Lecture 20

Question 1

Symptoms of Parkinson’s

Answer 1

1) Pill rolling tremor at rest
2) Cogwheel rigidity
3) Bradykinesia (slow movement)
4) Shuffling gait (small steps)
5) Hunched posture, smaller handwriting, and poor balance
6) Expressionless facial features

Question 2

What is Early-onset PD

Answer 2

Genetic version, affects young children (before age 20)
Rare, can be due to inbreeding
Also associated with PARK2 and LRRK 2 mutations in adults

Question 3

Correlation of Parkinson’s and environmental factors

Answer 3

Correlation with hydrographic areas (water) and use of pesticides, but not causation

Question 4

Where are cell bodies of dopamine neurons found

Answer 4

In the substantia nigra (in midbrain) and project to striatum
(Nigrostriatal pathway) into the forebrain

Question 5

What is Parkinson’s a primary result of

Answer 5

Degeneration of dopaminergic neurons in the nigrostriatal pathway (responsible for most motor symptoms)
Works contralaterally

Question 6

Outcome of rat’s left and right substantia nigra being lesioned

Answer 6

Lesions on both sides (by 6-OHDA) produced a deficit and the rats couldn’t respond to stimuli, thus having parkinsonism symptoms

Question 7

Function of dopamine in brain

Answer 7

Dopamine enables sensory–>motor flow of information, allow you to respond to stimuli
Dopamine (DA) is an enabler of sensorimotor integration in the striatum
No DA–>Sensory input canNOT produce motor output

Question 8

Outcome of vibrissae-elicited forelimb placing test

Answer 8

Rat with unilateral dopaminergic lesion with 6-OHDA on right side
1) Akinesia in affected forelimb, fails to place forelimb contralateral to lesion
Now test whiskers–>for sensory
When left whisker is stimulated, rat still reaches out with right forearm, sensory intact
2) Motor deficit affecting body contralateral to side of lesion

Question 9

What is MPTP

Answer 9

Protoxin that results in death of dopaminergic neurons in the brain
No effect in rats, but did affect mice

Question 10

Cell death by MPTP

Answer 10

MPTP–>lipophilic, passes BBB
Does not kill dopamine neurons in culture–>needs metabolite (MAO-B)

Question 11

Mechanism of MPTP

Answer 11

MPTP passes BBB–> MAO-B is found in astrocytes–>Astrocytes use MAO-B to convert MPTP to MPP+–>MPP+ exits astrocyte and selectively kills dopamine neurons in the brain (require DAT, dopamine axon terminals, to then be taken up to synaptosomes)

Question 12

How to block MPTP

Answer 12

1) Use dopamine transport blockers (DAT Blockers) to block MPP+ uptake by DAT (Nomifensine)
2) Use MAO-B inhibitor to block MPTP–>MPP+ conversion (Pargyline)

Question 13

Timing of blocking MPTP

Answer 13

MAOI (pargyline)–>must be administered before MPTP or right after MPTP to provide full protection to DA neurons
DAT blocker (nomifensine)–> can be given later (30 minutes after MPTP administration) and will still protect DA neurons

Question 14

How does MPTP kill DA neurons

Answer 14

MPP+ inhibits electron transport chain causing DA cells to run out of energy and die

Question 15

Environment equivalent to MPTP

Answer 15

Paraquat (pesticide), cannot pass BBB, but chronic exposure can lead to accumulation in the brain, not very selective, risk factor for Parkinson’s disease

Question 16

What is Rotenone

Answer 16

Environmental compound that causes dopamine depletion

Question 17

How does Rotenone cause dopamine depletion

Answer 17

Lipophilic–>passes BBB, depletes DA terminals in striatum leaving DA neurons with very few dendrites

Question 18

How does Rotenone affect the brain

Answer 18

Inhibits complex 1 of electron transport chain, starving all cells of energy, but dopamine neurons are more susceptible (require more energy)

Question 19

What structure is characteristic of Parkinson’s

Answer 19

Inclusion bodies that contain alpha-synuclein, often associated with Rotenone

Question 20

What is Alpha-synuclein

Answer 20

Insoluble protein that accumulates inside DA forming inclusion bodies (Lewy bodies)
Cell damage is progressive

Question 21

What is Rotenone sold as

Answer 21

“natural” toxin used to kill unwanted fish in cold-water lakes, causes animals to have PD-like symptoms (immobility and tremour)

Question 22

Progression of Parkinson’s

Answer 22

Genetic predisposition and/or environmental factors–>neuronal loss–>clinical symptoms (drug treats symptomatic symptoms, no presymptomatic drugs)

Question 23

First Line drugs for Parkinson’s

Answer 23

1) L-DOPA + Carbidopa (best at controlling motor deficits but most complications like dyskinesias)
2) (*)DA agonists on postsynaptic site (second best for motor control, less complications than L-DOPA)
3) MAO-B inhibitors
Want to delay treatment with L-DOPA

Question 24

Why is L-DOPA never taken alone

Answer 24

1) L-DOPA in liver–>inhibited by DOPA decarboxylase preventing conversion of L-DOPA to DA
2) Even if converts to DA–> gets converted to NA in periphery by different enzyme
3) L-DOPA absorption competes with high protein meals in the GIT

Question 25

Function of Carbidopa

Answer 25

Inhibits DOPA decarboxylase in periphery, prevent conversion of DA–>NA
CanNOT pass BBB, so only prevents conversion in periphery allowing DA to act in CNS

Question 26

DA in brain is subject to breakdown by

Answer 26

COMT and MAO-B so want to inhibit them
Breaks down MAO-B–>Selegiline
Breaks down COMT–> Tolcapone
Prevention of DA breakdown in CNS/brain

Question 27

What converts L-DOPA to DA

Answer 27

Aromatic amino acid decarboxylase (AAAD)
Conversion can occur in non-dopaminergic cells

Question 28

Problems with L-DOPA

Answer 28

1) Becomes ineffective overtime (in a few years) as therapeutic window narrows
Dose window between bradykinesia and dyskinesia decreases
2) On-off symptoms
3) Psychiatric problems (hallucinations, confusion, psychosis)
4) Complicated pharmacokinetics (need to take dose at regular intervals)
5) Formation of free oxyradicals, neurotoxic in long term (no hard evidence)

Question 29

Solution to MPTP induced immobility

Answer 29

MPTP induced immobility could be reversed by acute administration of either DA agonist (Ropinirole) of L-DOPA

Question 30

Adverse effects of DA agonists

Answer 30

Nausea, postural hypotension, and CNS effects