MDG5204 Chap.9 Parkinson Disease and the Blood-Brain Barrier
Parkinson Disease and the Blood-Brain Barrier
The disease the circuits predict
Parkinson disease is the course's main example of neurodegeneration. Its motor features are resting tremor, bradykinesia, rigidity and postural instability.
The idiopathic disease is not a single disorder, but its sporadic and familial forms share a common end-mechanism: the ubiquitin-proteasome system fails to clear abnormal proteins, which accumulate as aggresomes and trigger apoptosis.
Lewy bodies, inclusions containing alpha-synuclein and ubiquitin, mark the process, and the loss that produces the motor signs is the dopaminergic projection from the substantia nigra pars compacta to the striatum.
Why losing dopamine slows movement
Without dopamine, D1 receptors in the direct pathway and D2 receptors in the indirect pathway are both under-stimulated.
The direct pathway weakens and the indirect pathway strengthens, and both changes increase inhibition of the thalamus, reducing the drive to the motor cortex. The prediction from the previous chapter's circuit is hypokinesia, and that is what patients show.
Treating the dopamine deficit
Every drug strategy the course lists acts at one step of dopamine's life cycle.
Levodopa, the dopamine precursor, is combined with a peripheral decarboxylase inhibitor such as carbidopa and remains the gold standard, though long-term use brings dyskinesia and fluctuating motor control, so the dose is kept to the minimum that works. COMT inhibitors such as entacapone prolong each levodopa dose and are useful only alongside it. MAO-B inhibitors such as selegiline slow dopamine breakdown with mild benefit.
Dopamine agonists act directly on the receptors and may delay motor complications, though they are not superior to levodopa.
The barrier every brain drug must cross
The blood-brain barrier keeps the neuronal environment stable by controlling metabolic substrates and ions and excluding toxins and peripheral transmitters.
It exists at two sites, the choroid plexus epithelium and the brain capillaries, both sealed by tight junctions. Small lipid-soluble drugs cross by diffusion, selected molecules including L-dopa cross on carriers, and efflux pumps such as P-glycoprotein push drugs back out.
The barrier breaks down in hypertensive encephalopathy, brain injury, infection and tumours, and delivery strategies range from coupling a drug to a transported molecule to exploiting the porous capillaries of infection.
What this chapter covers
- 01
Motor features and the protein-clearance failure behind Parkinson disease
- 02
Loss of nigrostriatal dopamine and its effect on both motor pathways
- 03
Levodopa with carbidopa and its long-term limits
- 04
COMT inhibitors, MAO-B inhibitors and dopamine agonists
- 05
Functions and structure of the blood-brain barrier
- 06
Diffusion, carriers, efflux and strategies for delivering drugs to the brain
Worked example · free
Why levodopa is given instead of dopamine
- 2State why dopamine itself does not reach the brain.
- 2State how levodopa crosses and what happens inside the brain.
- 2Explain the role of carbidopa.
Key terms
- Lewy Body
- An eosinophilic inclusion containing alpha-synuclein and ubiquitin, the hallmark of Parkinson pathology.
- Bradykinesia
- Slowness of movement, one of the four motor signs of Parkinson disease.
- Levodopa
- The dopamine precursor that crosses the blood-brain barrier on a carrier and is converted to dopamine in the brain.
- COMT Inhibitor
- A drug that blocks catechol-O-methyltransferase so that more levodopa reaches the brain.
- P-Glycoprotein
- An efflux transporter that pumps drugs back out across the blood-brain barrier.
Parkinson Disease and the Blood-Brain Barrier FAQ
What causes the motor symptoms of Parkinson disease?
Degeneration of dopaminergic neurons in the substantia nigra pars compacta removes dopamine input to the striatum. Both basal ganglia pathways then shift towards greater inhibition of the thalamus, reducing cortical drive and producing slowness, rigidity, tremor at rest and postural instability.
Why is the levodopa dose kept as low as possible?
Although levodopa is the most effective drug at every stage, long-term treatment brings dyskinesia and fluctuating motor control at roughly 10% a year, and short-term use can cause nausea, vomiting and postural hypotension. Using the minimum dose that gives good motor function limits these problems.
What decides whether a drug can enter the brain?
Mainly its size, lipid solubility, charge and protein binding for passive diffusion, whether it is carried by a barrier transporter, and whether an efflux pump such as P-glycoprotein removes it. A damaged barrier, as in meningitis, lets in drugs that would otherwise be excluded.
Exam move
Draw the dopamine pathway from tyrosine to homovanillic acid and write each drug class at the step it acts on. Then list the four ways across the blood-brain barrier and attach one drug or molecule to each.
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