Drug Treatment of Motor System Disorders

Question 1

Neurodegenerative disease results from…

Answer 1

deterioration of neurons

Question 2

Two groups of NDD

Answer 2

1. Conditions affecting memory and conditions relating to dementia
2. Conditions causing problems with movement

Question 3

Examples of NDD

Answer 3

PD, Huntington’s Disease, Amyotrophic Lateral Sclerosis

Question 4

Why do NDDs commonly have no cure or disease modifying therapies?

Answer 4

There is a long prodromal period where neurodegeneration begins long before a patient experiences any symptoms.

Often around 70% of neurons are deteriorated by the time symptoms appear

Question 5

Current research in relation to NDD

Answer 5

Research into biomarkers in order to understand progression and facilitate early diagnosis

As well as this, research is currently invested in stem cell technology and treatments in this area, as well as gene therapy

Question 6

What do NDDs have in common with eachother?

Answer 6

• Pole of aging
• Glutamate excitotoxicity
• Mitochondrial dysfunction
• Apoptosis, autophagy leading to protein misfolding
• Neuroinflammation
• Interruptions to intracellular transport

Question 7

What is Parkinson’s Disease?

Answer 7

a continuous progressive neurological disease which results in an increased disability of movement

→ not a cause of death, but rather people die with the condition

Question 8

Pathophysiology of PD

Answer 8

Essentially:
In PD, selective loss of dopaminergic neurons in the SN results in a decreased inhibition of the striatum, however cholinergic neurons remain intact.

Typically, these dopaminergic neurons inhibit the GABAergic output from the striatum, whereas cholinergic neurons exert an excitatory effect.

Hyperactivity of these neurons contribute to the symptoms of PD

Question 9

The main aim of current treatment strategies of PD

Answer 9

to reestablish dopaminergic inhibition of GABA striatal output to balance cholinergic excitation
i.e., the administration of dopamine → THIS IS DIFFICULT AS IT DOES NOT CROSS THE BBB

Question 10

Most commonly used therapeutic in PD

Answer 10

L-DOPA → prodrug used to increase the synthesis of dopamine

Question 11

Other MOA for management of PD

Answer 11

• Inhibiting of DA catabolism → Selegiline (MAO B inhibitor), Tolcapone (Catechol-O-methyltransferase inhibitor)
• Blocking the uptake and enhancing the release of DA → Amantadine, however mechanism is not properly characterised
• Stimulating the DA receptor sites directly → Bromocriptine and Pramipexole (Agonists)

Question 12

Limitations of Current therapeutics of PD

Answer 12

→ Administration of L-DOPA to increase production of DA is only a symptomatic treatment, it does not stop or delay the progressive loss of neurons

→ Management of young onset PD needs to take into account the short efficacy and side effects of L-DOPA administration - after 5-7 years, effectiveness decreases and can result in dyskinesia (increased movement rather than a disability of movement!)

Question 13

What is Huntington’s Disease?

Answer 13

An autosomal dominant inherited neurodegenerative disorder
→ there is no sporadic form, solely genetic and due to mutation of one gene!
Caused by the insertion of multiple CAG repeats in the huntingtin gene, resulting in an N terminal polyQ expansion of the protein

Question 14

What are the characteristics of HD?

Answer 14

the selective loss of neurons projecting from (efferent) the striatum of the basal ganglia, but many neurons also die in the globus pallidus and the cerebral cortex
Disease severity depends on length of the polyQ stretch

Question 15

While we have known for nearly 30 years the mechanism of HD…

Answer 15

the actual function of the huntingtin gene is not fully understood

• Huntingtin k/o mice die in embryonic stages
• ? WT HTT has a role in membrane trafficking in the cytoplasm and is also involved in microtubule based axonal transport
• ? for nomral synaptic transmission as part of protein machinery localised to postsynaptic density
• Transgenic mice studies have shown it participates in NB cellular functions for neuronal homeostasis and survival

Question 16

Pathophysiology of HD

Answer 16

Normally, dopaminergic neurons originating in the substantia nigra inhibit the GABAergic output from the striatum, whereas cholinergic neurons exert an exciatatory effect

However in HD, some cholinergic neurons may be lost, however even more GABAergic neurons degenerate
→ this results in an imbalance in pathways toward more DA signalling

Question 17

Treatment of HD

Answer 17

Most pharmacological agents are used off label…

“No statement can be made regarding the best medical practice for control of motor and non-motor symptoms of HD”

Chorea is he only symptom for which there is a formally approved treatment → Tetrabenazine, which blocks the reuptake of DA into the presynaptic vesicle

Question 18

What are most commonly used off label in treatment of HD

Answer 18

Antipsychotics, as they will reduce DA activity through blockade of D2 receptors

Also, antidepressants

Question 19

NMDA receptor antagonists

Answer 19

There is evidence that these drugs which act on glutamate signalling may help therapeutically

• Side effect of L-DOPA: dyskinesia similar to HD - ? related to hyperphosphorylation of the NMDA receptor therefore increasing its function

perhaps by blocking this receptor it may be useful in reducing chorea associated with HD

Question 20

What is Amyotrophic Lateral Sclerosis (ALS)?

Answer 20

the most common of motor neuron diseases

Also commonly known as Lou Gehrig’s disease in the U.S.

