Stroke. 1997;28:1744-1748
(Stroke. 1997;28:1744-1748.)
© 1997 American Heart Association, Inc.
Plasma Insulin-like Growth Factor I and IGF Binding Protein 3 Levels in Patients With Acute Cerebral Ischemic Injury
Stefan Schwab, MD;
Matthias Spranger, MD;
Sebastian Krempien, MD;
Werner Hacke, MD;
Markus Bettendorf, MD
From the Departments of Neurology (S.S., M.S., S.K., W.H.) and Pediatric
Endocrinology, Department of Pediatrics (M.B.), University of Heidelberg
(Germany).
Correspondence to Stefan Schwab, MD, Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.
 |
Abstract
|
|---|
Background and Purpose The insulin-like growth factors
(IGF)
are synthesized in the brain and are involved in fetal brain
development.
An increased expression of IGF-I and IGF-II occurs in
cerebral
regions with neuronal damage after experimental hypoxic
injury.
Furthermore, the expression of mRNAs coding for IGF-I and the
binding
proteins IGFBP-2 and IGFBP-3 is augmented in response to
unilateral
ischemia in animal models. The secretory dynamics of
IGF-I in
human cerebral ischemia have not yet been
investigated.
Methods Plasma IGF-I and IGFBP-3 were measured sequentially
in 20 patients with acute ischemic stroke (within 24 hours and
3, 5, and 10 days thereafter). For analysis the patients were
assigned to three groups according to the diameter of the infarct area
as measured on CT scan: small (<1.5 cm), moderate (
1.5 cm and
5
cm), and large (>5 cm). Eight age-matched patients with nonvascular,
neurological illnesses served as controls.
Results Plasma IGF-I and IGFBP-3 plasma concentrations
after acute cerebral ischemia were strikingly lower than those
in control subjects and healthy individuals reported in the literature.
Plasma IGF-I levels in patients with large infarcts were significantly
statistically lower than those in control subjects (P<.05),
and plasma IGFBP-3 levels were significantly lower than those in
control subjects on days 5 and 10.
Conclusions IGF-I and IGFBP-3 plasma levels are decreased
in patients after cerebral ischemia. After acute
ischemic stroke, increased demand for growth factors, altered
tissue distribution, and accelerated metabolic clearance
rate or central inhibition of the somatotrophic axis may contribute to
these low plasma concentrations. Growth factors such as IGF-I and
IGFBP-3 may play an important role in the pathophysiology of acute
cerebral ischemia, and growth factors may have a considerable
effect on future therapeutic regimens.
Key Words: cerebral ischemia growth factors neuroprotection stroke outcome
 |
Introduction
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|---|
The
insulin-like growth factors (IGF-I and IGF-II) are polypeptide
growth
factors that mediate anabolic and somatogenic effects
of growth hormone
and are synthesized and secreted by numerous
cell types.
1
IGFs are also present in the brain and are involved
in brain
development.
2 3 Increasing levels of IGF-I are produced
in
the developing brain.
4 After experimental hypoxic injury,
there
is an increased expression of IGFs in regions with neuronal
loss
4 ; whereas postischemic expression of
IGF-I is localized to astrocytes
and microglia, IGF-II expression is
restricted to areas of infarction
where macrophages accumulate
several days after hypoxic injury.
5 6 In vitro studies
have indicated that IGF-I is a potent nonselective
neurotrophic
agent.
7 Recently IGF-I has been recognized as
an important
mediator in wound healing and tissue repair.
5 8 In many
tissues IGF is activated in response to injury. At
present
six distinct human IGFBPs have been identified that
modulate the
biological activity of IGFs.
1 In the circulation
IGFs are
bound mainly to IGFBP-3, the most abundant circulating
IGFBP after the
neonatal period, whereas in the cerebrospinal
fluid concentrations of
IGFBP-2 are higher than those of IGFBP-1
or IGFBP-3.
