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PCL470 > Huntingtons and Parkinsons > Flashcards

Huntingtons and Parkinsons Flashcards

1
Q

How many people are affected by huntington’s

A

rare inherited neurological disorder affecting 10 in 100,000 people of western european descent and 0.1 in 100,000 people of asian and adrican descent

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2
Q

how is huntington’s inherited

A
  • autosomal dominant - only need one copy
  • one in two chance of inheriting from an affected parent
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3
Q

huntington’s symptoms

A
  • chorea: uncoordinated movements, orolingual chorea, mental abilities and aspects of personality
  • onset is usually 40s/50s
  • no sudden loss of abilities but a progression
  • physical symptoms are noticed first but anectotally loved ones of people with huntingtons notice cognitive symptoms first
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4
Q

how is huntington’s and death associated?

A
  • people live for 15-20 years after initial onset
  • death caused due to associated complications
  • pneumonia (1/3), heart failure, choking, nutritional deficiency
  • suicide is an associated risk (4x higher than general population)
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5
Q

huntington’s aetiology

A
  • abnormal Hit gene on chromosome 4
  • gene encodes for abnormal Hit protein - polyglutamine gene
  • it encodes for >36 CAG repeats
  • > 39 is pathogenic
  • when 36-38 some may develop HD and some may not
  • probably gain of function but unknown
  • may interfere with regular Htt function
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6
Q

neuroanatomy of huntington’s

A
  • degerantion of neuronal cells in frontal lobes and cauduate nucleus (striatum) of basal ganglia
  • associated neuronal degeneration in temporal and frontal lobes in cerebral cortex –> reponsbible for higher order mental functioning, movements and sensations
  • affect medium spiny neurons in striatum
  • they receive DA from midbrain and release GABA
  • this inhiits release of NT from other nerve cells

loss of medium spiny neurons –> loss of GABA secretion –> decreases inhibition of thalamus –> thalamus increases output to cerebral cortex –> disorganized and excessive movemnt patterns of chorea

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7
Q

pharmacotherapy for parkinsons

A

motor chorea
- olanzepine (D2 blocker)
- tetrabenazine (dopamine depleting agent)
- banzodiazepines
- resperidone
- sulpiride
- amantadine

cognitive
- none that enhance cognition
- modafinil targets DAA
- cholinesterase inhibitors

psychiatric
- depression: SSRIs, TCAs
- psychotic behaviour: atypical neuroleptics/antipsychotics
- mood swings: sodium valproate –> side effect is weight gain which is benedicial

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8
Q

future therapies

A

drugs slowing disease progression
- coenzyme Q - trend to slow disease
- riluzole - no major effect
- creatine - no major effect
- monocycline

transplants to repair cell damahe
- cell implants, stem cells (mixed resulst)

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9
Q

L-DOPA/levodopa

A
  • intermediate in dopamine biosynthesis
  • prodrug to increase DA levels in PD
  • it can cross the BBB via active transport into presynaptic neurone and DA itself cannot
  • when levodopa crosses BBB it metabolized to DA by AAD (aromatic L amino decarboxylase) –> bypasses the rate limiting step of TH
  • excess precursor increases dopaminergic output
  • helps for straight posture and regular gait
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10
Q

cardidopa and denserazide

A
  • peripheral dopa decarboxylase inhibitors
  • prevent the metabolism of L-DOPA to DA in the periphery which could lead to hypotension and arrhythmia
  • when cardidop and L-dopa are combined there is more L-dopa transferring through BBB and a lower dose is required
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11
Q

neuroprotective factor of selegiline

A
  • MAOI
  • prevents nitrolysation of GAPDH which prevents cell death
  • when GAPDG is nitrosylated it can enter the nucleus and cause cell death by associating with mutated Htt and through degradation of N-Cor protein
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12
Q

parkinson’s disease

A
  • neurological disorder affecting chatecolamiine system in CNS
  • degeneration of DA neurone projecting from SN to striatum
  • this leads to DA depletion and loss of DA neurochemical markers –> DAT and VMAT2
  • less DAT is seen in caudate nucleus
  • presence of Lewy bodies: inclusions in cytoplasm of neurons formed by deposits of alpha-synuclein and ubiquitin
  • manifests as muscle rigidity, resting tremor, bradykinesia and akinesia, gait step smaller, freezing in the moment
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13
Q

parkinson’s aetiology

A
  • most cases are idiopathic
  • genetic causes account for 5-10% of PD cases
  • genetic causes have been assigned to different loci: PARK 1-19 which cause or increase risk of PD
  • mutations in alpha-synuclein (PARK 1/4) - autosomal dominant, Parkin (PARK 2) - recessive , DJ-1 (PARK 7)
  • variants in LRRK2 and SNCA cause PD –> causal and rare
  • exposures: insecticides increase risk, MPTP induced PD (toxins that kill DA neurone)
  • in us 1-1.5 million patients
  • higher risk in men than women
  • biggest risk is age (onset is usually 60)
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14
Q

