- Translocation of pro-apoptotic Bcl-2 family to mitochondria
- Mitochondrial cytochrome C released
- Oligomerisation of pro-apoptotic factor Apaf-1, forms apoptosome
- Recruits caspase 9, which activates caspase 3
what is alzheimer’s
progressive neurodegeneration
most common cause of dementia
Where does epigenetic modification normally occur
N terminus of histone tails
describe the mesocortical pathway
starts in VTA
through forebrain up to the cortex
Why is L-DOPA often prescribed with a peripheral DOPA decarboxylase inhibitor (DCC)
It can also be converted to dopamine in the periphery- bad.
By increasing the concentration gradient between the brain and periphery, more dopamine becomes available in the brain.
State the 5 dopaminergic receptors
D1, D2, D3, D4, and D5.
Explain the steps of dopamine synthesis + release
- tyrosine is converted to DOPA
- DOPA is converted to dopamine in cytoplasm
- Dopamine transported into storage vesicles
- dopamine released into synaptic cleft
- dopamine reuptaken
- any remaining dopamine is destroyed by MAO or COMT
what is the blood brain barrier
Several distinct barriers operating in parallel to restrict and regulate the passage of materials between the peripheral and cerebrospinal compartments
What is an Ki
The inhibition constant for a drug
the concentration of competing ligand in a competition assay which would occupy 50% of the receptors if no radioligand were present.
What is chaperone-mediated autophagy
chaperone complex delivers specific substrate proteins to lysosomes.
The substrate polypeptides are then translocated one by one through the lysosomal membrane protein and digested in the lysosomal lumen.
