Drug Treatment of Motor System Disorders Flashcards
(33 cards)
Neurodegenerative disease results from…
deterioration of neurons
Two groups of NDD
- Conditions affecting memory and conditions relating to dementia
- Conditions causing problems with movement
Examples of NDD
PD, Huntington’s Disease, Amyotrophic Lateral Sclerosis
Why do NDDs commonly have no cure or disease modifying therapies?
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
Current research in relation to NDD
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
What do NDDs have in common with eachother?
- Pole of aging
- Glutamate excitotoxicity
- Mitochondrial dysfunction
- Apoptosis, autophagy leading to protein misfolding
- Neuroinflammation
- Interruptions to intracellular transport
What is Parkinson’s Disease?
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
Pathophysiology of PD
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
The main aim of current treatment strategies of PD
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
Most commonly used therapeutic in PD
L-DOPA → prodrug used to increase the synthesis of dopamine
Other MOA for management of PD
- 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)
Limitations of Current therapeutics of PD
→ 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!)
What is Huntington’s Disease?
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
What are the characteristics of HD?
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
While we have known for nearly 30 years the mechanism of HD…
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
Pathophysiology of HD
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
Treatment of HD
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
What are most commonly used off label in treatment of HD
Antipsychotics, as they will reduce DA activity through blockade of D2 receptors
Also, antidepressants
NMDA receptor antagonists
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
What is Amyotrophic Lateral Sclerosis (ALS)?
the most common of motor neuron diseases
Also commonly known as Lou Gehrig’s disease in the U.S.
Symptoms of ALS
Progressive muscle wasting and weakness, culminating paralysis, respiratory failure and eventually death
Aetiology of ALS
Mostly sporadic cases, only 5-10% are familial
Most causative gene mutation of ALS
on the Cu/Zn superoxide dismutase 1 (SOD1)
Treatment of ALS
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.
