Neurodegenerative Disorders [7] Flashcards
What is excitotoxicity
Release of glutamate
Causes neuronal death
Mediated through NMDA receptors
Calcium entry needed
Increased calcium causes
Arachidonic acid production
Free radicals
Damage to proteins and lipids in cells
Impaired mitochondrial function
What is the effect of glutamate
It kills cells if there is long exposure
Defence against glutamate neurotoxicity
Mitochondrial energy metabolism
ATP production
Maintains Na/K pump
Sustains membrane potential
Sustains Ca2+ uptake by ER
What is oxidative stress
Production of free radicals (°OH) - damage cellular components
From brain mitochondrial oxidative phosphorylation
2 defence mechanisms for oxidative stress
Enzymes - superoxide dismutase
Antioxidants - glutathione
Main symptoms of Parkinson’s disease
Tremor
Muscle rigidity
Hypokinesia
What causes PD
Degeneration of the substantia nigra which produces dopamine
Neurochemical changes in PD patients
<10% normal DA levels
Loss of cell bodies of dopaminergic neurones
5-HT and NA levels also low
How does levodopa differ from DA
Levo has an extra COOH side chain
What does Levodopa do
Stimulates D2 receptors
What is levodopa coadministered with
Decarboxylase inhibitor
Most levodopa is metabolised by decarboxylase before reaching the brain
This means you can give a smaller dose of levo for better safety profiling
Adverse effects of Levodopa
GI effects
Cardiac arrhythmias
Dyskinesia
On-off phenomenon
2 dopamine agonists used for PD
Bromocriptine - used for on-off phenomenon
Pergolide - stimulates D1 & D2 receptors
Example of a MAOI for PD
Selegiline - can be taken with levodopa
MAO- B inhibitor
Slows break down of DA
Enhances effects of levo
