Download Neurodegenerative Disorders - London Metropolitan University

Neurodegenerative Disorders
• Progressive loss of neurons
• Progressive loss of synaptic
connections
– Parkinson’s Disease
– Alzheimer’s Disease
– Wilson’s Disease
A Story……….
• Barry Kidson: student and recreational drug
user (1976)
• Made MPPP (similar to opioid analgesic;
meperidine or Demerol)
• Injected
 burning sensation
Motor impairment: unable to speak or move
• Diagnosed as catatonic schizophrenic
 Antipsychotic drugs
Parkinson’s Disease
• Mainly affects > 60 years
 Tremors
 Rigidity
 Bradykinesia
 Hypokinesis
 Postural disturbances
• Cognitive dysfunction
• Dementia
– Severe impairment of memory, abstract
thinking and language
Remember: DA is not only about movement
Mesocortical DA
pathway
Mesolimbic DA
pathway
James Parkinson (1817);
“shaking palsy”
neuromelanin
Substantia Nigra: Dopamine (DA) main transmitter
• Immunohistochemical stain for
tyrosine hydroxylase show loss of
DA cells in Parkinson’s Disease
(PD): > 80% 
• Also, in PD, severe decline of DA
content in corpus striatum (caudate
nucleus and putamen) termination
of s.nigral axons
[123I]altropane imaging
• Binds to DA transporter
• Concentrated in striatum
 high density of dopaminergic
nerve terminals
• Red
= +++
• Yellow
= ++
• Purple
=+
Progressive damage to ascending
DA system  Parkinson’s
• Symptoms appear once striatal DA levels 70-80% of
normal
• Beyond threshold, correlation between degree of
damage to DA system and severity
• Pharmacotherapies aimed at increasing DA availability,
or stimulating DA receptors, reduce symptoms
• Destruction of nigrostriatal DA pathway produces
motor deficits as in PD
DA plus……….
• Hypokinesia most clearly related to DA loss
• Rigidity/tremor relate to complex disturbances
of ACh, NE, 5-HT, GABA
• Cholinergic neurones in Striatum contain
highest concentration of Ach, ChAT, AChE in
brain
• DA inhibits ACh release
• ACh hyperactivity  PD symptoms
6-OHDA (6-hydroxydopamine) Lesioning
• Bilateral 6-OHDA
show severe
behavioural
dysfunction
 Sensory neglect
 Motivational
deficits
 Motor impairments
Unilateral injection: postural asymmetry
Leaning and turning towards damaged side of brain
How does a loss of striatal DA produce
profound behavioural disturbances?
• Basal ganglia – subcortical system forms a
“loop” with the cerebral cortex
• Basal ganglia “gate” movement commands
originating in motor cortex
• DA projections to striatum helps keep gate open
• Loss of DA activity impairs gate opening; difficult
for individual to initiate and control voluntary
movements
Pharmacological intervention
• Anti-psychotic agents (eg to treat
schizophrenia) produce
extrapyramidal side effects
• Result from blockade of dopamine-2
receptors
Hypodopaminergic state
Parkinson’s also associated with
hypodopaminergic state
• DA replacement therapy
• Administration of DA agonist
• Administration of DA breakdown
inhibitor
Levodopa (L-DOPA)
dihydroxyphenylalanine
Oral: rapidly absorbed; 95% converted to
dopamine in plasma
1-5% crosses BB barrier to CNS (DA
cannot cross barrier)
DOPA converted to DA mainly within
presynaptic terminals of DA neurones in
basal ganglia
Always a problem
• L-DOPA destroyed by GI and Liver
enzyme……
• …..and converted to DA in peripheral
circulation  eg nausea
• Need to reduce high levels of systemic DA
while maintaining sufficient levels in brain
• Dopa decarboxylase converts DOPA to DA
• Selectively inhibit enzyme in systemic
circulation (but not in brain)
Carbidopa (Sinemet)
• Active in body, but does not cross BBB:
metabolic conversion occurs in CNS only
• Used in combination with L-DOPA
• Effective dose of L-DOPA  75%
• Reduced side effects
• No loss of CNS effects
COMT (catechol-o-methyltransferase)
inhibitors
• COMT active in liver and GI tract
• Half life of Sinemet increased by adding COMT
inhibitor
• Tolcapone (Tasmar) 1998
• Blocks COMT enzyme, increased half life of
L-DOPA
• Liver toxicity: withdrawn
• Entacapone 2001 (Comtan)
• Inhibits peripheral COMT, no effect on CNS
