Lecture 42 Flashcards
PD
chronic, progressive, irreversible disease resulting from a neurological deficit in the extrapyramidal system
PD symptoms
TRAP
resting TREMOR (primarily on one side of the body)
Rigidity (muscle stiffness)
Akinesia/bradykinesia (slow movement)
Postural instability (impair, balance, coordination)
PD pathophysiology
PD is characterized by a loss of dopaminergic neuron in the substantia nigra
PD involves a gradual loss of darkly pigmented, dopamine- releasing neurons in the substantia nigra pars compacta in the midbrain
Dopaminergic neurons in the SNpc project to the striatum in the basal ganglia, and PD involved 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 pathophysiology (continued)
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
Lewy bodies
are enriched with fibrillar forms of the protein a-synuclein
Braak stages of PD
Stage 1: lower brainstem
Stage 2: raphe
Stage 3: substantia nigra
Stage 4: mesocortex/thalamus
Stage 5: neocortex/prefrontal cortex
Stage 6: entire neocortex
Although stage 3 accounts for the classic symptoms, progression in other stages likely accounts for the non-motor symptoms
SN pars compacta
provides input to the basal ganglia, supplies dopamine to the striatum
involved in voluntary motor control and some cognitive functions
undergoes neurodegeneration in PD
Basal ganglia
striatum (caudate nucleus, putamen) and globus pallidus (external and internal segments)
Gpi: globus pallidus, internal (darker blue in figure SLIDE 9
Gpe: globus pallidus external (lighter blue in figure)
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 COMPLEX PATHWAY
signaling from the SNpc in both D1 and D2 receptors in the striatum favors thalamocortical signaling and this effect is disrupted in PD
Benztropine
antimuscarinics are used as adjunct therapies for tremor in PD
used only in low doses due to their side effects (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 the relative excess of activity in cholinergic pathways, and a cholinergic antagonist can partially compensate for this over-activity
L-DOPA
GOLD STANDARD
L-DOPA is a precursor of dopamine (DA)
in contrast to dopamine, L-DOPA is orally active and can enter the CNS
a favorable response to L-DOPA treatment is considered key to a diagnosis of PD
SE: nausea, hypertension, and psychosis
the dose of L-DOPA can be lowered (4x) by co-administration of carbidopa, a peripherally-acting DOPA decarboxylase inhibitor this combo drug is called SINEMET
Why is there this difference in bioavailability between L-DOPA and dopamine?
because DA has a net positive charge at pH 7 and L-DOPA does not
L-DOPA patho
L-DOPA must be converted to dopamine in the SN, but no the periphery
carbidopa inhibits DOPA decarboxylase in the periphery
carbidopa doesn’t penetrate the BBB, and this it cannot inhibit DDC in the substantia nigra
Challenges associated with L-DOPA therapy
on/off oscillations (after several years of L-DOPA treatment
this problem can be alleviated by administrator L-DOPA (as opposed to pulsatile) manner
LOOK AT SLIDE 13
Challenges associate with L-DOPA therapy (continued)
A key limitation associated with prodrug conversion
L-DOPA must be converted to dopamine by DDC in surviving nigral dopaminergic neurons
*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
