A New Horizon in Neuroprotection: Erythropoietin

A NEW HORIZON IN
NEUROPROTECTION:
ERYTHROPOIETIN?
Reza Nejat, M.D.,
Anesthesiologist, FCCM
former Assistant Professor, SBMU,
Bazarganan Hospital, IRAN
2

Neuro-protection and EPO
 EPO:
 A must for
 survival,
 Proliferation,
 differentiation
 of erythroid
progenitor cells
 Prevents apoptosis in
progenitor cells
3

 EPO, produced by:
 Renal interstitial cells
similar to neurons
express marker antigens found
in neuronal cells
 Ito cells in the liver;
very similar to the EPO-
producing renal fibroblast-like
interstitial cells,
4

 EPO and EPO-R can be
found in the:
 Nervous system,
 Cardiovascular system,
 Digestive system,
 Endocrine system,
 Female and male
reproductive system,
 Respiratory system
 Spleen
5

 EPO production and secretion regulated
by:
 the tissue O2 supply (kidney, liver, brain)
 HIF-1 pathway
6

the expression of EPO-R is:
sensitive or not to hypoxia???
regulated by:
pro-inflammatory cytokines:
TNFα, IL-1β 
Erythropoietin 
probably other unidentified factors:
Janus Kinase 2 (JAK2)?
7

 Ischemic/hypoxic/hemorrhagic
and other types of brain injuries:
 lack of oxygen and nutrients
 pro-inflammatory mediators in
neurovascular unit:
 TNF-α, IL-1, IL-6,
 BBB dysfunction, brain edema and
hemorrhagic transformation
 neural cell apoptosis and death
 REPERFUSION???
8

 Strategy against CNS
insults:
restore delivery of
oxygen and nutrients
(angiogenesis)
⇊ edema and saving the
integrity of BBB, {ASAP}
⇊ apoptosis and
supporting the cells
supporting neurogenesis
and synaptogenesis
(ECM)
9

 Low amount of EPO is produced
de novo in the CNS
 tissue hypoxia in the CNS increases:
EPO concentration
EPO-R expression
10

 EPO and EPO-R:
In healthy brain ⇊
 In injured brain ⇈
EPO vs EPOL
EPOR vs EPORβ
11
Redox Biology. 2018; 14: 285- 294

 auto-phosphorylation of
JAK-2 results in activation
of:
RAS/MAPK
STAT5
PI3K/AKT
PKC
up-regulating anti-apoptotic
proteins Bcl-2 and Bcl-XL
EPO+EPO-R
activates
JAK-2
RAS/MAPK
STAT5
upregulation of
Bcl-2, Bcl-XL
12

 auto-phosphorylation
of JAK-2 results in
activation of:
PI3K/AKT:
inhibits pro-apoptotic
molecules:
BAD, GSK-3β,
caspase-3/-9
PI3K/AKT
inhibition of
activation of
JAK-2
EPO+EPO-R
GSK-3β
caspase -3/-9
BAD
13

 auto-phosphorylation
of JAK-2 results in
activation of:
 PI3K/AKT:
Expression of eNOS
(endothelial Nitric
Oxide Synthase)
eNOS
PI3K/AKT
EPO+EPO-R
JAK-2
NO 
vasodilatation
NADPH oxidase inhibition
ROS 
14

 auto-phosphorylation of
JAK-2 results in activation
of several signaling
pathways:
 PI3K/AKT:
Down-regulation of NF-ƙB??:
suppresses pro-inflammatory
cytokines likeTNF-α and IL-6
and simultaneously
increases anti-inflammatory
cytokine IL-10 level.
EPO+EPO-R
JAK-2
NF-ƙB
Downregulation?
Upregulation?
TNF-α
IL-6
IL-10
anti-
inflammatory
effect
15

 a multicenter double blinded
clinical study in Germany:
EPO had no cell-protective
effect or even might be
hazardous in humans.
 Ehrenreich H, Weissenborn K, Prange H.
Recombinant Human Erythropoietin in the
Treatment of Acute Ischemic Stroke. Stroke. 2009;
40: e647-e656
16

 phase II double blinded placebo
controlled study in infants with
moderate to severe hypoxic/ischemic
encephalopathy:
 High Dose EPO with HypoT could:
1) diminish MRI brain injury,
2) improve the motor function of
the infants after 1 year,
3) the mortality did not differ
significantly
Pediatrics. 2016; 137(6): e20160191
17

 EPO expression in the nervous system
is regulated by:
 the tissue O2 supply
 HIF-1 pathway
 In non-hypoxic circumstances:
mechanical damage
infection
metabolic stress (glucose , insulin?)
oxidative stress
elevated temperature
intense neural activity
enriched environment
 pro-inflammatory cytokines
18

