THE ROLE OF NEUROTROPIC

VITAMIN IN NEUROLOGIC
DISORDERS

NEUROTROPIC VITAMIN IN
NEUROLOGIC DISORDER

Sering dijumpai:
- Diabetic
polyneuropathy
- Carpal tunnel
syndrome
- Lumbal-cervical
radiculopathy
- pain

Jarang dijumpai:
Wernicke ensefalopati
Subacute Combined
Degeneration

Batasan Nyeri
Pengalaman sensoris dan emosional , tidak
menyenangkan terkait dengan jejas jaringan
yang nyata atau potensial atau yang dapat
digambarkan

sebagai

suatu

kerusakan

jaringan.

The International Association for the Study of Pain

(IASP,), adopted from Merskey.

Classifications of Pain
Nociceptive

Pathophysiology

Mixed
Neuropathic

Acute

Duration
Chronic

CENTRAL PAIN
TISSUE INJURY OR
INFLAMMATION
Arthritis
Trauma
Burn

NEUROPATHIC PAIN
Diabetic neuropathy
Trigeminal Neuralgia
Nerve root compression
( herniated disc )

Postthalamic stroke
Multiple sclerosis
Psychologic mechanisms
Rx : Tricyclics
Physical therapy and
psychotherapy

Sensory nerve
Sym
nerv pathe
tic
e

Rx : NSAIDs
Narcotics

Rx : Tricyclics (e.g.,amitriptyline),
carbamazepine, phenytoin,
capsaicin

Vasomotor
and thropic
changes

Sympathetically
mediated pain
(reflex sympathetic
dystrophy )
Rx : Phenoxybenzamine
Sympathetic nerve block

Sites of origin of pain within the nociceptive pathway

Burning, feeling like the feet are on fire

Stabbing, like sharp knives

Modified by Meliala 2006

Freezing, like the feet are on ice,

although they feel warm to touch

Lancinating, like electric shocks

HIPERALGESIA

Reaksi yang meningkat terhadap stimulus

nyeri
(noksius)
ALODINIA

Nyeri akibat stimulus yang tidak nyeri (nonnoksius/inocuous)

PRESENTATION ACROSS PAIN STATES VARIES

Neuropathic Pain
Pain initiated or caused by a
primary lesion or dysfunction
in the nervous system
(either peripheral or
central nervous system)1

Mixed Pain
Pain with
neuropathic and
nociceptive
components

Examples
Peripheral
Postherpetic neuralgia
Trigeminal neuralgia
Diabetic peripheral neuropathy
Postsurgical neuropathy
Posttraumatic neuropathy
Central
Poststroke pain
Common descriptors2
Burning
Tingling
Hypersensitivity to touch or cold

Examples

Low back pain with

radiculopathy
Cervical
radiculopathy
Cancer pain
Carpal tunnel
syndrome

1. International Association for the Study of Pain. IASP Pain Terminology.

2. Raja et al. in Wall PD, Melzack R (Eds). Textbook of pain. 4th Ed. 1999.;11-57

Nociceptive Pain
Pain caused by injury to
body tissues
(musculoskeletal,
cutaneous or visceral)2

Examples

Pain due to inflammation

Limb pain after a fracture
Joint pain in osteoarthritis
Postoperative visceral pain
Common descriptors2
Aching
Sharp
Throbbing

SENSITIZATION OF NOCICEPTORS IN
INFLAMMATION
1
Prostaglandins produced in
response to tissue injury;
increase sensitivity of
nociceptor (pain)

Painful stimulus

Pain-sensitive tissue

Prostaglandin

Mast cell

Substance P

Histamine
Bradykinin
Substance P

3
Nociceptor

Blood
vessel

2
Nociceptor then releases
substance P, which dilates
blood vessels and increases
release of inflammatory
mediators, such as
Bradykinin (redness & heat)

3
Substance P also promotes
degranulation of mast cells,
which release histamine
(swelling)

Fase Inflamasi (1)

Akut:
Pelepasan autakoid:
Histamin
: vasodilatasi, permeabilitas
vaskular
Serotonin
: permeabilitas
Bradikinin
: vasodilatasi, nyeri
Prostaglandin : vasodilatasi, permeabilitas
kemotaksis
Leukotrin
: permeabilitas, kemotaksis

The Continuum of Pain1

Insult
Time to resolution
Acute
Pain

<1 month

Usually obvious tissue damage

Increased nervous system
activity

Pain resolves upon healing

Serves a protective function

Chronic
Pain

3-6 months

Pain for 3-6 months or

more2

Pain beyond expected

period of healing2

Usually has no protective

function3

Degrades health and

function3

1. Cole BE. Hosp Physician. 2002;38:23-30.

2.Turk and Okifuji. Bonicas Management of Pain. 2001.
3. Chapman and Stillman. Pain and Touch. 1996.