Parkinson’s genetic component key points

A
  • there is a genetic component
  • genes have been identified to be causal: SNCA and LRRK2
  • some causes are autosomal dominant or recessive
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15
Q

MPPP –> MPTP –> MPP+ mechanism

A
  • MPTP byproduct of MPPP synthesis that induces PD
  • MPPP is a synthetic opioid and is an analog of demerol
  • MTPT crosses the BBB and is converted to toxic metabolite MPP+ by MAO-B in glial cells
  • MPP+ is selectively taken up by DAT and accumulates in DA neurons –> neuron expressing high DA are most susceptible
  • MPP+ induces Parkinsonism by inhibiting complex 1 in the electron transport chain in the mitochondria which causes oxidative stress and can causes loss of DA neurons
  • VMAT2 can take up MPP+ in the cell into vesicles so it can’t act on the mitochondria
  • since VMAT2 modulates the toxicity of MPP+, cells with high VMAT2 are more protected
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16
Q

Deprenyl

A
  • MAO-B inhibitor prevents the conversion of MPTP to MPP+ in the cell
17
Q

GBR 12909

A
  • blocks DAT transport of MPP+ into the cell
18
Q

how is tyrosine converted to DA

A
  • tyrosine converted to dopa by tyrosine hydroxylase (rate limiting step)
  • dopa converted to dopamine by dopa decarboxylase or amino acid decarboxylase (rapid conversion)
19
Q

When does levopoda become inadequate?

A
  • one to three years after disease progression mono therapy is inadequate
20
Q

L DOPA adverse drug reaction

A

early
- hypotension
- nausea
- GI bleeding
- disturbed respiration
- hair loss
- arrhythmia

late
- psychiatric
confusion
extreme emotional states
vivid dreams
L-DOPA induced dyskinesia

21
Q

L DOPA induced dyskenisea and how is it helped?

A
  • after long term use people develop irregular movements
  • patients with motor fluctuations on levodopa can benefit from addition of DA agonist to smooth motor fluctuations and improve symptoms
22
Q

Why don’t we have a good genetic animal model for motor impairments in PD?

A
  • rodents may be more resistant to dopamine loss
  • may have evolved this way because mice with dopamine loss that can’t run away die
  • you can decrease DA neurons in mice by 90-95% and they are still able to walk
  • can’t decrease DA neurons by 100% because it can’t walk but also can’t move around to eat and survive
  • the only way to study 100% DA neuron killing are through unilateral killing
23
Q

normal neurotransmission vs lack of DA transporter

A
  • DA in EC space is 6x higher when DAT is knocked out because there is no way to recycle DA
  • this reduces DA stores in vesicles by 90%
  • all DA that is available is coming from synthesis by TH
  • if TH is inhibited then DA release is inhibited
24
Q

DAT-KO mice as a PD model
- what effect does aMT have on DA levels and behaviour
- what are the effects of L DOPA and MDMA

A

DA levels
- aMT blocks TH which induces severe DA depletion in the striatum of DAT-KO mice
- when aMT is administered there is a decrease in DA in striatal tissue of WT mice and none in DAT-KO mice because there are no vesicle stores of DA, and there is no decrease in striatal EC DA in WT and but it goes down to 0 after an hour in DAT-KO mice because there is nothing left to release from vesicles

behaviour
- DAT-KO mice after aMT administration: the animals can’t initiate movement
- locomotion at 0, low number of steps, high catalepsy (freezing), long time grasping on rod

LDOPA
- restored locomotor activity in DAT-KO mice after aMT was administered
- LDOPA/CD also had a good response and needed less DA to have an effect
- there was very little response to DA receptor agonists
- this may be because DA receptor agonists stimulate system constantly while L-DOPA stimulates in pulses

MDMA
- high doses restored locomotor activity
- but MDMA is not transformed into DA
- MDMA seems to be able to increase locomotor activity independent of DA system

PCL470 (14 decks)

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