9
Specific changes in the pattern of IGFBP expression
occur in the
injured brain. IGFBP-3, physiologically
expressed
in very low amounts in the central nervous system, is
markedly
induced within the first few days after experimentally induced
injury,
preferentially in the cortex.
4 In contrast,
IGFBP-2 is produced
by the choroid plexus. Increased expression of mRNA
coding for
IGF-I and the binding proteins IGFBP-2 and IGFBP-3
was observed
as a response to unilateral ischemia in the infant
rat, as in
focal ischemia in adult rats.
10 11
Critical illness, surgical procedures, and various drugs used in
intensive care medicine have been reported to suppress
hypothalamic-pituitary function.12 13 14 Alterations of
pituitary hormone secretion in acute stroke have been suggested, but
the clinical impact of endocrine function after acute cerebral
ischemia and its potential role during patient convalescence
remain unknown. The present study was conducted to evaluate IGF-I
and IGFBP-3 plasma levels in patients with cerebral ischemia
and to correlate IGF-I and IGFBP-3 plasma levels to the extent of focal
ischemia after acute ischemic stroke.
 |
Subjects and Methods
|
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Plasma IGF-I and IGFBP-3 levels were measured sequentially in
20
patients with acute ischemic stroke who were admitted to
the
Department of Neurology within 24 hours after onset of symptoms.
Eight
age-matched control patients being treated at the same
time in the
neurological department because of intervertebral
disk protrusion
served as controls. Blood samples were drawn
between 8
AM
and noon from indwelling venous catheters within
the first 24 hours
after stroke and again 3, 5, and 10 days
thereafter. Samples were
immediately centrifuged (1500
g, 10
minutes), and
plasma was stored at -80°C until assayed.
IGF-I and IGFBP-3 levels
in plasma were measured by standard
RIAs. The IGFBP-3 RIA was purchased
from Nichols Institute Diagnostics.
Plasma levels of IGF-I
were determined after acid-ethanol extraction
by RIA, which is used for
routine hormone measurements in our
laboratory. The samples from each
individual were measured in
duplicates in the same assay.
The study was approved by the local ethics committee. Patients with (1)
concomitant cardiac, renal, hepatic, or cancerous disease; (2) recent
head trauma; (3) recent history of transient ischemic attacks;
or (4) CT and/or MR tomographic results inconclusive for the location
of the ischemic lesion were excluded from this study. All
patients were evaluated by CT and/or MR tomography on days 1 and 4
after stroke. Clinical examination was performed on admission and daily
thereafter.
The examinations were scored according to the 58-point SSS and the
Glasgow Coma Scale.15 16 Ten days after stroke, clinical
outcome was assessed by the SSS and Rankin Scale.17
According to the clinical examination and imaging results, the patients
were classified as having small (SI; largest diameter of infarct on CT
<1.5 cm, SSS
40), moderate (MI; largest diameter
1.5 cm and
5
cm, SSS
30), or large infarct (LI; largest diameter >5 cm, SSS
<30). Patients were either fed with an oral diet that supplied at
least 2000 kcal and 16 g of nitrogen or received regular meals
with at least 2000 kcal as standard. The body mass index was calculated
as weight (in kilograms) divided by height (in meters) squared.
Patients received no medication known to suppress the somatotrophic
hormone axis.
Results are expressed as mean±SD. Statistical analysis was
performed by nonparametric tests as appropriate
(Wilcoxon signed-rank test).
 |
Results
|
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Patients
Twenty patients (14 men and 6 women ) aged 31 to 76 years (mean,
62
years) and 8 control subjects (6 men and 2 women) aged 35 to
73
years (mean, 60 years) were studied. Eight patients had LI,
in 7
patients due to cardiac embolism and in 1 due to dissection
of the
internal carotid artery and supraocclusional middle cerebral
artery
embolism. Six patients showed MI on CT; the cause of
infarction was
cardioembolic with atrial fibrillation in all
patients. Six patients
had SI due to either middle cerebral
artery branch occlusion or lacunar
infarct. The initial SSS
score was 11 to 25 (mean, 23) in the LI group,
30 to 37 (mean,
33) in the MI group, and 40 to 56 (mean, 45) in the SI
group.