EXAMPLE OF CHRONIC NOCICEPTIVE PAIN:

OSTEOARTHRITIS OF THE KNEE
Osteoarthritis

Normal joint

Synovial
fluid

Synovial
membrane

Inflammation
as bones rub
together

Joint
capsule
Cartilage

Thinned
cartilage

Fase Inflamasi (2)

Subakut: aktivasi respon imun
kronik: pelepasan mediator:
IL-1, IL-2, IL-3 : aktivasi limfosit, produksi
prostaglandin
TNF-
: produksi prostaglandin
Interferon
PDGF
: kemotaksis & proliferasi fibroblast

SENSITIZATION OF CENTRAL NERVOUS SYSTEM

Immune cells

Immune response
Cytokines
Chemokines

Macrophage

Surface
antigens
Microglia

Injury

Monocyte
Vitamin
B complex

Adenosine
triphosphate
Cannabinoids
Neuropeptides

Sensitization
of central
nervous
system

Glutamate
Bradykinin
COX-2
Induced nitric
oxide
synthase

TNF , growth factors, IL 1,

IL 8

Neuroanatomi dan Patofisiologi Nyeri

Bagian dari sistim saraf yang bertanggung jawab
untuk sensasi dan persepsi nyeri dapat dibagi
menjadi tiga area, yaitu:
Jaras afferent
SSP (susunan saraf pusat)
Jaras efferent

THE PAIN PATHWAY

Brain
Dorsal Root
Ganglion

Pain Perception

Dorsal Horn

Spinal Cord
Nociceptor

Gottschalk A et al. Am Fam Physician. 2001;63:1979-84.

Fields HL et al. Harrisons Principles of Internal Medicine. 1998:53-8.

Jaras Afferent
Nociceptors (reseptor nyeri) jaras afferent
berakhir pada kornu dorsalis dari medula
spinalis (neuron afferent pertama)
Neuron afferent kedua membentuk bagian
spinal dari jaras afferent sampai talamus
(traktus spinotalamikus)
Neuron ketiga terbentuk mulai talamus sampai
ke korteks serebri

PAIN SERIES OF EVENTS

PERCEPTION
PAIN

MODULATION
TRANSMISSION

TRANSDUCTION

There are Two Sensory Afferent Neurons

1. Large myelinated A fibers
Very fast conduction velocity
Respond to innocuous stimuli
2. Small myelinated A & C unmyelinated fibers
Slow conduction velocity
Respond to noxious stimuli
Large A
fibers

Dorsal root
ganglion

A
Small
fibers
C

Peripheral sensory
Nerve fibers

Dorsal Horn

NORMAL IMPULSE
TRANSMISSION
Impulses reach terminals of presynaptic neuron
Presynaptic
neuron

Glutamate

Substance P

NMDA receptor is
blocked by Mg2+

Synaptic cleft

Postsynaptic
neuron

NK-1

NMDA
receptor

AMPA
receptor

NORMAL IMPULSE TRANSMISSION

Glutamate is released into synaptic cleft

Presynaptic
neuron

Glutamate

Substance P

NMDA receptor
remains blocked
by Mg2+

Synaptic cleft

Postsynaptic
neuron

NK-1

NMDA
receptor

AMPA
receptor

NORMAL IMPULSE TRANSMISSION

Glutamate binds to AMPA receptor and impulse is transmitted to postsynaptic neuron

Presynaptic
neuron

Glutamate

Substance P

NMDA receptor
remains blocked
by Mg2+

Synaptic cleft

Postsynaptic
neuron

NK-1

AMPA
receptor

Tissue damage

PERIPHERAL
ACTIVITY

Nerve damage

Hyperalgesia

Spontaneous
pain

Allodynia

CENTRAL
SENSITIZATION

Decreased
Increased
threshold to
Expansion ofspontaneous
peripheral
activity
receptive
stimuli
field

