L2: Drug Treatment of Motor Disorders

Question 1

what mediators do microglia release when activated?

Answer 1

NO-, COX-2, O2-

Question 2

give examples of what activates microglia

Answer 2

Beta-amyloid plaques, stroke, TBI, infection, pollutants, genetic factors

Question 3

what is associated with parkinson’s disease (symptoms)

Answer 3

increasing disability of movement

Question 4

mean age of onset of PD

Answer 4

55 years

Question 5

what % of PD is genetic/familial

Answer 5

10%

Question 6

what is the autosomal dominant genotype of PD

Answer 6

Mutation in the alpha-synuclein protein that plays a role in synaptic vesicle trafficking and neurotransmitter release

Question 7

monkey’s exposed to what produces symptoms like PD?

Answer 7

MPTP - an opioid analgesic

Question 8

describe the pathway involved in PD (Normal vs PD)

Answer 8

normal: DA neurons in the substantia nigra normal inhibit GABAergic output in the striatum and cholinergic neurons exert an excitatory effect.
In PD: loss of DA neurons, no impact on cholinergic neurons, hyperactivity of cholinergic neurons causes excitotoxicity which contributes to the symptomology of PD

Question 9

describe the autosomal recessive PD

Answer 9

Mutations in parkin, PINK1, DJ01 gene

Question 10

describe atropine

Answer 10

atropine is a muscarinic receptor antagonist which aims to antagonise cholinergic receptors to account for the loss of DA neurons.

Question 11

side effects of atropine

Answer 11

dry mouth, constipation, urinary retention

Question 12

describe L-dopa

Answer 12

precursor of DA that can cross BBB, does not stop progressive loss of DA neurons in SN, rec. for older patients as it only works for around 10 years

Question 13

what drugs can atropine be given with to improve PD-like symptoms?

Answer 13

antipsychotics

Question 14

what drugs should be used in earlier onset PD

Answer 14

not L-dopa, DA-R antagonists, anticholinergics, deep brain stimulation, monoamine oxidase inhibitors, amantadine

Question 15

describe the gene mutation associated with Huntingtin’s Disease

Answer 15

CAG repeats (35+) causing an N terminal polyQ (glutamate) tail on the Huntingtin protein

Question 16

what loss of neurons is associated with HDD

Answer 16

Selective loss of neurons projecting from the efferent branch of the striatum of the basal ganglia, death of neurons also seen in globus pallidus and cerebral cortex

Question 17

what is disease severity of HD directly linked to?

Answer 17

the length of the PolyQ tail at the N terminal of the Htt protein

Question 18

is there more loss in the cholinergic or GABAergic neurons in HD?

Answer 18

More neuron loss in GABAergic, some loss in cholinergic

Question 19

how does DA output normally affect GABAergic output, how is this impacted in HD

Answer 19

normally DA inhibits the GABAergic output from the striatum. the loss of GABAergic neurons puts this off balance, more DA in the synapse, more movement, hyperkinesia (symptom of HD)

Question 20

how is the change in DA levels described in HD and how does this impact symptoms

Answer 20

the change in DA levels is biphasic and moves from high levels of DA causing hyperkinetic stage and then decreased DA as HD progresses causes hypokinetic stage of disease

Question 21

name the drug that treats chorea, a hyperkinetic disorder similar to HD

Answer 21

Tetrabenazine

Question 22

what does tetrabenazine inhibit

Answer 22

VMAT-2 is inibited by tetrabenazine and this promotes monoamine degradation, ie promotes DA degradation

Question 23

how does deutetrabenazine differ from tetrabenazine

Answer 23

it is a different isotope of hydrogen

Question 24

what receptors do all Anti-psychotics block? where might this be useful in treating motor disorders

Answer 24

D2 receptors, this can be useful for treating chorea and HD as it decreases the amount of DA in the synapse, improving the hyperkinesia

Question 25

what effect does degeneration of GABAergic neurons have?

