Lecture 42 - Parkinson's Disease Pathophysiology and Pharmacology Flashcards
Parkinson’s disease is
an age-related neurodegenerative disorder
age is a major risk factor: PD affects ~3% of individuals >65 yo, mean age of onset 62.5 years; more common in males
it is a chronic, progressive, irreversible, disease resulting from a neurological deficit in the extrapyramidal system (noncortical voluntary motor control)
PD symptoms (TRAP)
→ resting tremor (primarily on one side of body)
→ rigidity (muscle stiffness)
→ akinesia/bradykinesia
(slow movement)
→ postural instability (impaired balance, coordination)
→ mask-like appearance
→ speech difficulties, cognitive deficits, depression
PD is characterized by
a loss of dopaminergic neurons in the
substantia nigra.
PD involves a gradual loss
of darkly pigmented, dopamine- releasing neurons in the substantia nigra pars compacta (SNpc) in the midbrain.
- dopaminergic neurons in the SNpc project to the striatum in the basal ganglia, and PD involves a loss of neurotransmission through the nigrostriatal system.
- Some studies suggest that 50% of the nigral dopamine neurons, or 70-80% of the nerve terminals in the striatum, are lost before
patients present with motor symptoms.
PD is also characterized by the presence of
Lewy bodies in various regions of the brain.
- surviving neurons in the brains of PD patients have dense, spherical protein deposits called Lewy bodies. (intracellular inside neuron in cytosome)
- Lewy bodies are found not only in the SN, but also in other brain regions including the cortex.
- Lewy bodies are enriched with fibrillar forms of the protein α-synuclein.
α-Synuclein neuropathology: the Braak stages
PD neuropathology may begin in the brainstem. Heiko Braak identified 6 pathological stages:
Stage 1: lower brianstem
Stage 2: raphe
Stage 3: substantia nigra (necessary for classic PD sx)
Stage 4: mesocortex/thalamus
Stage 5: neocortex/prefrontal cortex
Stage 6: entire neocortex
although stage 3 accounts for classic sx, the progression in other stages likely accounts for the non-motor sx
alpha synuclein Lewy bodies spread throughout brain as disease progresses
early stage: brain stem; mid stage: mid brain + substantia nigra; late stage: cortex
Basal ganglia
striatum (caudate nucleus, putamen) and globus
pallidus (external and internal segments) (continued)
Dopamine neurons signal through two pathways:
→ a direct pathway involving D1 receptors in the striatum:
(SNpc → striatum → Gpi/SNpr → thalamus → cortex)
→ an indirect pathway involving D2 receptors in the striatum: (SNpc → striatum → Gpe → STN → Gpi/SNpr →
thalamus → cortex)
→ signaling from the SNpc to both D1 and D2 receptors in the striatum favors thalamocortical signaling, and
this effect is disrupted in PD.
Antimuscarinics are used as
adjunct therapies for tremor in PD; ex. benztropine
- antimuscarinics are only used in low doses due to their side effects (key side effect: cognitive deficits).
- in the control of motor movement, acetylcholine is excitatory, whereas dopamine is inhibitory (in the indirect pathway).
- the loss of dopamine results in a relative excess of activity in cholinergic pathways, and a cholinergic antagonist can partially compensate for this over-activity.
- the most effective treatments increase dopaminergic transmission, either by increasing endogenous dopamine or by directly stimulating dopamine receptors.
What is the gold standard for PD therapy
L-DOPA, want to increases levels of dopamine
- L-DOPA is a precursor of dopamine (DA) (occurs immediately upstream of DA on the DA synthesis pathway).
- in contrast to dopamine, L-DOPA is orally active and can enter the CNS; why is there this difference in bioavailability between L-DOPA and dopamine? DA has a net positive charge at pH 7.
- a favorable response to L-DOPA treatment is considered key to a diagnosis of PD.
- at high doses L-DOPA produces side-effects including nausea, hypertension, and psychosis.
- the dose of L-DOPA can be lowered (4x) by co-administration of carbidopa, a peripherally-acting DOPA decarboxylase inhibitor. The combination drug is called ‘Sinemet’.
L-DOPA penetrates BBB, dopamine does not
L-DOPA must be converted to
dopamine in the SN, but not in the periphery.
L-DOPA can cross BBB, dopamine has a + charge, can’t cross BBB
L-DOPA converted to dopamine by DDC - dopadecarboxylase
Carbidopa inhibits
DOPA decarboxylase (DDC) in the periphery.
carbidopa doesn’t penetrate the BBB, and thus it
cannot inhibit DDC in the substantia nigra.
prevents conversion to dopamine in the periphery, because we want it to be produced in the CNS
Challenges associated with L-DOPA therapy
on/off oscillations (after several years of L-DOPA treatment)
- immediately after dosage, the drug can produce exaggerated and aberrant motor effects known as ‘dyskinesias’.
- after plasma levels decline, the drug may fail to provide any effect (‘off’ state).
- dyskinesias and on/off effects are major problems in long-term therapy with levodopa.
- this problem can be alleviated by administering L-DOPA in a continuous (as opposed to pulsatile) manner; new liquid-based subcutaneous infusion is in Phase III clinical trial (ND0612).
A key limitation associated with prodrug conversion for L-DOPA
- L-DOPA must be converted to dopamine by DOPA decarboxylase (aka aromatic L-amino acid decarboxylase) in surviving nigral dopaminergic neurons.
- However, the disease is progressive, and eventually patients become unresponsive to L-DOPA.
- One way to address this challenge is to use dopamine receptor agonists – this is reasonable because the postsynaptic dopamine receptors are still present in the striatum.
DA receptor agonists:
apomorphine
