Psychiatric and movement disorders Flashcards
main NT involved in movement control
dopamine
three dopaminergic pathways
1) Tuberohypophyseal pathway
2) mesocortical pathway
3) nigrostriatal pathway
Tuberohypophyseal pathway
Neurones which are dopaminergic , start with their cell body in the hypothalamus and spread out in the brain
Mesocortical pathway
starts in VTA (ventral tegmental area) up to the cortex
Nigrostrialtal pathway
starts in the SN (substantia nigra) and ends in Str (corpus striatum)
- Where cell death and damage occurs in Parkinsons disease
Parkinsons
A neurodegenerative disorder involving death and damage to the nigrostriatal pathway which starts in the substantial nigra and ends in the corpus striatum. All to do with dopaminergic neurones dying and muscles become rigid due to inhibition of movement
How is the brain stimulated in those with parkinsosn
high output by GABergic effects, increased inhibition of the thalamus and therefore decreased excitation of motor cortex causing BRADY KINESAI
Symptoms of Parkinsons
- bradykinesia- suppression of voluntary movement
- muscle rigidity
- cogntitive impairment variable
- tremor at rest- pill rolling
- temor lessons with voluntary movement
- shuffling gait
causes of parkinsons
- idiopathic
- cerebral ischaemia
- viral encephalitis
- drug induced
idiopathic
arises spontaneously or for which the cause is unknown.
dopamine will be found to be low in which tissue
substantia nigraand corpus striatum
In Parkinson’s there is a high output by GABAergic efferents
Increasing inhibition of thalamus
Decreased excitation of cortex (from thalamus)-bradykinesia
nigrostriatal pathway
1) Dopaminergic neurone releases dopamine into the corpus striatum (nerve terminal )
2) Inhibitory to corpus striatum
3) This inhibition to the corpus striatum excites glutamatergic and cholinergic neurones
3) GABAergic neurons are inhibited which activates motor 4) This is excitatory to glutamatergic neurones leading to the motor cortex
5) Meaning the motor cortex is activated more by glutamine
which dopaminergic pathway is linked with addiction
Mesolimbic
voluntary movement is controlled by inhibitory and excitatory neurones in
- motor cortex
- basal ganglia
- thalamus
when these neurone die or are disrupted this is when disease occurs
what is Anticipation in disease
signs and symptoms of some genetic conditions tend to become more severe and appear at earlier ages as the disorder is passed from one generation the next
- most often seen with genetic disorders of the nervous system e.g. huntingtons
wen does anticipation typically occur
with disorders caused by an unusual type of mutation called a triucleotide repeat expansion.
–> The number of repeats can change as the gene is passed from parent to child. If the number of repeats increases, it is known as a trinucleotide repeat expansion. In some cases, the trinucleotide repeat may expand until the gene stops functioning normally. This expansion causes the features of some disorders to become more severe with each successive generation.
Deep brain stimulation
is a neurosurgical procedure involving the implantation of a medical device called a neurostimulator, which send electrical impulses , through implanted electrodes to specific target int he brain for the treatment of movement and neuropsychiatric disorders.
negatives of DPS
limitations of deep brain stimulation has been that it requires brain surgery and carries an associated risk of hemorrhage, stroke, infection, and hardware failure.
DBS more detail
- uses electrical currents to target abnormal brain activity –> tigers blood flow and the release of NT (e.g. dopamine)
- connecting malfunctioning connections in the brain
- electrodes are implanted in target area of patients brain then can be turned on externally
epigenetic markers are
non-hereditary changes to the histone code or to any molecules other than the DNA itself
where does epigenetic modification normally occur
at the N terminus of histone tails
methylation
silences
acetylation
activates
siRNA
small interfering RNA regulates gene expression
0e.g. certain proteins made that relate to movement disorders are prevented by siRNA
L-DOPA is used to treat
parkinsons
L-DOPA and BBB
dopamine is unable to pass the BB since it is hydrophilic. Therefor eL-DOPA is given and the aim is for it to be converted by DOPAdecarboxylate to dopamine within the brain to help with movement control
which enzyme converts L-DOP in the periphery to dopamine and why is this badd
Dopadecarboxylate
- bad since we want as much of the L-DOPA to be converted in the brain as possible, since this is where it is useful
which inhibitor is used to prevent L-DOPA being converted to dopamine in the periperhy
Carbidopa- only works in periphery
which enzyme in the brain converts dopamine to inactivate metabolites
MAO-B
MAO-B
converts dopamine to useless metabolites ion the brain
which enzyme converts L-DOPA to 3-O-Methyldopa- in the periphery?