DEVELOPMENT OF CENTRAL SENSITIZATION

Injury or trauma causes increased nerve activity

Presynaptic
neuron

Glutamate

Substance P

NMDA receptor is
blocked by Mg2+
and Vitamin

Synaptic cleft
Postsynaptic
neuron

NK-1

NMDA
receptor

AMPA
receptor

DEVELOPMENT OF CENTRAL SENSITIZATION

Substance P and excessive levels of glutamate are released into the synaptic cleft

Presynaptic
neuron

Glutamate

Substance P

NMDA receptor is
blocked by Mg2+
and Vitamin

Synaptic cleft
Postsynaptic
neuron

NK-1

NMDA
receptor

AMPA
receptor

DEVELOPMENT OF CENTRAL SENSITIZATION

Substance P binds to NK-1 receptors, causing NMDA receptors to release Mg 2+ ions

Presynaptic
neuron

Glutamate

Substance P

Synaptic cleft
Postsynaptic
neuron

NK-1

NMDA
receptor

AMPA
receptor

DEVELOPMENT OF CENTRAL SENSITIZATION

Glutamate molecules can now bind to AMPA and NMDA receptors

Presynaptic
neuron

Glutamate

Substance P

Synaptic cleft
Postsynaptic
neuron

AMPA
receptor

DEVELOPMENT OF CENTRAL SENSITIZATION

Increased impulses transmitted to postsynaptic neuron

Presynaptic
neuron

Substance P

Synaptic cleft

Postsynaptic
neuron

Glutamate

ACTIVATION AND SENSIZITATION

DORSAL HORN NEURONS

N/P

C
VDC

Pre-synaptic

SP
Glu

BDNF

NO
PGE2

Gq/11

NK1
Gs

PLC

Na+

Ca2+

KA-R

AC

IP3
DAG

TrkB

AMPA-R

NMDA-R

Scr

cAMP

Gs
PKA

cAMP

PKA
PKC

EP

AC

COX/LOX
PGE2

Post-synaptic
Increased excitability

Carpenter and Dickenson, 2005

NOS

NO

Modified Meliala 2006

Efek Analgetik dan Neuroprotektif dari

Vitamin Neurotropik
(Zimmerman, 2006)
1.NMDA receptor antagonism
2.Block at Ca2+ channels
3.Blok of cytokine formation (eg: TNF-) and
receptor Binding

Terima Kasih atas

Perhatiannya

Tipe Nyeri Berdasarkan

Neurofisiologi
Nyeri nosisepsi, diinduksi oleh eksitasi nosiseptor
yang memiliki fungsi proteksi
yang dapat mengalami eksitasi kronik akibat
penyakit
Nyeri neuropatik, diinduksi oleh kerusakan atau
penyakit pada sistim saraf
Akibat eksitasi abnormal dari sistem nosiseptif.

Sindroma nyeri campuran

Terdapat komponen neuropatik dan nosiseptif secara
bersamaan atau berurutan.

Klasifikasi Nyeri
Berdasarkan awitan (onset), maka nyeri
dapat di-kelompokkan dalam:
Nyeri akut
Nyeri kronik
Breakthrough pain (Peningkatan intensitas nyeri pada
kondisi nyeri kronik).

NORMAL vs. OA JOINT

Normal knee
capsule
cartilage
synovium

Osteoarthritic knee
thickened capsule
cyst formation
sclerosis in
subchondral bone
fibrillated cartilage
synovial hypertrophy

bone

osteophyte formation
Source: ARMS Training Module

ACRFP

ACRFP
Source: ARMS Training Module

Pain Rating Scales

10 Pain Intensity Scale

Mild

Moderate

Pain threshold
Pain tolerance

Severe

10

PAIN MEDIATORS
Cell Damage

Aa

K+

BK

Brain

PG
Nociceptor
Spinal cord
HISTAMINE
Mast Cell
Peptides, eg, SUBSTANCE P
SEROTONIN
Aa = arachidonic acid; BK = bradykinin; PG = prostaglandin

