Parkinson's Disease Flashcards
what is Parkinson’s
abnormalities in the control of movement
age-related
no cure: treatments only relieve symptoms
death results from pneumonia
symptoms of Parkinson’s
- Bradykinesia
- slowness of movement
- difficulty initiating movement - Muscle rigidity
- Tremor (occurs during rest/disappears with movement)
- Postural instability
- results in shuffling gait and frequent falls
what pathway is selectively lost in Parkinson’s
loss of nigrostriatal dopaminergic neurons
= leads to decrease in dopamine conc in striatum
- associated with motor disturbances
cellular effects of Parkinson’s
Lewy bodies
- abnormal, circular, cytoplasmic inclusions surrounded by a clear halo
located in substantia nigra _ adjacent sucortical sites
genetics of Parkinson’s
- mutations in a-synuclein
- neuronal protein located in PREsynaptic neuronal processes - may regulate vesicle transport / NT release - mutations in park2
- E3 ubiquitin ligase: may tag proteins for degradation //
tag membrane-bound receptors for recycling
both proteins present in Lewy bodies
environmental factor associated with Parkinson’s
- aluminum
- pesticides
- oxidative damage: neurons in substantia nigra especially sensitive
how does loss of dopamine-releasing neurons + GABA releasing neurons => bradykinesia
DIRECT Pathway
dopaminergic neurons in substantia nigra are lost
=loose ability to stimulate GABAnergic neurons
GABA has inhibitory activity = lost
synapse with second GABAergic neuron = more active => inhibition of GLUTanergic neurons which synapses with the motor cortex (less stimulated)
evidence that Parkinson’s is due to the loss of dopamine
- drugs that enhance dopaminergic function = reduce symptoms of Parkinson’s
- the destruction/interference with nigrostriatal dopaminergic neurons in animals => similar motor deficits
- correlation between loss of dopamine-releasing neurons / severity of motor symptoms in Parkinson’s in humans
drug therapy strategies for Parkinson’s
- supply exogenous dopamine (precursor)
- inhibit dopamine metabolism (MAO-B)
- dopamine receptor agonists
- muscarinic cholinergic receptor antagonist
- what is a metabolic precursor of dopamine
L-dopa
-used for late-stage Parkinson’s (reduces bradykinesia, rigidity, tremor)
side effects: dyskinesia (involuntary/repetitive movements)
nausea/vomiting
hypotension (decarboxylation of L-dopa > dopamine in PNS)
- what do you co-administer L-dopa with
CARBIDOPA - peripheral decarboxylase inhibitor
minimizes side effects of L-dopa
cannot cross BBB = enhances action of L-dopa centrally
increases plasma conc
lengthens half-life of L-dopa
- dopamine receptor agonist
bromocriptine, pergolide, pramipexole
direct activation of dopamine R on POSTsynaptic cells (presynaptic dopamine-releasing cells = more susceptible to degradation than postsynaptic cells
. not as effective = more PNS side effects compared to L-dopa
= different effects on multiple subtypes of dopamine R
. less likely to promote dyskinesia than L-dopa
pramipexole use enhances compulsive behaviour
- specific inhibitor of MAO-B (breaks down dopamine)
SELEGILINE
used to decrease breakdown of dopamine in striatum (lots of MAO-B)
used alone in early stages of Parkinson’s with L-dopa to help decrease metabolism of dopamine derived
- anticholinergics
M1 receptor antagonist
used to treat tremor symptoms
use limited - frequent/often serious side effects:
confusion, hallucinations, decreased short term memory
PNS side effects: dry mouth, blurry vision, urinary retention
Parkinson’s drug lose efficacy over time
combination drug treatments - more effective for long term use
