NeuroChemistry

dr. Ilhamuddin, M.Si.

Biochemistry
Department
Medical Faculty
Hasanuddin University

Pokok Bahasan
Pendahuluan
Metabolisme otak
Neurotransmitter
Clinical applications

Functional imaging: PET

Neuronal Structure

Sinaps:
celah, t4
endrit: menerima
rangsang
pemindahan rsg;
penghubung
antar
neuron
Sel-sel
Schwan:
sel bermielin
merupakan isolator listrik yg
mengelilingi
akson
Soma (Badan
sel): T4
keluarnya dendrit dan
akson Akson: meneruskan rangsang
PSY4080 6.0D

Neurotransmitter Function

Blood brain barrier

selectivity

Free permeability (passive diffusion):

small molecules: H2O, O2, CO2, NH3, ethanol
lipid soluble molecules: steroid hormones

Carrier mediated transport:

glucose: GLUT-1 (insulin independent)
amino acids

Transport of Glucose
GLUT1 (55 kd form):
localized in microvessels of the blood-brain barrier.

Moves glucose from the capillary lumen to the brain

interstitium.

GLUT3 / GLUT1 (45 kd form):

transport glucose from interstitium into neurons and

glial cells.

Metabolisme Otak
Laju respirasi sangat tinggi
Massa ~2% dari total: konsumsi O2 ~ 20%

konsumsi glukosa ~ 60%

Konsentrasi glukosa < ~2,5 mM
disfungsi otak
Akibat overdosis insulin: koma, kerusakan
irreversibel, kematian

Metabolisme Otak (Energi)

Sumber energi: Hanya dari glukosa darah; saat

kelaparan: badan keton (alternatif)

Cadangan glikogen sangat sedikit
Umumnya asam lemak tidak dapat melalui sawar
otak, kecuali asam lemak esensial
As. amino tidak dapat menghasilkan ATP tidak
ada glukoneogenesis
Energi umumnya untuk (Na+/K+)ATPase membran
plasma memelihara potensial membran bagi
transmisi impul saraf transpor aktif

Metabolisme Otak (Energi)

Excitatory firing Glu uptake by glia Na+ influx

ATP consumption by Na-K-ATPase activation of

glycolysis lactate transported to neurons

Hypoglycemia
Hypoglycemia: plasma glucose conc below 50 mg/dL
76 -72 mg/dL suppression of insulin secretion
~67 mg/dL counterregulatory hormones
Conservative definition: plasma glucose <75 mg/dL

Hypoglycemia ventromedial hypothalamus

suppression of insulin increase

counterregulatory hormone (glucagon/
epinephrine growth hormone/cortisol)

Metabolisme Otak (Asam amino)

Metabolisme as. amino aktif Konsentrasi

intraseluler sangat tinggi:

Glutamat (5-10 mM) & aspartat (2-3 mM)

GABA (gamma aminobutirat): pintasan khas

pada otak
Glisin, aspartat, gutamat & GABA penting
sebagai bahan baku
Neurotransmitter: substansi sinyal kimia
yang disekresi (dari neuron ke neuron/organ
target)

Ammonia handling in the

brain
NH3 is a waste product of deamination

reactions (GlnGlu, Glu2-OG etc.)

Metabolism:
Glutamin synthetase: NH3 + Glu Gln
Gln is metabolized in the liver/kidneys

Ammonia toxicity:
NH3 + 2OG + NADH Glu + NAD+
Krebs cycle impairment: 2-OG depletion
Glu excess, excitotoxicity

Ammonia handling
Clinical consequences: liver disease impairs

brain function
principle: insufficient urea synthesis NH3

accumulationneurotoxicity
Hepatic encephalopathy: gr.I-IV
Fulminant liver failure (i.e. paracetamol
poisoning) threatens live also by ICP

Functional imaging of the

brain
PET = positron emission tomography
18F-2-deoxy-2-fluoroglucose
taken up by glia, phosphorylated but not further
metabolized
active areas of the brain accumulate tracer

