Lecture 20 Flashcards
Symptoms of Parkinson’s
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
What is Early-onset PD
Genetic version, affects young children (before age 20)
Rare, can be due to inbreeding
Also associated with PARK2 and LRRK 2 mutations in adults
Correlation of Parkinson’s and environmental factors
Correlation with hydrographic areas (water) and use of pesticides, but not causation
Where are cell bodies of dopamine neurons found
In the substantia nigra (in midbrain) and project to striatum
(Nigrostriatal pathway) into the forebrain
What is Parkinson’s a primary result of
Degeneration of dopaminergic neurons in the nigrostriatal pathway (responsible for most motor symptoms)
Works contralaterally
Outcome of rat’s left and right substantia nigra being lesioned
Lesions on both sides (by 6-OHDA) produced a deficit and the rats couldn’t respond to stimuli, thus having parkinsonism symptoms
Function of dopamine in brain
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
Outcome of vibrissae-elicited forelimb placing test
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
What is MPTP
Protoxin that results in death of dopaminergic neurons in the brain
No effect in rats, but did affect mice
Cell death by MPTP
MPTP–>lipophilic, passes BBB
Does not kill dopamine neurons in culture–>needs metabolite (MAO-B)
Mechanism of MPTP
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)
How to block MPTP
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)
Timing of blocking MPTP
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
How does MPTP kill DA neurons
MPP+ inhibits electron transport chain causing DA cells to run out of energy and die
Environment equivalent to MPTP
Paraquat (pesticide), cannot pass BBB, but chronic exposure can lead to accumulation in the brain, not very selective, risk factor for Parkinson’s disease
What is Rotenone
Environmental compound that causes dopamine depletion
How does Rotenone cause dopamine depletion
Lipophilic–>passes BBB, depletes DA terminals in striatum leaving DA neurons with very few dendrites
How does Rotenone affect the brain
Inhibits complex 1 of electron transport chain, starving all cells of energy, but dopamine neurons are more susceptible (require more energy)
What structure is characteristic of Parkinson’s
Inclusion bodies that contain alpha-synuclein, often associated with Rotenone
What is Alpha-synuclein
Insoluble protein that accumulates inside DA forming inclusion bodies (Lewy bodies)
Cell damage is progressive
What is Rotenone sold as
“natural” toxin used to kill unwanted fish in cold-water lakes, causes animals to have PD-like symptoms (immobility and tremour)
Progression of Parkinson’s
Genetic predisposition and/or environmental factors–>neuronal loss–>clinical symptoms (drug treats symptomatic symptoms, no presymptomatic drugs)
First Line drugs for Parkinson’s
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
Why is L-DOPA never taken alone
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
