Parkinsons Flashcards
What are the steps and enzymes involved in dopamine synthesis
Tyrosine taken up into dopaminergic neuron terminals by tyrosine transporters.
Tyrosine -> Dopa by Tyrosine hydroxylase
Dopa -> Dopamine by Dopa decarboxylase.
VMAT2 -> packages into vescicles.
What three things can happen to dopamine after release into synaptic cleft?
- Re-uptaken into neuron by dopamine transporter (DAT)
- Metabolised in microglial cells-> Mono-amine oxidase / Catechol-o-methyl transferase (COMT) -> Producing DOPAC / HVA
- Taken up into a noradrenalin neuron and converted to noradrenalin by Beta-hydroxylase.
What type of neurotransmitter/hormone is dopamine?
Catecholamine - Tyrosine derivative.
Structure: Benzene ring, 2 hydroxyl groups, a single amine group.
Where in the brain is dopamine primarily produced?
Substantia nigra (pars compacta) and ventral tegmental areas.
Define Parkinson’s disease
A neurodegenerative disorder - progressive degeneration of the nigrostriatal pathway resulting in depletion of dopamine. This causes alterations in muscle activity and function
causes of parkinson’s disease
- Idiopathic
- Genetic predisposition
- Glucocerebrosidase mutation: causes impaired autophagy function i.e. cannot effectively clear dysfunctional cellular components
- Dardarin (LRRK2): most commonly assoc with autosomal dominant PD
- Parkin (PARK2): autosomal recessive PD - Post-infection: HIV, HSV, Syphillis.
5 non-motor signs of PD
- Anosmia (loss of smell)
- Orthostatic hypotension
- Urinary urgency
- Sudden onset sleep/daytime sleepiness
- Mood changes
- Constipation
why does bradykinesia/Akinesia happen in PD?
Alterations to the direct and indirect pathway now that dopamine is gone:
Direct pathway: double effect
(i) dopamine no longer exciting the striatal neurons of direct pathway. Therefore activity of direct pathway is turned down. Therefore the excitatory effect of the direct pathway on the motor cortex is turned down.
(ii) inhibitory Cholinergic interneurons within striatum are now unopposed, further turning down the direct pathway.
Indirect pathway:
(i) loss of inhibition of indirect pathway by dopamine now makes the indirect pathway more active i.e. more inhibition of the thalamus therefore less excitation of motor cortex.
(ii) inhibitory cholinergic interneurons continue to excite the indirect pathway- further contributing to the dampening of motor function.
Glutamate (excitatory) is released from neurons travelling from what part of brain involved in basal ganglia circuit?
From:
Cortex
Subthalamic n
Thalamus
GABA (inhibitory) is released from neurons travelling from where?
Striatum (putamen/caudate)
Globus pallidus
How does dopamine elicit the vomit response
Dopamine or a dopamine agonist binds the D2 receptor in chemoreceptor trigger zone in medulla. This is a Gi coupled receptor resulting in downstream signalling which results in the message being relayed to the solitary nucleus. From there the message is transmitted to the vomit centre of the medulla.
Vagus and enteric nervous system are engaged to elicit the response:
Gastric relaxation
Relaxation of esophageal sphincter
Contraction of diaphragm
Contraction of abdominal muscles.
describe the 4 components of the blood brain barrier
- Tight junctions and adherens junctions between the endothelial cells of the cerebral capillaries - prevents passage of hydrophilic molecules.
- Continuous basement membrane of capillaries (no fenestrations)
- Astrocyte foot processus projecting onto capillaries
- Pericytes
- structural support
- physical barrier
- modulate cerebral blood flow through contraction
-phagocytic function
4 things that can disrupt the BBB
- Radiation exposure
- Infection
- Hypertension
- Physical trauma
what is the structure of the brain- CSF barrier
Tight junction between ependymal cells
Pia mater
basement membrane
Fenestrated capillaries
Blood
Ependymal cells are columnar/cuboidal epithelial cells lining the ventricles and central canal.
- their apical/ciliated surface secrete and circulate CSF.
-Forms blood CSF barrier
Produces 500ml CSF a day
five functions of astrocytes
- pH balance: maintains normal pH balance in CNS through removal of excess H+ ions.
- Neurotransmitters: Synthesizes and secretes glutamate, and can uptake GABA, glutamate and ATP.
- Detoxification: can remove ammonia to prevent neurotoxicity through the glutamine-glutamate cycle -> converts it to glutamine then the glutamate and returned back to neuron.
- Signal transmission/memories/ synaptic modulation: Gap junctions allow passage of small molecules + cell-cell transmission. Partakes in long-term potentiation and in functional synaptic plasticity whereby pre-existing synapses are strengthened.
- Blood brain barrier
Function of microglial cells.
These are histiocytes of CNS i.e. immune cells.
scavenger cells.
Release inflammatory cytokines and chemokines when activated.
what is alpha-synuclein, what is its function and how is it implicated in PD
Alpha synuclein is a monomer, unfolded protein that functions in:
- synaptic vesicle formation
- calcium homeostasis
- Normal golgi-apparatus function
- catecholamine metabolism
Involvement in PD:
- Genetic mutations/post-translational errors can result in misfolding of a-synuclein
- folds into an insoluble, beta-pleated oligomer.