Ten days after stroke, the mean score in the LI group was 25;
in
this group 1 patient died on day 8. The mean score was 36
in the MI
group and 49 in the SI group. The calculated body
mass index showed no
significant alteration during the observation
period
(Table

).
IGF-I Plasma Levels
The plasma levels of IGF-I in patients with stroke were
significantly lower than those of the control group and the reference
data reported in the literature.18 The mean plasma levels
of IGF-I were 105±23 ng/mL on day 1, 102±26 ng/mL on
day 3, 110±32 ng/mL on day 5, and 96±23 ng/mL on day
10, all of which were decreased compared with control values of
161±10, 172±15, 166±18, and 156±14 ng/mL (P<.05
on days 3 and 10) and compared with the reference data given in the
literature (190±30 ng/mL). Among the different subgroups of
stroke victims, the mean values obtained on days 1, 3, 5, and 10 were
85±27, 83±21, 88±29, and 72±34 ng/mL in patients with LI and
115±23, 124±26, 119±37, and 107±32 ng/mL, respectively, in
patients with MI. In the group of patients with SI, IGF-I levels were
125±17, 132±26, 143±21, and 130±32 ng/mL. The IGF-I levels
in patients with LI were the lowest among all stroke subtypes, and the
difference was statistically significant compared with control values
at any time point (P<.05). Moreover, a clear trend to lower
IGF-I levels depending on the size of infarction was obvious (Figs 1
and 2
).
Since no differences were detected within
subgroups during the clinical course, IGF-I data were pooled for
further statistical analysis (Fig 3
).

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Figure 1. Plasma level of IGF-I in patients with acute stroke.
Data are mean±SD. *P<.05 versus control. Age-matched data
from the literature are from Blum.18
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Figure 2. Plasma levels of IGF-I in patients with stroke of
different sizes. Data are mean±SD. *P<.05 versus
control.
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Figure 3. Pooled plasma levels of IGF-I in patients with
stroke of different sizes and control subjects. Data are mean±SD.
*P<.05 versus control.
|
|
IGFBP-3 Plasma Levels
The mean plasma levels of IGFBP-3 in the 20 stroke patients
were 2.3±0.9 mg/L on day 1, 2.4±1.0 mg/L on day 3,
2.1±0.6 mg/L on day 5, and 2.2±1.1 mg/L on day 10. The
values on days 5 and 10 were significantly lower than the control
values of 3.2±0.7 and 3.4±0.9 mg/L, respectively
(P<.05). Among the stroke subgroups, the mean values on
days 1, 3, 5, and 10 were 1.8±0.4, 2.0±0.6, 1.9±0.7, and 1.8±0.3
mg/L for patients with LI; 2.1±0.4, 2.2±0.6, 2.9±0.2, and
2.5±0.7 mg/L for those with MI; and 2.8±0.8, 3.1±0.3,
2.7±0.9, and 3.0±0.5 mg/L for those with SI. Again, the values
of those patients with LI were the lowest measured, and the difference
was statistically significant compared with those of control subjects
and those of patients with SI and MI on days 5 and 10
(P<.05) (Figs 4
and 5
).
Similar to the IGF-I levels, data on
IGFBP-3 from all stroke patients were pooled for further statistical
analysis (Fig 6
).

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Figure 4. Plasma level of IGFBP-3 in patients with acute
stroke. Data are mean±SD. *P<.05 versus control.
|
|

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Figure 5. Plasma level of IGFBP-3 in patients with stroke of
different sizes. Data are mean±SD. *P<.05 versus
control.
|
|

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Figure 6. Pooled plasma levels of IGFBP-3 in patients with
stroke of different sizes and control subjects. Data are mean±SD.
