L2: Drug Treatment of Motor Disorders Flashcards
what mediators do microglia release when activated?
NO-, COX-2, O2-
give examples of what activates microglia
Beta-amyloid plaques, stroke, TBI, infection, pollutants, genetic factors
what is associated with parkinson’s disease (symptoms)
increasing disability of movement
mean age of onset of PD
55 years
what % of PD is genetic/familial
10%
what is the autosomal dominant genotype of PD
Mutation in the alpha-synuclein protein that plays a role in synaptic vesicle trafficking and neurotransmitter release
monkey’s exposed to what produces symptoms like PD?
MPTP - an opioid analgesic
describe the pathway involved in PD (Normal vs PD)
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
describe the autosomal recessive PD
Mutations in parkin, PINK1, DJ01 gene
describe atropine
atropine is a muscarinic receptor antagonist which aims to antagonise cholinergic receptors to account for the loss of DA neurons.
side effects of atropine
dry mouth, constipation, urinary retention
describe L-dopa
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
what drugs can atropine be given with to improve PD-like symptoms?
antipsychotics
what drugs should be used in earlier onset PD
not L-dopa, DA-R antagonists, anticholinergics, deep brain stimulation, monoamine oxidase inhibitors, amantadine
describe the gene mutation associated with Huntingtin’s Disease
CAG repeats (35+) causing an N terminal polyQ (glutamate) tail on the Huntingtin protein
what loss of neurons is associated with HDD
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
what is disease severity of HD directly linked to?
the length of the PolyQ tail at the N terminal of the Htt protein
is there more loss in the cholinergic or GABAergic neurons in HD?
More neuron loss in GABAergic, some loss in cholinergic
how does DA output normally affect GABAergic output, how is this impacted in HD
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)
how is the change in DA levels described in HD and how does this impact symptoms
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
name the drug that treats chorea, a hyperkinetic disorder similar to HD
Tetrabenazine
what does tetrabenazine inhibit
VMAT-2 is inibited by tetrabenazine and this promotes monoamine degradation, ie promotes DA degradation
how does deutetrabenazine differ from tetrabenazine
it is a different isotope of hydrogen
what receptors do all Anti-psychotics block? where might this be useful in treating motor disorders
D2 receptors, this can be useful for treating chorea and HD as it decreases the amount of DA in the synapse, improving the hyperkinesia
what effect does degeneration of GABAergic neurons have?
degeneration of GABAergic neurons causes hyperactivity of DA neurons
give examples of antipsychotics
olanzapine, tiapride, risperidone
give examples of antidepressants
sertraline, citalopram, paroxetine
degeneration of what type of neurons is associated with Amyotrophic Lateral Sclerosis?
degeneration of motor neurons (ventral) is associated with ALS
What effect does motor neuron loss have on ALS patients
muscle weakening and wasting
what % of ALS is familial?
5-10%
what is the most common cause of death in ALS
respiratory failure due to lack of motor innervation to muscles of respiration
what is the most common causative genetic mutation in ALS
the Cu/Zn superoxide dismutase (SOD1) gene
describe Riluzole mechanism, where approved, etc.
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.
describe Edaravone mechanism and where approved
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
how does SOD1 mutation cause ALS
produces excessive ROS, inducing oxidative stress, oxidation of CYS residue of TDP-43 leads to acetylation and aggregation of TDP-43
name the 4 types of Multiple Sclerosis
relapsing remitting MS
Primary progressive MS
Progressive Relapsing MS
Secondary Progressive MS
describe T cell involvement in MS
T cell population against myelin, attack myelin and destroy it, insufficient propagation of APs along neurons, causing symptoms of MS
What do the therapies for MS mainly do?
dampen the immune system to suppress the T cell response to myelin
when is immunosuppression ineffective against MS?
Immunosuppression is ineffective if the patient has entered the progressive phase of the disease
name the drug that targets lymphocyte trafficking to treat MS? and mechanism?
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
what type of MS is natalizumab approved for?
Relapsing Remitting Multiple Sclerosis
name another group of drugs that target lymphocyte trafficking used as a DMT for MS
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
name two drugs that target nucleic acid metabolism that can be used to treat MS
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
name drugs that target B cell populations in MS
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