- aggregates within neurons to form lewy bodies.
- Genetic causes of misfolding linked to familial PD
- post-translational linked to sporadic forms of PD
- Because there is a defective ubiqutin-proteosome-system, as well as defective autophago lysosomal systems, the abnormal protein cannot be tagged for destruction - generally done by E3 ubiquitin ligase. The misfolded proteins therefore form lewy bodies
- overall the oxidative damage caused results in neuronal apoptosis.
outline 3 ways that PD management is optimised by medications
- Replenishment of dopamine -> Levodopa
- Maximising the amount of levo-dopa crossing the BBB before it is converted to dopamine/ 3-o-methyldopa peripherally -> Dopa decarboxylase inhibitors / COMT inhibitors respectively.
- Prolonging the duration of action of dopamine centrally by preventing its breakdown -> COMT + MAO-B inhibiors
where is levodopa absorbed from?
upper small intestine via an amino acid transporter
What drug is used as decarboxylase inhibitor
Carbidopa
5mg carbidopa : 20mg levodopa
Combination is called Co-Careldopa
Name 2 COMT inhibitors
- Entacapone: Does not cross the BBB, therefore only works peripherally (prevents levo-dopa -> 3-o-methyldopa
- Talcapone: Does cross the BBB but can cause acute liver injury -> should only use if not responsive to Entacapone
Overall, Combo of Levodopa, DD inhibitor, COMT inhibitor is called STALEVO.
Name 2 classes of Dopamine agonists
When might dopamine agonists be used in PD management
Can be used as a monotherapy in early stages of disease or along with levodopa
Non-Ergot derivatives
-Pramipexole (D3 mostly)
- Ropinirol (D2,3)
- Rotigotine (D1,2,3)
- Apomorphine (D1,2)
Ergot derivatives
- not used commonly as assoc with pulmonary, periotoneal and pericardial fibrosis.
When might Mono-amine oxidase inhibitors type B be used?
Name 2 MAO inhibitors
Selegiline
Rasagiline
Can be used as monotherapy or with levodopa in patients with end-dose fluctuations.
On what chromosome is the gene effected in Huntingons disease? What happens as a result of this mutation.
Chromosome 4.
Results in abnormal trinucleotide repeat CAG sequences in Huntingtin protein.
37-80 repeats seen usually, healthy individual will have 10-26
Results in degeneration of caudate nucleus and putamen mostly as awell as loss of cortical neurons.
Inclusion bodies formed by accumulation of huntingtin proteins.
Signs: Choreiform movement, psychotic behaviours, character change.
What is meant by parkinsonism? Name two drugs that can induce parkinsonism.
Parkinsonism refers to a group of movement disorders that share symptoms similar to those of Parkinson’s disease, such as tremors, bradykinesia, rigidity, and postural instability. Parkinsonism is not a specific diagnosis but rather a clinical syndrome with various potential causes, including neurodegenerative diseases, certain medications, toxins, and other medical conditions
Two drugs that can induce:
- Typical Antipsychotics e.g. Chloropramazine
- Antiemetics e.g. Metochlopramide
List 3 other underlying conditions that may cause parkinson’s disease rather than idiopathic?
Genetic abnormalities e.g. LRRK2, PARK2, PINK1
Exposure to pesticides
Post-infection with HSV, HIV, Syphillis
What is the number 1 risk factor for parkinon’s disease?
Age. Risk increases with older age.
What type of drug is Carbidopa? why might it be administered along with Levo Dopa?
Carbidopa is a Dopa Decarboxylase inhibitor. It works peripherally by inhibiting the enzyme Dopa Decarboxylase thereby preventing metabolism of Levo-dopa to dopamine. This allows for Levo-dopa to cross the BBB (dopamine does not cross BBB). Because DDI’s do not cross the BBB themselves, it does not prevent subsequent conversion of Levo-dopa to Dopamine centrally.
Therefore DDI’s are given to:
(i) Allow for Levo-dopa to cross the BBB
(ii) Prevent side effects caused by peripheral conversion to dopamine.
Explain how selective monoamine oxidase type B inhibitors produce their beneficial effect in Parkinson’s Disease.
Selective MOA-B inhibitors such as selegiline, rasagiline, work by inhibiting the breakdown of dopamine to DOPAC/ HVA within the CNS. This therefore prolongs Dopamine’s effects within the CNS.
Benefits of MAO’s
(i) Prolongs dopamine’s effects
(ii) Allows for dose reduction of levo-dopa
Indications
(i) Monotherapy for idiopathic PD
(ii) Administered with levodopa for patients with end dose motor fluctuations
4 peripheral and 4 central sides effects of dopaine
Peripheral
-postural hypotension
-arrythmias
-nausea/vomitting
-flushing
Central
-dyskinesa
-motor fluctuations
-sudden onset sleeo
-psychological disturbances e.g. hallucinations, psychosis, confusion
What are the 4 main dopamine pathways
- Nigrostriatal
- Mesolimbic
- Mesocortical
- Tuberohypophyseal