Answer 25

degeneration of GABAergic neurons causes hyperactivity of DA neurons

Question 26

give examples of antipsychotics

Answer 26

olanzapine, tiapride, risperidone

Question 27

give examples of antidepressants

Answer 27

sertraline, citalopram, paroxetine

Question 28

degeneration of what type of neurons is associated with Amyotrophic Lateral Sclerosis?

Answer 28

degeneration of motor neurons (ventral) is associated with ALS

Question 29

What effect does motor neuron loss have on ALS patients

Answer 29

muscle weakening and wasting

Question 30

what % of ALS is familial?

Answer 30

5-10%

Question 31

what is the most common cause of death in ALS

Answer 31

respiratory failure due to lack of motor innervation to muscles of respiration

Question 32

what is the most common causative genetic mutation in ALS

Answer 32

the Cu/Zn superoxide dismutase (SOD1) gene

Question 33

describe Riluzole mechanism, where approved, etc.

Answer 33

Riluzole is approved in Europe, it blocks voltage-gated Na+ channels, has antiglutamate action (stops Glu release and promotes Glu uptake) to dampen the excitotoxicity, this helps prolong lifespan of motor neurons, prolongs median survival by 3 months.

Question 34

describe Edaravone mechanism and where approved

Answer 34

Edaravone is approved in Japan for ALS and post stroke. It is a free radical scavenger which is helpful for combatting oxidative stress associated with SOD1 mutation which causes ALS via excessive oxidative stress

Question 35

how does SOD1 mutation cause ALS

Answer 35

produces excessive ROS, inducing oxidative stress, oxidation of CYS residue of TDP-43 leads to acetylation and aggregation of TDP-43

Question 36

name the 4 types of Multiple Sclerosis

Answer 36

relapsing remitting MS Primary progressive MS Progressive Relapsing MS Secondary Progressive MS

Question 37

describe T cell involvement in MS

Answer 37

T cell population against myelin, attack myelin and destroy it, insufficient propagation of APs along neurons, causing symptoms of MS

Question 38

What do the therapies for MS mainly do?

Answer 38

dampen the immune system to suppress the T cell response to myelin

Question 39

when is immunosuppression ineffective against MS?

Answer 39

Immunosuppression is ineffective if the patient has entered the progressive phase of the disease

Question 40

name the drug that targets lymphocyte trafficking to treat MS? and mechanism?

Answer 40

Natalizumab is a recombinant humanized mab that binds VLA-4 on T cell surface which prevents T cell interaction and binding with VCAM-1 on endothelium of BBB, preventing T cell entry to brain

Question 41

what type of MS is natalizumab approved for?

Answer 41

Relapsing Remitting Multiple Sclerosis

Question 42

name another group of drugs that target lymphocyte trafficking used as a DMT for MS

Answer 42

S1P receptor modulators, such as siponimod, fingolimod. T cells egress from the lymph node when they have become effector T cells and express S1PR1 on their surface which permits them to recognise the S1P gradient in the periphery, permitting their movement. Naive T cells downregulate the expression of S1PR to keep them in the LN, S1P receptor modulators interfere with T cell sensing of S1P gradient in the periphery and prevent T cell egress from the LN

Question 43

name two drugs that target nucleic acid metabolism that can be used to treat MS

Answer 43

Mitoxantrone is a type II topoisomerase inhibtor that disrupts DNA synthesis and DNA repair in both healthy and cancer cells, T cells are rapidly dividing cells. oral teriflunomide inhibits de novo synthesis of pyrimidine by blocking dihydroorotate dehydrogenase, inhibiting the proliferation of rapidly dividing cells, such as activated T cell

Question 44

name drugs that target B cell populations in MS

Answer 44

Ocrelizumab is a monoclonal antibody directed at B lymphocytes expressing high levels of CD20, binds to CD20 and renders the cell ineffective alemtuzumab causes rapid and prolonged depletion of CD52+ Lymphocytes followed by slow replacement of unaffected cells