Neurotransmitter synthesis

1. ACETYLCHOLINE
MYSTHEMIA GAVIS
ORGANOPHOSPHate POISONING
CATECHOLAMINES
PARKINSON’S DISEASE

2. Acetylcholine Synthesis and Degradation
+ choline
Acetyl-CoA
Pyruvate
PDH complex
(FAD, lipoamide, TPP)
Choline acetyltransferase
(CAT)
(inhibited by mercurials)
Acetylcholine
Acetylcholinesterase (AChE)
(membrane associated; inhibited by
nerve agents, sarin)
Acetate + choline
Reuptake
or diet

3. Acetylcholine Receptor
a
a
b
g (or e)
d
Miyazawa, A., Y. Fujiyoshi, and N. Unwin. 2003. Structure and gating
mechanism of the acetylcholine receptor pore. Nature 423:949-955.
ACh
ACh
AChR

4. Acetylcholine Receptor
http://www.med.upenn.edu/ins/faculty/lindstro.htm
Jon M. Lindstrom, Dept Neuroscience
School of Medicine, University of Pennsylvania

6. Myasthenia gravis
Formation of auto-antibodies to the ACh receptors
present in the myoneural junction
Damage to the receptors (focal lysis) by the auto-antibodies,
resulting in cross-linking & endocytosis
Marked reduction in number of receptors
Clinical signs, particularly episodic weakness of muscles
supplied by cranial nerves
 Auto-immune disease
Figure: Causation of Myasthenia gravis

7. Diagnosis
 The diagnosis is suspected from a combination of the
history, clinical findings & certain laboratory tests
(eg, electromyography, measurement of circulating
auto-antibodies)
 Diagnostic test: administration of appropriate dose of
the short-acting agent edrophonium (Tensilon)

8. Treatment
 Pyridostigmine
 Neostigmine
 Diisopropylfluorophosphate (DFP):
irreversible inhibitor of cholinesterase
 Immunosuppressants: Azathioprine

9. Organophosphate poisoning
 Worldwide million cases each year, resulting in
20,000 deaths
 Most occur through ingestion of suicidal intent
 Most serious poisoning occurs by ingestion,
cutaneous absorption & inhalation of sprays rarely
causes serious toxicity

10. toxicity
Organophosphorus compounds , parathion & malathion
are powerful neurotoxic agents
They inhibit acetylcholine esterase (both red cell
cholesterase & plasma cholinesterase) through
phosphorylation of the active centre of the enzyme.
Acetylcholine accumulates in the nerve endings
The transfer of nerve impulse across synapses & at the
nerve-muscle junction is prevented

11. Clinical
features In mild to moderate poisoning:
 Headache
 Blurred vision
 Excessive salivation
 Lacrimation
 Sweating
 Wheezing &
 Lethargy
(patient should be kept under observation for at least
24 hrs)

12. Severe poisoning:
 Coma
 Convulsions
 Respiratory muscle paralysis
 Bradycardia
 Hypotension
.

13. Diagnosis
 Depends on the estimation of cholinesterase in serum
& RBC
Antidote:
 Atropine sulfate
 Cholinesterases reactivators
- diacetyl monoxime
- pralidoxime

14. Management
 Provide artificial ventilation with a high inspired
oxygen concentration, after which atropine should
be given: 2-4 mg I.V (children 0.05mg/kg) every 10
min until atropinization is achieved
 Atropine therapy should be continued for 48 hrs &
patient should be observed for 72 hrs
 Pralidoxime : 1g (children 20-40 mg/kg) in 100ml
oof saline over 30 min intravenously should ideally
be started within 4 hr of exposure

15. Catecholamines
 Derived from tyrosine
 So named because of the presence of catechol
nucleus
 Produced by the adrenal medulla and sympathetic
ganglia
 Include: - epinephrine (adrenaline)
- nor-epinephrine (nor-adrenaline)
- dopamine

16. Tyrosine
DOPA
Dopamine
Nor-epinephrine
Epinephrine
Metanephrine VMA
(vanillyl mandelic acid)
Tyrosine hydroxylase
DOPA decarboxylase
Dopamine hydroxylase
N-methyl transferase
Catechol-O-methyl transferase (COMT)
MAO
Catecholamines synthesis & degradation
O2
H2O
Tetrahydro-
bioterin
Dihydro-
bioterin
NADPH+H
NADP+
PLP
CO2
Cu++
Vit.C
SAM
SAM
SAH
SAH

17. Functions of catecholamines
 Epinephrine & nor-epinephrine increase the blood pressure
 Adrenaline also ↑es the rate & forces of myocardial contration
 Epinephrine causes relaxation of smooth muscles of bronchi
 Adrenaline is anti-insulin in nature, it ↑es glycogenolysis &
stimulate lipolysis
 Adrenaline is released from adrenal medulla in response to
fright, flight, exercise & hypoglycemia

18. Parkinson’s disease
 Characterized by tremor, bradykenesia, muscle rigidity and
postural instability
 Pathologic characteristic of parkinson disease is
degeneration of the pigmented cells in the substantia nigra
 When normal, these cells synthesize and use dopamine as a
neurotransmitter & thus are said to be dopaminergic
 Dopaminergic neurons are found in a number of areas of the
brain, including the nigrostriatal, mesolimbic, mesocortical
& tuberohypophysial

19.  Neuropathologic finding: Lewy bodies (eosinophilic
intraneuronal cytoplasmic inclusion bodies, consist of
neurofilaments & other amorphous material
 The lowering of dopamine raises the ratio of acetylcholine
listed to dopamine in the cells of nigrostriatal system bcz
levels of acetylcholine are not so affected. This imbalance
contributes to the various disorders of movement found in
parkinson dosease
 Signs of parkinson disease appear when the level of
dopamine in the nigrostriatal system has dropped by 80%

20. Dopamine receptors
 The actions of dopamine in the brain are mediated by a
family of dopamine receptor proteins
 The five dopamine receptors (D1, D2, D3, D4 & D5) can be
divided into two groups
D1 class:
 D1 & D5 proteins have a long intracellular carboxy-terminal
tail
 They stimulate the formation of cyclic AMP & phosphatidyl
inositol hydrolysis
D2 class:
 D2, D3 & D4 receptors share a large third intracellular loop
 They decrease cyclic AMP formation & modulate K+ &
Ca2+ currents

21. Biochemical Basis for Parkinson’s
Disease
 Connections of substantia nigra to
striatum & back are the
nigrostriatal pathways
 Striatum output is GABAergic
 Its activity modulated by the
balance between cholinergic
striatal interneurons (+) &
substantia nigral DA (-)
 Degeneration of nigrostriatal
pathway (mainly DA cells in SN)
is crucial for parkinson’s
 The DA/ACh imbalance leads to
the ACh (no-go) predominance
& immobility

22. Treatment
 Anticholinergic therapy
 Treatment with Dopamine precursors: L-DOPA
 Dopamine receptor agonists: Bromocriptine
Other drugs:
 Antiviral agents: amantadine
 Mazindol
 Selegiline

23. Parkinsonism
Causes are:
 Parkinson disease (level of dopamine decreases)
 Viral infections
 Exposure to high levels of Mn2+
 Drugs: reserpine, neuroleptics (antipsychotics)
 β-N-methyl-amino-L-alanine (BMAA)
 1-mehtyl-4-phenyl-1,2,3,6-tetrahydropyridine
(MPTP)