Platelet

PERIPHERAL SENSITIZATION
Cell Damage

Inflammation

Sympathetic
Terminals

Release of pain and inflammatory mediators

e.g. bradykinin, H+, prostaglandins

High Threshold

Nociceptor

Central sensitization
Hyperalgesia
Allodynia

Low Threshold

Spinal cord

HYPERALGESIA
Primary
Sensitization of primary neurons threshold to
noxious stimuli within site of injury
May include response to innocuous stimuli
pain from supra threshold stimuli

Secondary
Sensitization of primary neurons in surrounding
uninjured areas

Raja SN, et al. In: Wall PB, Melzack R, eds. Textbook of Pain. 4th ed; 1999:1157.

ALLODYNIA
Pain evoked by innocuous stimuli
Central sensitization pain
produced by A fibers1
Possibly mediated by spinal NMDA
receptors2

1. Woolf CJ. Drugs. 1994;47(suppl 5):19.

2. Dolan S, Nolan AM. Neuroreport. 1999;10(3):449452.

Ungkapan Nyeri
Aching = nyeri
Stabbing = tertusuk /
tikam
Tender = nyeri tekan
Tiring = nyeri melelahkan
Numb = baal
Dull = nyeri tumpul
Crampy = nyeri kram
Throbbing = nyeri seperti
tercekik
Gnawing = nyeri seperti
digigit
Burning = rasa terbakar

Shooting = rasa menyentak

Sharp = nyeri tajam
Exhausting = nyeri melelahkan
Nagging = perih
Unbearable = tidak
tertahankan
Squeezing = seperti diremas
Pressure = seperti ditekan
Penetrating = rasa tertembus
Miserable = menyusahkan
Radiating = menjalar
Deep = nyeri dalam

Pokdisus Nyeri. Penuntun Praktis Nyeri

Neuropatik, 2007

Terminologi Seputar Nyeri

Allodynia
Nyeri yang disebabkan oleh stimulus secara
normal tidak menimbulkan nyeri
Hyperalgesia
Respon yang berlebihan terhadap stimulus
yang secara normal menimbulkan nyeri.
Hyperpathia
Sindroma dengan nyeri bercirikan reaksi nyeri
abnormal terhadap stimulus, khususnya
stimulus berulang, seperti peninggian batas
ambang.
Pokdisus Nyeri. Penuntun Praktis Nyeri Neuropatik, 2007

Terminologi Seputar Nyeri

Hypoalgesia
berkurangnya respon nyeri terhadap stimulus
yang dalam keadaan normal menimbulkan
nyeri
Paresthesia
Sensasi abnormal, yang tidak menyenangkan
baik spontan ataupun dengan pencetus .
Neuralgia
Nyeri pada daerah distribusi saraf.

Terminologi Seputar Nyeri

Analgesia
Hilangnya respon nyeri terhadap stimulus yang dalam
keadaan normal menimbulkan nyeri.

Anesthesia dolorosa
Nyeri pada area atau regio yang semestinya bersifat
anestetik.

Causalgia
Sindroma yang timbul pada lesi saraf paska trauma
yang ditandai nyeri seperti terbakar, alodinia,
hiperpatia yang menetap, seringkali bercampur
dengan disfungsi vasomotor serta sudomotor dan
kemudian diikuti oleh gangguan trofik.

NORMAL vs. RA SYNOVIUM

Normal

Rheumatoid Synovitis
bursitis
bone

tendonitis
synovitis

monocyte

Source: ARMS Training Module

cartilage
lining cell
hyperplasia
pannus
polymorph
exudate
mononuclear
infiltrate
fibrosis

ACRFP

ACRFP
Source: ARMS Training Module

Guideline:
American Pain Society
Treatment of Chronic Pain in OA
Plus, as needed:
Mild pain
Acetaminophen*

Continued
pain?

Moderate-to-severe
pain/inflammation
COX-2 selective
NSAID
Continued
Yes
pain?
Conduct GI risk
factor analysis

Nonpharmacol
ogic
interventions
Glucosamine
Tramadol
Adjunctives
Intra-articular
hyaluronic
acid

High risk
Nonselective NSAID
plus PPI or
misoprostol

Not high risk

Nonselective NSAID

Continued pain?
Adapted from APS Arthritis Guidelines,
2002.