EPO, Protects the neural
cells against:
oxygen tension,
calcium channel
dysfunction
excitotoxicity,
ROS or other free
radicals
19

 EPO
facilitates energy production
in mitochondria:
stabilizing mitochondrial
membrane potential
20

EPO in the nervous system:
 apoptosis,
 inflammatory responses
 re-establishment of compromised
functions by support of :
1) proliferation,
2) migration,
3) differentiation
4) survival
of progenitor/stem cells to
compensate for the lost or injured
cells
21

 EPO, protects BBB
through:
 its effects against VEGF-
induced injury
 having cytoprotective
effect on endothelial cells
in ischemic insults
 inhibiting AQP-4-induced
astrocyte swelling through
activating JNK and MAPK
22

 rhEPO could protect BBB:
 By up-regulating theTJ
proteins through
  MMP,
  glial cell inflammatory
reactions,
  TNF-α levels,
  NF–кβ activation.
23

 EPO through activating
PI3K/Akt pathway
regulates:
TIMP-1 gene transcription,
TIMP-1 mRNA induction,
TIMP-1 expression
24

 EPO supports
regenerating neurons
and astroglial cells by:
regulating MMP-2, MMP-9
andVEGF
VEGF receptors 1, 2 and
3 in hypoxia
25

 EPO has pro-angiogenic
property:
 Induces endothelial cell to:
 proliferate,
 migrate,
 produce nitric oxide (NO),
 degrade ECM delicately,
 differentiate
 Mobilizes the endothelial
progenitor cells,
26

 activation of EPOR in
cultured young rat
cerebellar and hippocampal
neurons:
reduces glutamate release
 by inhibiting calcium-
dependent exocytosis of this
excitatory amino acid
27

 rhEPO in reperfusion injury:
 Prevents from up-regulation
of IL-1β and IL-18, MMP-2 and
MMP-9
 Protects against oxygen
toxicity and free radicals
(ROS, RNS) through:
  pro-inflammatory
mediators
28

 EPO :
TNF-α, IL-6, and
monocyte chemo-attractant
protein-1 (MCP-1)
 TNF-α, IL-1:
Inhibits EPO production
29

Neuro-protective effects of EPO
 EPO, in neonatal rats after:
 hypoxic/ischemic injury
stimulated:
 Oligodendrogenesis,
 attenuated white matter
damage
 EPO, in adult rats after:
 stroke
 amplified myelinating
oligodendrocytes,
 increased myelinated axons in
peri-infarct white matter,
 improved functional outcome
30

EPO:
 increased water permeability
of astrocyte AQP-4 induced by
group I mGluR agonists
31

The 1st case:
 64 yrs???,
woman
 LOC
 IVH
32

Neuro-protective effects of EPO
34

35
 2nd case:
 81 yrs, man,
 LOC
 ICH

June 14, 2018 June 21, 2018
36

38
3rd case:
 49 yrs,
woman
 Headache,
 GCS: 12-13/15
 SAH

39
May 10, 2018

40
May 21, 2018

42
The 4th case:
 Post tonsilectomy hemorrhage due to carotid
artery rupture in a 6-yr-old boy
 Vascular surgeon ligated and repaired the left
CA
 Left side infarction (MCA territory)
 LOC
 EPO started immediately 1st POD and continued
for 40 days

44
The 4th case:
 On day 7 extubation was done unsuccessfully
which traumatized trachea which ended in fast
progressive emphysema with futile re-
intubation.
 As to the delay in intubation hypoxic
encephalopathy occurred with widespread
edema of the brain with eventual multiple sites
of infarction in the brain
 Once again EPO

 The 5th case:
 49 yrs, woman
 Hx: headache for 4
months, treated for
migraine
 Sudden LOC
 First CT: widespread
brain edema and infarct
 MRI: edema and infarct,
suspicious of aneurysm
48

The 5th case:
49

The 5th case:
50

The 5th case:
51

The 5th case:
52

The 5th case:
53

The 5th case:
54

The 5th case:
55

 The 6th case:
 47 yrs, female
 LOC after 3 days of headache
 Hx of epilepsia
 No apparent hx of head
trauma
 SDH (subacute)
 Double midriasis 5 minutes
before craniotomy and fixed
midsize pupils without reflex
to light postop
56

The 6th case:
57

 The 6th case:
 Postop Day 1
58

 The 6th case:
 Post-op day 4
59

 The 6th case:
 Post-op day 7
60

 Till now EPO:
anti-apoptotic,
anti-oxidant,
anti-inflammatory
neuro-protective by
stimulation of :
Angiogenesis
Neurogenesis
synaptogenesis
61

Thanks for your patience
rezanejat.com
icuaticu.com
2icuedu.com
62

A New Horizon in Neuroprotection: Erythropoietin

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