Functional imaging: PET

NEUROTRANSMITTER
Antarsel
saraf terdapat celah impuls

diteruskan melalui subs. kimia: neurotransmitter

& neurohormon

NEUROTRANSMITTER sekresi ke celah sinaps,

Neurotrasmitter:

jangkauan sempit, lama hidup pendek

Neurohormon: sekresi ke aliran darah, lebih
luas, lama

CHEMICAL SYNAPSES

NEUROTRANSMITTERS
5 criteria defining neurotransmitters
1) Synthesis of transmitter substance in the neuron
2) Storage of neurotransmitter or precursor in the
presynaptic nerve terminal
3) Release of the neurotransmitter into the synaptic
cleft to bind to target receptors on the postsynaptic
membrane resulting in specific change in activity
4) Mechanism of removal of transmitter from the
synaptic cleft
5) Exogenous application of neurotransmitter mimics
the
action of endogenously released transmitter

LIFE CYCLE OF A TRANSMITTER

Stages 1 & 2
Accumulation of a precursor amino acid into the neuron which is
metabolized to yield the mature transmitter (ZZ)
Stage 3
Transmitter is then accumulated into vesicles by the vesicular transporter
for storage and release.
Stages 4 & 5
Transmitter is released into synaptic cleft to interact with postsynaptic receptors or autoreceptors that regulate transmitter release,
synthesis or firing rate.
Stage 6 9 Inactivation and termination of the action of the released transmitter by
reuptake through neuronal transporter proteins, enzymatic degradation,

Substances that can be considered possible

Neurotransmitters or Neuromodulators

Table 2.

Biogenic amines
acetyl choline
Catecholamines :
Dopamine*
Norepinephrine*
Epinephrine*
5-hydroxytryptamine
= serotonin*

Amino acids
Glutamic acid*
Aspartic acid
Glycine
-aminobutyric acid*
= GABA
Taurine
Proline

Other primary amines

Histamine
Octopamine
Phenylethylamine
Phenyletahanolamine
Polyamines
Putrescine
Spermine
Spermidine
Purines
Adenosine
ATP, etc

Substances that can be considered possible

Neurotransmitters or Neuromodulators
Neuropeptides
Substance P
Carnosine
Thyrotropin-releasing hormone
(TRH)
Neurotensin
Somatostatin
-endorphin

Enkephalin
Angiotensin I
Angiotensin II
Oxytocin
Vasopressin
Cholecystokinin
Bradykinin
(De Robertis: 690).

Acetylcholine
Glutamate
GABA
Glycine
Norepinephrine
Dopamine
Serotonin

Regarded as
Established
transmitters

Aspartate
Taurine
A large number
of peptides

Possible candidate
transmitters

Metabolism dopamine
1. Dopamine Synthesis from tyrosine
that
catalyzed by tyrosine hydroxylase
2. Dopamine storage in synaptic
vesicle
3. Dopamine release by exositosis
4. Dopamine binding to the
postsynaptic
receptor
5. Dopamine reuptake

Fig. 11. Schematic diagram illustrating the release of dopamine by a

neuron in the substantia nigra and also showing the sites of action
of drugs that ameliorate or induce parkinsonism.

Biosintesis Katekolamin

Some of the Neurotransmitters found in

Nervous Tissue.
EXCITATORY
: Acetylcholine,
Aspartate,
Dopamine,
Histamine,
Nor
epinephrine, Epinephrine, ATP,
glutamate, 5-hydroxytryptamine.
INHIBITORY : GABA, Glycine
(Devlin : p.931)

PSY4080 6.0D

Neurotransmitter Function

35

PSY4080 6.0D

Neurotransmitter Function

36

IONIC ACTIONS OF NEUROTRANSMITTERS

BBB clinical significance

CNS infection:
BBB protects against bacteria entry, but also
antibodies and antibiotics
Kernikterus:
hyperbilirubinemia damages the brain in
neonates but not in adults
Parkinsons disease:
=lack of dopamin in basal ganglia
cannot be treated with dopamin (does not cross
BBB), but its precursor L-DOPA is useful

NEUROTRANSMITTERS & DISEASES

ACh

Mysthesia Gravia,
Alzheimers disease
Dopamine
Parkinsons Disease
Serotonin, NE
Depression
Glutamate
Excitotoxicity following stroke

Cholinergic system
(Acetylcholine)

Dopaminergic system
(Dopamine)

Serotonergic system (Serotonin)

Noradrenergic system
(Norepinephrine)