Yes

Surgical
intervention
Intra-articular
injection of hyaluronic
acid for knee pain
Intra-articular
glucocorticoid injection
for other joint pain

*Paracetamol in some

Guideline:
American Pain Society
Treatment of Chronic Pain in RA
DMARDs*
Les
s

Sulfasalazi
ne

More or less
aggressive
disease?
Continued pain
and
inflammation?
Yes

Mild pain
Acetaminophen

Continued
pain?
*DMARD = disease-modifying
antirheumatic drug.

Plus, as needed:
Mo
re

Sulfasalazine
Methotrexate
Leflunomide
Biologic
therapy

Glucosamine
Tramadol
Adjunctives

Moderate-to-severe
pain/inflammation
COX-2 selective
NSAID
Yes

Nonpharmacolo
gic
interventions

Intra-articular
hyaluronic acid
Surgical
intervention
Conduct GI risk factor
analysis (as in OA
algorithm)

Adapted from APS Arthritis Guidelines,

2002.

Multimodal Management
of OA and RA
Pharmacologic

Nonpharmacologic

Analgesics
Exercise/Weight loss
Anti-inflammatory agents Physical therapy
DMARDs
Other

Surgical
Osteotomy
Arthroplasty

Harris C. Geriatrics. 1993;48:39-46.

Hochberg MC et al. Arthritis Rheum. 1995;38:1535-40.
Hochberg MC et al. Arthritis Rheum. 1995;38:1541-6.
ACR Ad Hoc Committee on Clinical Guidelines. Arthritis Rheum.

Medications for neuropathic pain

Descending inhibitory pathways
(NE/5HT, opioid receptors)
Alpha adrenergic agents
Opioids
SNRIs
SSRIs
Tramadol
TCAs

Central sensitization

Ca2+

NMDA

Gabapentin
Lamotrigine
Levetiracetam
Oxcarbazepine
Pregabalin
Dextromethorphan
Ketamine
Methadone
Memantine

Peripheral mechanisms

Na+

Carbamazepine
Lamotrigine
Lidocaine
Oxcarbazepine
Topiramate
TCAs

NE: norepinephrine; 5HT: 5-hydroxytryptamine; NMDA: N-Methyl D-Aspartate;

SNRI: selective norepinephrine reuptake inhibitor; SSRI: selective serotonin reuptake inhibitor; TCA: tricyclic
antidepressants

Pharmacological Treatment Strategies Based

on Signs and Symptom
Sign/Symptom

Suggested
Treatment

Probable
Mechanism

Stimulus-evoked Signs:

Static
Mechanical
and Thermal
Hyperalgesia

Topical anaesthetic
(EMLA)
Lidocain local
infusion or block
Topical Capsaicin

Pheriperal

sensitization

Sign/
Sympto
m
Neuroma
Sign

Punctate
Hyperalgesia

Suggested Treatment
Anticovulsant
(Carbamazepin,Phenytoin)
Anti-arrhytmics/anaesthetics
(Mexiletine and Lignocaine)
Tricyclic antidepressant
(Amitriptyline)?

Probable
Mechanism

Topical anaesthetics (EMLA)

Lidocain local infusion or block
Topical Capsaicin
Anticonvulsant (Cbz,Phenytoin)
Anti-arrhytmics/anaesthetics
(Mexiletine and Lignocain
Tricyclic antidepressant
(Amitriptyline)?

Ectopic
discharge
(Na+ channel
accumulation)

Experimentally :
Wind-up
Clinically :
central
sensitization of
A fibres

Sign/
Symptom
Allodynia

Suggested
Treatment
Gabapentin
Baclofen
Opioids
Clonidine
Tricyclic
antidepressant
(Amitriptyline)
Local anaesthetic
block
Sympathetic
ganglion blockade
NMDA antagonist

Probable
Mechanism

Central

sensitization of
A fibres
Central
reorganization of
A fibres
Loss of inhibitory
controls

Sign/
Symptom

Suggested
Treatment

Probable
Mechanism

Stimulus-independent symptoms:
Anticonvulsants
Paraesthesia (Carbamazepin,
Phenytoin)
s
Anti-

Ectopic
discharges of A
fibres

Dysaesthesi
as

Ectopic
discharges of A
fibres

arrhytmics/anaesthetics
(Mexiletine and Lignocaine)
Tricyclic antidepressants
(Amitriptyline)?
Anticonvulsants
(Carbamazepin,Phenytoin)
Antiarrhytmics/anaesthetics
(Mexiletine and Lignocaine)
Tricyclic antidepressant
(Amitriptyline)?

