UNIVERSITY COLLEGE LONDON

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UNIVERSITY COLLEGE LONDON Department of
Pharmacology PARKINSONS and ALZHEIMERS
DISEASES James Parkinson described the Shaking
Palsy in 1817. This disease, now named after
him, is unique in that the symptoms result from a
single transmitter deficit due to the loss of
dopamine neurones in the substantia nigra. The
degeneration of these neurones means that
dopamine is depleted from the nigrostriatal
projection zones in the striatum. The cause of
the neuronal death is unknown but it is likely
that about 70-80 of the nigrostriatal neurones
have to die before the symptoms appear. Although
flawed designer drugs (MPTP a toxic opioid
metabolite that triggered PD in several young
Americans) and environmental chemical factors
have been implicated in the aetiology of PD,
there is little evidence to suggest that the
disorder is anything other than an ongoing loss
of vulnerable neurones as part of the ageing
process. Life events may speed the process.

• Symptoms
• Muscle rigidity.
• Akinesia (poverty of movement)
• Tremor at rest.

Anatomy of motor systems The substantia nigra
contains dark pigmented neurones, hence the name,
and these dopamine neurones project to the
striatum. The striatum (caudate-putament)
projects to the thalamus via the globus pallidus
and receives inputs from the cortex. This
curcuitry allows motor programmes to be
established. The loss of the nigrostriatal
projection could be likened to clutch failure
so the basal ganglia gearbox locks up hence
the rigidity. There are inhibitory GABA
projections from the striatum back to the
substantia nigra and intrinsic excitatory
cholinergic striatal neurones. Activity in these
latter neurones which lose their inhibitory
dopamine control are mostly responsible for the
tremor in PD. The loss of the inhibitory GABA
striato-nigral pathway produces the uncontrolled
motor activity seen in Huntingdons Chorea.
Huntingdons Chorea, unlike PD. Is a genetic
disorder.

• Pharmacology of dopamine transmission.
• The loss of dopamine neurones in PD means that
  therapy is aimed at restoring the function of the
  transmitter. However, there are two ways by
  which this can be
• Replenishment of the transmitter or
• Mimicking the receptor effects of dopamine.
• In addition, the loss of dopamine control on
  acetylcholine neurones in the striatum means that
  muscarinic receptor antagonists can be used to
  control the tremor (no value aginst
  rigidity/akinesia).

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• However there are other dopamine pathways in the
  CNS and dopamine has peripheral actions so that
  augmenting dopamine function can produce marked
  side-effects.
• Dopamine pathways
• Nigrostriatal pathway (A9 nucleus to
  caudate-putament). Fails in PD.
• Mesolimbic pathway (A10 nucleus to nucleus
  accumbens). Reward pathways. Psychosis?
• Mesocortical pathway (A10 nucleus to frontal
  cortex). Psychosis?
• Median eminence to anterior pituitary.
  Inhibition of prolactin secretion.
• Chemoreceptor trigger zone (CTZ/) vomiting
  centre. Dopamine induces emesis (disinhibition).
• Synthesis
• Tyrosine L-DOPA Dopamine DOPAC/HVA
• Tyrosine Hydroxylase DOPA decarboxylase
  Monoamine
• Oxidase B
• Receptors
• There were two dopamine receptors (D1 and D2) but
  there has been a recent proliferation so that
  there are now 5 cloned receptors. The receptors
  are inhibitory although some excitatory D1
  effects have been reported. The receptors are
  G-protein coupled D1 and D2 are coupled to
  adenyl cyclase and IP3 respectively. The D1 and
  D5 appear to be similar and the D2, D3 and D4
  have similar pharmacological profiles.
• THERAPY FOR PARKINSONS DISEASE
• Augment Dopamine function
• L-DOPA
• Dopamine does not cross the blood brain barrier
  but L-DOPA does. It is then converted to
  dopamine by DOPA-decarboxylase. Since most
  dopamine neurones are dead it is though that some
  L-DOPA may be converted in other monoamine
  neurones or the remaining cells have increased
  compensatory capacity. The akinesia and rigidity
  are improved more than the tremor and L-DOPA,
  which usually works best in the less elderly
  patients, produces improvements in movement over
  the first 18 months or so of therapy. This then
  is maintained for about 2-3 years before a
  gradual decline occurs, probably as more and more
  dopamine neurones die. Large doses (oral
  100-500mg per day) of L-DOPA are needed but due
  to metabolism in the periphery only about 2
  enters the brain.