COMPT
name some COMP inhibitors
tolcapone and entacapone
why is entacpone the preferred compete inhibitor to tolcapone
due to liver toxicity
why is MAO useful
makes dopamine more available by preventing its breakdown
dopamine synthesis
Dopamine sysnthesis proceeds from tyrosine via tryosine hydroylase (TH) catalysis to levodopa (L-dopa), and subsequent decarboxylation by dopa decarboxylase (DDC) to dopamine.
what metabolised dopamine
interneuronaline monoamines (MAOs) and by glial astrocyte MAOA and MAOB
MAO-B
these enzyme are involved in the breakdown of serotonin and dopamine into inactive metabolites reducing its active amount
inhibition of MAO-B
Inhibition of MAO-B
Inhibiting MAO-B prolongs the action of dopamine in the brain, improving Parkinson’s symptoms
Inhibitors: Selegiline
Inhibits MAO-B
Metabolized to amphetamines- bad
Makes dopamine more available by preventing tis breakdown
Also has a mild anti-depressant effect
name a MAO-B inhibitor
selegilline
MAOIs and overall cheese reaction
if too much tyramine is eaten (cheese and wine), whilst on antidepressants (MAO inhibitors), tyramine inhibits MAO-A, so lots of unchanged tyramine is able to pass the gut. Therefore tyramine is taken to the brain and increases release of noradrenaline from adrenergic neurone- increasing stress response - hypertension
Why does treatment with L-DOPA help treat Parkinson’s?
Parkinson’s diseaseis primarilycausedby low and fallingdopaminelevels.
A person withParkinson’shas abnormally lowdopaminelevels.
Dopamine-generating cells, known asdopaminergicneurons (types of nerve cells) in the substantia nigra part of the brain have died.
Increase in dopamine
Helps parkinson sufferers
Regain control of movement
L-DOPA is a
prodrug and precursor of dopamine used to improve symptoms of Parkinson
BBB
Selective barrier containing astrocytes, endothelial and epithelial cells. Tight junctions between endothelial cells
dopaminergic receptors
GaS
dopaminergic receptors and GaS
Stimulates adenylate cyclase conversion of ATP → cAMP
Activated protein kinase A that phosphorylates downstream activators
Serine and threonine residues within target
Cardiac Muscle contraction due to phosphorylation of L - Type calcium ion channels through B1 adrenergic receptors → Gas
80% of proteins
misfold
Alzheimers disease
A progressive neurological disease which affects multiple brain functions, including memory, swallowing, language, personality
Effects temproal lobe too- storage of new info is hard
Fatal 8-10 years after symptoms
Exact cause is unknown
misfolding in Alzheimers
- caused by the accumulation of B-amyloid plaques in the brain of AD patients
- in a healthy brain these protein fragments ar broke down and eliminated
- in Alzheimers, the fragments accumulate to form hard, insoluble plaques
-these plaques form between neurones in the brain
causing tau neurobifillary tangles
Pyrions disease
A group of progressive neurodegenerative conditions.
A prion is a type of proteins that can trigger normal proteins in the brain to fold abnormally. Prion diseases can affect both humans and animals and are sometimes spread to humans by infected meat products.
Pyrions diseases and protein misfolding
-Spongiform encephalopathies
Prion protein altered glycossylation becomes misfolded
PrPC PRPSc
examples of pyrions disease
- CJD (Creutzfeld-Jakob) (most common to affect humans)
- BSE (mad cows)
protein misfiling in Parkinsons
Protein clumps called Lewy bodies found in Parjinsons disease are caused by misfiled a-synuclein
- misfolded alpha synuclein moves between neighbouring cells and can cause cell death
- when cells involved in the dopaminergic pathway are affected, this is when parkinson occur
overall Lew bodies caused by misoflded alpha-synuclein cause
neuronal cell death (nigrostrial dopaminergic neurones) - causing parkinsons
Huntington disease
Progressive neurodegeneration: lifespan reduced (15-20 years)
Cognitive disorders: impulse control, task organization, flexibility, learning
Movement disorders: involuntary jerking/writhing/twitching movements (chorea), rigidity (dystonia), speech/swallowing, posture/balance/gait
Psychiatric disorders
what causes huntingtons
CAG repeats in huntingtin= glutamine residues
Trinucleotide repeats
40+ Gln= decreased solubility= aggregates
Anticipation – next generation have an earlier onset of the disease
the mutation which causes HD
The mutation that causes HD is known: an abnormal expansion of CAG repeats in the IT15 gene results in an autosomal dominant trait. The huntingtin (Htt) protein has an abnormal number of glutamine repeats (polyQ)
This abnormally long polyQ within the Htt protein, confers one or more toxic function to mutant Htt leading to neurodegeneration