Sign/
Symptom
Continuou
s burning
pain

Suggested
Treatment
Topical anaesthetics
(EMLA)
Lidocaine local infusion or
block
Topical Capsaicin
Gabapentin
Baclofen
Clonidine
Tricyclic antidepressant
(Amitriptyline)
Phenytoin

Probable
Mechanism
Pheripheral

sensitization
Loss of inhibitory
mechanism
Ectopic discharge of C
fibres

Sign/
Symptom

Suggested
Treatment

Paroxisma Anticonvulsant
(Carbamazepin,Phenytoin)
l shooting Antiarrhytmics/anaesthetics
of
(Mexiletine and Lignocain)
lancinatin Tricyclic antidepressant
(Amitriptyline)
g pain
Gabapentin ?

Probable
Mechanism

Ectopic

discharge of C
fibres

HAS10

PAINFUL DIABETIC
NEUROPATHY

Pain associated with neuropathy caused by DM

affecting sleep
mood
mobility
ability to work
interpersonal relationships
overall self-worth
and independence.

impact on patients quality of life

Cynthia,2005

DIABETIC NEUROPATHY :
SIGNS AND SYMPTOMS

HAS10

SENSORY

Positive
Spontaneous pain
Burning
Pricking
Squeezing
Tingling*
Knife-like
Lancinating
Electric shock
Aching
Trobbing
Freezing
Tightness

MOTOR

AUTONOMIC

Weakness
atrophy

Negative
Numbness*
Deadness
Loss of sensation
Loss of balance

Distal

Proximal

Focal

Stimulus-evoked pain
Allodynia*
Hyperalgesia

allodynia

foot ulceration

Sudomotor
Pupilary
Cardiovaskular
Urinary
Gastrointestinal
Sexual

HAS10

HAS10

Stage of DPN
Stage of neuropathy :
No neuropathy
Clinical neuropathy :
Chronic painful
Acute painful
Painless with complete/partial sensory loss
Late complications

(International Neuropathy Guidelines)

HAS10

DIAGNOSIS OF DIABETIC
PERIPHERAL NEUROPATHY
Symptoms
Signs
Test for autonomic function
Electrodiagnostic
Quantitative sensory testing

Assess physical, emotional and social function

and psychological comorbidity
(depression, anxiety, substance abuse)

min. 2/5

HAS10

DIAGNOSIS OF DIABETIC
PERIPHERAL NEUROPATHY (cont)
Other methods of assesment :
Nerve Biopsy
Nerve Exposure :
Microelectrode and epineurial vessel
fluorescein angiography
Microlight-guide spectrophotometry
Skin Biopsy
Corneal Confocal Microscopy
MRI ?

photography &

HAS10

Diabetic Peripheral Neuropathic:

The presence of symptom and/or sign
of peripheral nerve dysfunction in
people with diabetes after exclusion
of other causes

(Soliman & Gellido, 2002)

Classification of Diabetic Neuropathy

Diffuse Neuropathy
Distal symmetric sensorimotor polyneuropathy
Autonomic neuropathy

Sudomotor neuropathy
Cardiovascular autonomic neuropathy
Gastrointestinal neuropathy
Genitourinary neuropathy

Symmetric promixal lower limb motor neuropathy

(amyotrophy)

Focal Neuropathy
Cranial neuropathy
Radiculopathy/plexopathy
Entrapment neuropathy
Thomas, 1997

Tiga Stase Neuropati Diabetika (ND)

Vinik, 2002

Neuropati fungsional.
Tidak tampak adanya kelainan patologik
Perubahan biokimiawi --- timbul gejala
Reversibel
Neuropati struktural
Terjadi kerusakan struktural serabut saraf yang
menimbulkan gejala
Reversibel
Kematian neuron
Kematian neuron menyebabkan penurunan kepadatan
serabut saraf
Irreversibel