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• The production of dopamine in the brain leads to
  
• Central side-effects
• Dyskinesia (uncontrolled movements).
• Psychotic effects (schizophrenia is treated with
  dopamine antagonists.
• Reductions in prolactin release.
• On-off effects. Uncontrolled swings from
  akinesia to dyskinesia, usually occurring after
  several months of therapy and as the dose of
  L-DOPA wears off.
• The production of dopamine in the periphery leads
  to
• Peripheral side-effects.
• Hypotension displacement of noradrenaline so
  reducing sympathetic tone.
• Nausea dopamine activates the CTZ which
  although in the brain stem, lacks a blood brain
  barrier.
• As a consequence, adjuncts are used to prevent
  peripheral formation of dopamine.
• Adjuncts to L-DOPA
• DOP decarboxylase inhibitors
• Carbidopa and benserazide ar inhibitors of DOPA
  decarboxylase and so prevent the L-DOPA being
  converted to dopamine. The key point is that
  these drugs do not cross the blood-brain barrier
  and so allow conversion to only occur in the
  brain. Thus doses of L-DOPA can be reduced so
  peripheral side effects are reduced. Used in
  combination tablets with L-DOPA and the
  improvement in movement is faster in onset and
  smoother.
• Monoamine oxidase inhibitors
• Selegiline is a selective monoamine oxidase B
  inhibitor that reduces the breakdown of dopamine
  in the CNS this allows more effective therapy.
  It is thought to reduce the ongoing neuronal
  degeneration to some extent.
• Dopamine receptor agonists.

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• Muscarinic antagonists.
• Atropine and benztropine correct the relative
  cholinergic excess that occurs as a result of the
  dopamine deficiency. Tremor is reduced and they
  can be useful supplements to L-DOPA therapy.
• HUNTINGDONS CHOREA
• This inherited disorder has symptoms of
  uncontrolled movements which mainly results from
  a loss of striatal neurones, especially the GABA
  neurones which project back down to the
  substantia nigra. This loss of inhibition
  results in a lack of inhibition of the dopamine
  neurones and can be partly controlled by D2
  receptor antagonists. Reducing the dyskinesia
  without causing akinesia is very difficult
• OTHER MOTOR DISORDERS
• Tics, sudden stereotyped movements are of unknown
  origins but respond to dopamine antagoists.
  Tourettes syndrome also involves vocal tics.
• PS. To realize that a motor disorder does not
  involve a D registration Ford Escort.
• ALZHEIMERS DISEASE
• Unlike Parkinsons Disease, there is a genetic
  linkage to this degenerative disorder. The
  neuronal loss is less specific and involves the
  Cholinergic pathway from the nucleus basilis to
  the cortex, a subsequent loss of nicotinic
  receptors, reductions in some somatostatin
  neurones and a number of other changes. The
  latter include plaques and tangles (extracellular
  deposits of protein and erroneous filaments
  respectively. The major symptoms are termed
  dementias and can also be caused by non-organic
  factors such as stroke, brain damage and alcohol.
  Prevalence, like Parkinsons increases with age.
  Individuals suffer a loss of memory (often
  short-term memory), lose contact with the outside
  world, lose verbal and intellectual comprehension
  and treatment, as yet, has at best, highly
  marginal benefits. The treatment strategy, like
  Parkinsons disease, is to replace the lost
  transmitter. However, due to lack of effective
  drugs acting on cholinergic neurones, the
  difficulty in getting drugs into the brain and
  the extensive peripheral roles of acetylcholine
  no useful drugs have been developed. Most
  promising has been anticholinesterases (tacrine)
  but even this drug has been disappointing.

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STRIATUM
C O R T E X THALAMUS
ACh
BROMOCRIPTINE
OD2
L-DOPA
DA
DOPAC
SELEGILINE
HUNTINGDONS CHOREA
DA NEURONAL LOSS
SUBSTANTIA NIGRA
DOMPERIDONE CTZ
Nausea vomiting
L-DOPA
BLOOD VESSEL
DA
BBB
carbidopa