Glutamate
Excitotoxity = excesive Glu release
epilepsy, traumatic brain injury
Na+ and Ca2+ IC accumulation

swelling

GABA
Inhibitory

STROKE
STROKE : Berkurangnya aliran darah

(KERUSAKAN OTAK TERLOKALISIR)

- Paralisis
- Kebutaan
- G3 kemampuan bicara
- Hilangnya kesadaran permanen
Patomekanisme:
Tromboembolik a. serebri pasokan O2
+glukosa me<<< kerusakan otak

Proses Kerusakan Otak Trombosis

Serebri
1. Induksi: Iskemia menyebabkan

depolarisasi memb. neuron pelepasan

Glutamat uk Ca2+ eksitasi aliran
masuk Ca2+ dan Na+ >>> kematian
sel
2. Amflifikasi:Pelepasan tambahan
glutamat eksitasi ljt neuron
sebelahnya
3. Ekspresi: Kadar Ca 2+ >>
vasokonstriksi trombosis memburuk

Penyakit Parkinson
Defisiensi Dopamin dlm Substansia

Nigra dan Korpus Striatum

Akibat dari degenerasi sel yang
mensintesis dan menggunakan
dopamin ( dopaminergik)
R/ a. Antikolinergik
b. Prekursor Dopamin
c. Agonist Reseptor Dopamin

Penyakit ALZHEIMER
Proses degeneratif Apoptosis

( korteks serebri dan hipokampus)

Mikro: penimbunan plak amiloid beta
protein
perubahan neurofibriler & vaskuler
Plak amiloid neurotoksik >> ion
Ca2+ intrasel hiperfosforilasi dan
pembtk filamen helix berpsg pd
simpul neurofibriler

Genetik Alzheimer
Mutasi gen amyloid precursor protein

(Kr 21)
Proteolisis APP fragmen A beta
Protein
Deposisi A beta P >> kdr Ca 2+
mengaktifkan protein kinase
filamen heliks kekacauan
neurofibriler
Deposisi A beta P dan hiperfosforilasi
meenahun plak & kekacauan

Penyebab lain Alzheimer

Penurunan kolin asetiltransferase &

Ach
Pe>> almunium dlm plak

R/ obat spesifik belum ada

SKIZOFRENIA
Abnormalitas struktur lobus

temporalis medialis dan pelebaran

ventrikulus otak
Hiperdopaminergik
kategori
1. Kdr Dopamin Otak
2. Metabolik Dopamin
3. dll

Migrain

Teori depolarisasi
Teori vaskuler
Teori serotinin
Teori saraf
Teori saraf + vaskuler
- trigger stess
- vasokonstriksi peb. darah
- Serotonin released
- Substant P iritasi srf & vaskuler

When Reading Emotion

Adults Rely More on the Frontal Cortex

While Teens Rely More on the Amygdala

dopamine
transporters

Terima Kasih
&
Selamat Belajar

Pustaka
Biokimia Harper
Atlas Berwarna & Teks Biokimia

Devlin TH, 1993. Textbook of Biochemistry

with Clinical Correlation 3rd edition. New
York : Wiley-Liss Inc, 931, 937- 938
Goldstein M, 1983. Biochemistry A Functional
Approach 3rd edition. Tokyo : WB Saunders
Company,650-652, 654, 648

KEJANG (TRMSK K. DEMAM)

PUSING
HILANG KESADARAN
EPILEPSI
GERAKAN TIDAK TERATUR
GANGGUAN GERAK DAN KOORDINASI
GANGGUAN OTOT
GANGGUAN JALAN
LUMPUH
GANGGUAN BICARA
PELUPA
PERUBAHAN PERILAKU (TERMASUK AGRESIF)
STRESS
DEPRESI
CEMAS
SUSAH TIDUR
PEMARAH
NGAMUK
PENURUNAN FUNGSI BERPIKIR
PERUBAHAN EMOSI & MOOD
GANGGUAN BELAJAR
PINGSAN
GANGGUAN KOMUNIKASI
GANGGUAN PERILAKU
KELELAHAN

METABOLIK ENSEFALOPATI
KOMA
BRAIN DEATH
TENSION HEADACHE
MIGRAINE
CRANIAL ARTERITIS
TRIGEMINAL NEURALGIA
CLUSTER HEADACHE
TIA
CEREBRAL INFARCTION
INTRACEREBRAL HEMATOMA
SUBAR