Teori Terjadinya ND
Teori metabolik
Hiperglikemia

Teori Vaskuler
Terjadi penurunan aliran darah ke endoneurium yang
disebabkan oleh adanya resistensi pembuluh darah akibat
hiperglikemi.
Kekurangan Neurotrophic factor
Penurunan Nerve Growth Factor (NGF) ---- transport
aksonal yang retrograde (dari organ target menuju badan
sel) terganggu.
Penurunan kadar NGF pada kulit pasien DM berkorelasi
positif dengan adanya gejala awal small fibers sensory
neuropathy

Hyperglycemia and Nervous System

Increases the production and stabilization of
reactive oxygen species (ROS) damage
peripheral neurons, particularly mitochondria
apoptosis via caspases and proapoptotic Bcl proteins
mitochondrial damage and neuronal impairment
Loss of Schwann cells, myelinated axons, and sensory
neurons in DRG

DNA content is decreased in axonopathy associated

with diabetic neuropathy

Leininger, 2007

Hyperglycemia and Nervous System

Neuronal mitochondrial DNA is more prone to
oxidative damage than is glial mitochondrial DNA
possibly contributing to neuropathic progression

Disruption of mitochondrial membranes in

diabetic neuropathy induces local apoptosis
New therapeutic potential: anti Bcl protein
prevent Bcl action and apoptosis preserves
neuronal function
Research is still in progress

Leininger, 2007

Mitochondria and Diabetic Neuropathy

CoQ10

Cyto-C

H+

H+
+

III

e-

II

e-

e-

IV

D
NA

DH
NA

O2

GSSG

Catalase

H2O + O2

Outer
Mitochondrial
membrane

O
2

Matrix

Mitochondrial
membrane damage

P
AT

2H2O

H2O2

Pi

SOD

Mitochondrial DNA Damage

Leininger, 2007

2 GSH

O2 -

O 2 -

Inner
Mitochondrial
membrane

P
AD

O2

H+

H2O

Intermembrane
space

Axonal polyneuropathyDemyelinating Neuropathy

Neuronopathy (Ganglionopath
Polyneuropathy is caused by the degeneration of axon terminals and results in symmetric
distal sensory loss with shading to normal sensation. A compression neuropathy often
results in demyelination with the axon left relatively intact. Sensory loss follows a
radicular pattern. When the neuronal cell body dies the condition is called
"neuronopathy." If the cell body is in the sensory ganglion the condition is often referred
to as "ganglionopathy." The pattern is usually random

FT-NP

VGSC

PAIN
PAIN

NON0
PAIN
PAIN
BRAIN

Opioids
GABA
Na+

Altered Activity

CBZ
OXC
LTG

VGSC

Na2+

Ca2+

VGSC
VGSC

VGCC
Na+

Ca++

Ca2+

Mg2+

GLUTAMATE

Altered Properties
PEPTIDES Ca2+

NMDA ++
AMPA
Kainate
Hyperexitability

Rowbotham et al, 2000

Modifikasi Meliala, 2003

INTRACELLULAR SECOND MESSENGER

MECHANISM OF NOCICEPTOR SENSITIZATION
ANALGESIA
HYPERALGESIA
PGE2

PGI2

8(R), 15(S)
diHETE

Gs

ADEN

5-HT

ADEN

A2

1a

A1

ADENYL
CYCLASE
ATP

OPOID

OXC
CBZ

GI

cAMP
+
PKA
P

Na

2+

Levine & Reichling, 1999

Na 2+
Modifikasi Meliala, 2003

Pathophysiology of DN
Oxidative stress
Advance glycation end products (AGES)
Protein Kinase C (PKC)
Polyol Pathway Flux

Pathophysiology of diabetic neuropathy

Classification of DN
Symmetric Distal
Polyneuropathies

Large fiber/distal
symmetric polyneuropathy
Small-fiber neuropathy
Diabetic autonomic
neuropathy
Diabetic neuropathic
cachexia

Asymmetric
neuropathies

Cranial mononeuropathy
Somatic
mononeuropathies
Diabetic thoracic
radiculoneuropathy
Diabetic radiculoplexus
neuropathy

Dianna Quan. Diabetic Neuropathy. eMedicine. Update.Oct30,2008 Cited.06/08/2009