Parkinson's (dopamine signaling)

The DA synthesis pathway

• Tyrosine —→ DOPA via tryosine hydroxylase

• DOPA —→ DA via DOPA decarboxylase

How does DA enter vesicles?

• VMAT

What terminates DA signalling?

• Reuptake into preSN by DAT

• MAO metabolism then excretion in urine

Briefly describe how DAergic neurones are important

• Only 0.0005% of neurones (comp. 20% GABAergic)

• Still important, split into 4 main pathways at different parts of the brain

Describe DA receptors

• D1/5 Gs GPCRs

• D2-4 Gi GPCRs, inhibits Ca2+v

• D1/2 most widely expressed

• D2 is preSN on DA and non-DA neurones, inhibitory for negative feedback, therefore D2 antagonists increase DA release

What are the symptoms of Parkinson’s disease?

• Tremor that can be suppressed during movement

• Slow movement

• Tiredness, depression, pain, constipation

What is the neurochemical basis for PD?

• Loss of DA neurones in the motor control pathway - here especially due to increased metabolic demand increasing ROS risk

• Post-mortem can have <10% healthy DA levels and DA neuron cell body loss (ROS damage in DA metabolism by MAO, then reduced proteosome activity with age decreases degradation of misfolded or damaged neurones)

What is the “perfect world” treatment for PD and why is there still a problem?

• Induced pluripotent stem cells made from patient fibroblasts forced to differentiate into DA neurones and transplanted into brain

• Still unclear how to prevent these new neurones degenerating, esp. if the area of the brain itself is still at a high ROS exposure and little proteosome activity

What do current drugs that target PD do?

• Counteract DA deficiency to relieve symptoms

• Do not protect, block, or slow damage - neurodegeneration still happens

Describe L-DOPA as a treatment for RA

• Crosses BBB and can be transported into brain via amino acid transporters, where dopamine decarboxylase can turn it into DA

• DA itself is not hydrophilic enough to cross BBB and no specific transporters (good, want to restrict DA produced to the brain) so cannot be given as a drug itself

• Extra DA synthesized is taken up by VMAT into vesicles to increase DA release during an AP from the remaining DA neurones

• Efficacy decreases in humans as PD progresses, so DA neurones themselves could also be important e.g. receptors

• Co presc with carbidopa

Discuss carbidopa as a treatment for PD

• Blocks DOPA decarboxylase

• However, cannot cross BBB, so only blocks peripheral DDC

• Therefore L-DOPA not inactivated before it reaches the brain, increasing bioavailability

• Decreased L-DOPA dose required

Discuss the problems of using L-DOPA

• Lots of PK problems

• Involuntary movement of face/limbs

• Short ~2hr half life means Cp and efficacy fluctuates, worsening for minutes or hours and then suddenly returning to normal

• Activation of D2 can cause vomiting

• Too high a dose can cause too high DA and schizophrenia-like symptoms

What is done to try and stabilze the plasma concentration of L-DOPA?

• Sustained release L-DOPA

• Carbidopa furhter inhibtis L-DOPA breakdown in periphery

How can nausea as a consequence of L-DOPA be helped with co-prescription?

• Domperidone

• D2 antagonist but BBB impermeable, which is good as area of receptors causing nausea is not protected by BBB due to their importance in chemosensing in the blood, so only antagonise D2 in nausea-inducing area

Describe dopamine receptor agonists as a PD treatment, naming one

• Better tolerated as less fluctuation in effficacy then L-DOPA

• Can cause tiredness, predisposition to impulse control disorder

• No effect on vesicles, just agonises pre-existing DAR

• Rotigotine

How is rotigotine given?

• Transdermal patch

• Mitigate short half life which could cause too many fluctuations, so slow release

Describe how MAOis could be used for PD, give an example

• MAO-B prefers DA

• Selegiline

• Synergistsic wtih L-DOPA

• Inhibits MAO-B to increase DoA of DA

• Metabolized to amphetamine, so can lead to excitement and insomnia