Question 21

Symptoms of ALS

Answer 21

Progressive muscle wasting and weakness, culminating paralysis, respiratory failure and eventually death

Question 22

Aetiology of ALS

Answer 22

Mostly sporadic cases, only 5-10% are familial

Question 23

Most causative gene mutation of ALS

Answer 23

on the Cu/Zn superoxide dismutase 1 (SOD1)

Question 24

Treatment of ALS

Answer 24

No cure…

Riluzole (only approved drug in Europe) - only prolongs median survival by about 2/3 months… minor effect

Edaravone is a potent radical scavenger (I.V.) to help people recover from stroke in japan, while it is also used to treat ALS in Japan and the U.S.

Question 25

Is Multiple Sclerosis a NDD?

Answer 25

NO

Question 26

4 main types of MS

Answer 26

Progressive relapsing
Relapsing remitting
Secondary progressive
Primary progressive

Question 27

Symptoms of MS depend on..

Answer 27

the pattern of lesions within the CNS which are divided into:
Motor, Somatosensory, Cognitive, Fatigue, Genitourinary dysfunction

Question 28

Role of T cells in MS

Answer 28

→ T cells are found in MS lesions early in disease, and are more reactive towards myelin components

T cells become activated in the lymph system where they are exposed to certain antigens, including transcription factors as well as other myelin related antigens and in MS, enter the CNS through blood vessels. Once in the CNS, T cells release chemicals that cause inflammation and damage. This results in damage to myelin, nerve fibres and the cells that make myelin

Question 29

Treatment of MS

Answer 29

No cure

BUT there are disease modifying therapies which work by suppressing the immune system - however this is not effective in progressive phases of disease as the damage has already been done

Question 30

Agents targeting nucleic acid metabolism in MS

Answer 30

Lymphocytes are rapidly dividing cells in MS - they can be therapeutically targeted (strategy similar to some anticancer drugs)

Mitoxantrone (Novantrone, infusion), type II topoisomerase inhibitor;
It disrupts DNA synthesis and DNA repair in both healthy cells and cancer cells by intercalation between DNA bases.

Oral cladribine (Mavenclad, 2-chloro-2’-deoxyadenosine):
Purine analogue taken up into rapidly proliferating cells, including B and T lymphocytes, to be incorporated into DNA synthesis. It mimics nucleoside adenosine;
however, it is resistant to breakdown by adenosine deaminase and accumulates in cells, interfering with their ability to process DNA.

→ Mitoxantrone and cladribine are used to treat certain forms of leukaemia.

Oral teriflunomide (Aubagio) is the active metabolite of leflunomide. It Inhibits de novo pyrimidine synthesis by blocking the enzyme dihydroorotate dehydrogenase. It inhibits the proliferation of rapidly dividing cells, including activated T cells.

Question 31

Agents targeting lymphocyte trafficking in MS

Answer 31

Natalizumab Is a recombinant humanised monoclonal antibody that binds α4β1 integrin (VLA4) on the surface of T lymphocytes and prevents them from binding to VCAM1 on the endothelium of the blood-brain barrier and entering the CNS.
Approved for treatment of patients with active relapsing-remitting multiple sclerosis (for individuals who have not responded to a first-line disease-modifying therapy or who have very active disease).
Also used to treat Crohn’s Disease.

Fingolimod, Siponimod & Ozanimod (S1P receptor modulators)

T cell egress from lymph nodes requires S1P1 receptors that bind the chemoattractant lipid S1P. [S1P] in blood and lymph are higher than in lymphoid tissues. Circulating naive T cells have low levels of S1PR1 because the receptor is internalised after binding S1P in the blood. Therefore, naive T cells that have recently entered a lymph node cannot exit the node.
S1PR1 is eventually re-expressed, T cells sense the S1P gradient and exit the node.
S1P receptor modulators downregulate S1PR1, interfering with the sensing of the S1P gradient and blocking exit of naive and effector cells from the lymph node and reentry of CNS reactive T cells into the circulation.

Question 32

Agents targeting specific T cell populations

Answer 32

Glatiramer (Copaxone)
Random polymer of 4 amino acids that are found in myelin basic protein (MBP).
Originally designed to mimic Myelin Basic Protein to induce EAE (Experimental autoimmune encephalomyelitis). But it was found to suppress the disease and as a result came to be trialled in human MS
Originally believed to act as a decoy by drawing the immune system’s attack away from the myelin
Glatiramer affects various levels of the immune response, inducing deviation from the proinflammatory to the anti-inflammatory pathways (e.g. induction of Th2/3 and regulatory T cells (Tregs) and downregulation of both Th1 and Th17 cells

Dimethyl fumarate (Tecfidera)
Based on a psoriasis treatment (DE: Fumaderm; UK: Skilarence)
Precise mechanism of action of DMF is not clear
It affects transcription pathways that shifts T helper cells (Th) from a Th1 and Th17 profile to a Th2phenotype, causing immunosuppression

Question 33

Agents targeting specific B cell populations in MS

Answer 33

Ocrelizumab
Monoclonal antibody directed at B-lymphocytes expressing high levels of CD20.
Ocrelizumab binds to a CD20 epitope that overlaps with the epitope recognized by rituximab (autoimmune disorders and cancers)

Alemtuzumab (Lemtrada)
Monoclonal antibodies cause rapid and prolonged depletion of CD52+ lymphocytes followed by slow replacement of unaffected cells.
Also used to treat chronic lymphocytic leukaemia (CLL)

CD52 is present on mature lymphocytes, but not on the stem cells from which they were derived. On T and B cells expressing CD52, alemtuzumab activates ADCC, CDC and caspase dependent apoptosis