*P<.05 versus control.
|
|
 |
Discussion
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|---|
We found the plasma levels of IGF-I and IGFBP-3 decreased in
patients
with acute stroke over a period of 10 days after onset of
symptoms.
To the best of our knowledge, this is the first study to
measure
the plasma levels of IGF-I and IGFBP-3 in patients with
ischemic
stroke. In animal models IGF-I mRNA and protein as
well as IGFBP-3
have been shown to be increased in the damaged
brain.
11 We
found the peripheral plasma level
of the growth factor and of
its binding protein decreased in the acute
stage of ischemic
stroke compared with that of control subjects
and the data given
in the literature. The decline was similar in all
stroke subtypes,
but the patients with LI showed statistically
significantly
lower levels of IGF-I and had significantly lower levels
of
IGFBP-3. Although the mechanism for the reduction of plasma
IGF-I
and IGFBP-3 levels remains obscure, several explanations
are possible.
In animal models of cerebral ischemia, both IGF-I
and IGFBP-3
play a role in the central nervous system response
to injury. Since the
study of Nieto-Sampedro et al,
19 it is
well known that
growth factors are expressed in the brain 3
to 10 days after traumatic
brain injury. IGF-I is expressed
over a comparable time course after
hypoxic ischemic injury,
and IGF-I given after hypoxia
can reduce neuronal loss in several
regions of the
brain.
20 21 Guan et al
11 suggested that IGF-I
serves
as an endogenously protective mechanism to limit
injury. Since
IGF-I is neuroprotective given after, but not before, an
experimental
injury, it seems likely that IGF-I acts on mechanisms
occurring
after the injury itself.
10 21 IGF-I has been
shown to interfere
with apoptosis in nonneuronal and neuronal
cells.
22 23 Similar
to these findings from animal data, an
overexpression of IGF-I
and its binding proteins can be assumed in
patients after cerebral
ischemia. Reinhardt and
Bondy
24 showed that IGFs can cross
the blood-brain barrier
and selectively accumulate in specific
hypothalamic and anterior
thalamic nuclei. A recent study from
Guan et al
25 revealed
an enhanced movement of radioactive-labeled
IGF-I into the cerebrum via
the white matter tracts and perivascular
spaces after hypoxic injury.
Therefore, the low plasma levels
of IGF-I may be explained as
redistribution or shift of the
IGF-I "pool" from
peripheral blood to brain.
After polytrauma or severe surgical trauma during massive activation of
the immune system (for instance, in sepsis, malignant disease, or
cachexia), IGF and IGFBP-3 levels are significantly
diminished.18 Several studies showed alterations of the
IGF system in patients with acute trauma,26 27 28 whereby the
severity of injury strongly influences the plasma IGFBP-3
concentrations.29 The catabolic state persists even with
high caloric intake and balanced diets and reverses only when the
general condition of the patient has improved. Numerous mechanisms
account for erosion of body mass, including the counterregulatory
hormones glucagon, glucocorticoids, and
catecholamines.30 Proinflammatory
cytokines such as tumor necrosis factor or interleukin-1 are
activated.30 Sustained critical illness is
characterized by weight loss, muscle wasting, and organ system
failure.31 Several investigations used recombinant human
growth hormone or IGF-I for therapy of catabolic illness; however,
further studies are needed to substantiate the reported positive
effects of such therapeutic strategies.32 A recent study
on the effect of malnutrition on clinical outcome after acute stroke
described acute stroke to be moderately hypercatabolic with low caloric
requirements.33 In this study malnutrition was a distinct
predictor of poor outcome. However, the half-life of IGF-I and its
binding protein IGFBP-3 may be as long as 15 hours.1 18
Therefore, it is unlikely that the low levels of both IGF-I and IGFBP-3
measured in our study within the first 24 hours after ischemic
stroke are due to the development of a catabolic state. Moreover, the
majority of our patients had no other clinical symptoms to suggest
catabolic illness at any stage during their disease.