COMT; inhibition of peripheral L-DOPA
breakdown increases central L-DOPA (hence DA)
Stalevo (2004)
• Combination product
 Levodopa
 Carbidopa: increases DA in brain
 Entacapone: inhibits degradation of L-DOPA
through inhibition of its degradative enzyme
COMT
• Combination provides more brain DA, for longer
time periods: less “wearing off”
Limitations of L-DOPA
• Each dose becomes less effective
• Increasing dose leads to movement
disorders (dyskinesias)
– cf rigidity, akinesia of PD)
• May accelerate the cause of PD
– ie ameliorating the symptoms may aggravate
the disease
Dopamine receptor agonists
• Loss of response to L-DOPA
• Progressive inability for neurones to
synthesise and store DA
• Receptor agonists  postsynaptic
DA receptors
DA Agonists
• Bromocryptine
• Pergolide
• Pramipexole
• Ropinirole
 Marginally effective
 Bothersome side effects
 Drowsiness, dizziness,
nausea, hallucinations,
insomnia
Selegiline
• Monoamine oxidase MAO: 2 isoenzymes
– MAO-A: NE and serotonin
– MAO-B: DA (striatum)
• Selegiline preferentially inhibits MAO-B (in doses
< 10mg day-1)
• Therefore preserves small amounts of DA present
• Slows down progression of disease
• Selegiline is metabolised to several by products
(including amphetamine and methamphetamine)
What about Barry Kidson?
• Aimed to produce MPPP
• Contaminant MPTP
 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
• Neurotoxin – destroys DA neurons in substantia
nigra: depletes striatal DA
 cf 6-OHDA
• Behavioural syndrome similar to PD
• Responds to treatment with L-DOPA
Pharmacology of Alzheimer’s Disease
• Some issues:
– Definite diagnosis only made PM
– Antemortem diagnosis 10-15% error
– Syndrome
– Changes in test scores may be significant
statistically but clinically meaningless
– Lack of evidence that drug treatment improves
QOL for sufferers (or carers)
AD not just associated with cognitive
impairment…………………….
• Depression:
– treated with antidepressants that lack
anticholinergic side effects (eg SSRIs
• Treatment for apathy:
– eg psychostimulants, buproprion
(antidepressant), bromocryptine etc
• Psychosis, agitation:
– New (atypical) antipsychotic agents
– Mood stabilizers, sedating antidepressant
(trazodone)
Cholinergic Hypothesis of Cortical Dysfunction
• Centrally acting muscarinic blocking agents
induces loss of recent memory
• 80-90% loss of Ach in cerebral cortex and
hippocamus of AD patients; decrease in ChAT,
and choline uptake
• In AD patients, loss of neurons in “nucleus
basalis of Maynert”
• In some AD studies, decrease in muscarinic and
nicotinic receptors
Ach central pathways
Note: basal forebrain cholinergic system (BFCS)
Acetyl choline precursors
• Choline
• Lecithin (phosphatidyl choline)
• NO EFFECT
• In symptomatic AD: too few
presynaptic cholinergic neurons to
have clinical effect
Cholinesterase Inhibitors
enhancement of cholinergic transmission
• TACRINE
• “Modest” improvement in test of memory
and cognition in 40% of AD patients
• No improvement in functional measures
affecting QOL
 4 times daily
 Cholinergic side effects – nausea, abdominal
cramps, hepatotoxicity
Some better ones……..?
• Donezepil: not hepatotoxic
• Rivastigmine: longer lasting; CNS
selective; fewer peripheral side effects
• Galanthamine: plant alkaloid (snowdrop
family); two effects
– Cholinesterase inhibitor
– Activation of brain nicotinic Ach receptors
Different approaches
 Glutamate receptor NMDA implicated in memory
processes, dementia and pathogenesis of AD
 Excess glutamate – excitotoxicity
 MEMANTINE
 “Moderate affinity” non-competitive NMDA
antagonist
 Reduces clinical deterioration in moderate to
severe AD patients
ACh and Glucose Metabolism
Nootropics (smart drugs)
Inhibiting Neurodegeneration
• AD molecular targets becoming known
• Transgenic animal models available
• Schenk et al (1999) immunised AD
transgenic mice with A protein
 Prevented plaque formation (and reversed it)
• Non-steroidal anti-inflammatory drugs (eg
indomethacin, ibuprofen) reduce
likelihood of developing AD