In the last few years it has become increasingly apparent that cerebral
injuries can cause distinct abnormalities of the endocrine system.
Hypercortisolism is frequently seen in patients with acute
stroke.34 Some studies showed an association of increased
plasma and urinary cortisol levels and poorer functional outcome after
stroke. A dysregulation of the hypothalamic-pituitary axis early after
stroke was proposed.34 35 36 37 The hormonal circadian pattern
of ß-endorphin and cortisol was abolished during the acute phase of
ischemia.35 In addition to these findings, several
other abnormalities have been described, eg, elevated nocturnal
prolactin release,36 impaired thyrotropin-releasing
hormonestimulated secretion of thyroid-stimulating hormone, and low
basal thyroid-stimulating hormone.35
In most studies no specific location of brain lesion could be
identified as being responsible for dysregulation of the
hypothalamic-pituitary axis. In addition to these abnormalities,
alterations of gonadotropins have also been described after stroke.
Pepper et al37 suggested in their study on alterations of
luteinizing hormone and follicle-stimulating hormone in postmenopausal
women that stroke involving the caudate nucleus may interrupt
neurotransmitter pathways involved in control of gonadotropin secretion
and therefore may lead to a severe reduction of gonadotropin
concentrations. Similar abnormalities have been described on the growth
hormone level in patients with stroke; Culebras and
Miller,36 for example, found low growth hormone levels
after stroke. The suprahypothalamic regulation of growth hormone
secretion mediated by various neural mechanisms may be affected in
patients with thalamic or cortical-subcortical lesions involving the
thalamus.36 Sander and Klingelhöfer38
found higher catecholamine levels in patients with stroke
involving the insular cortex. Elevated catecholamine levels
in stroke patients may have a direct inhibitory action on
growth hormone secretion. It has been shown by van den Berghe and
colleagues14 that dopamine attenuates growth hormone
secretion. For the low IGF-I and IGFBP-3 levels measured in our study,
this explanation is at least possible in parts. Since IGF-I is strongly
regulated by growth hormone, disturbed suprahypothalamic regulation
might cause the low levels of plasma IGF-I, at least in those patients
with LI or MI. In patients with lacunar stroke this explanation seems
unlikely. However, even in these patients cortical-subcortical
structures that connect to the thalamus may be affected.
Since IGF-I has been shown to be capable of rescuing motor neurons from
both naturally occurring and axotomy-induced death,39 40
it has already been introduced into clinical studies in the treatment
of motor neuron disease.41 42 Other studies have suggested
a neuronal-protective effect leading to reduced neuronal loss in the
cortex, striatum, and dentate nucleus after transient hypoxic injury in
the rat and other species.4 19 43 44 45 Our clinical data
showed that IGF-I and IGFBP-3 levels are altered after cerebral
ischemia. Further studies are necessary to elucidate the
pathophysiological mechanisms of this alteration
after ischemic stroke. However, further experimental stroke
therapies targeting the IGF system should be promising and need to be
further evaluated.
 |
Selected Abbreviations and Acronyms
|
|---|
| IGF |
= |
insulin-like growth factor |
| IGFBP |
= |
insulin-like growth factor binding protein |
| LI |
= |
large infarct (>5 cm diameter on CT scan, SSS <30) |
| MI |
= |
moderate infarct ( 1.5 and 5 cm diameter on CT scan, SSS 30) |
| RIA |
= |
radioimmunoassay |
| SI |
= |
small infarct (<1.5 cm diameter on CT scan, SSS 40) |
| SSS |
= |
Scandinavian Stroke Scale |
|
Received February 28, 1997;
revision received May 2, 1997;
accepted May 16, 1997.
 |
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