(Stroke. 1997;28:1744-1748.)
© 1997 American Heart Association, Inc.
Articles |
Plasma Insulin-like Growth Factor I and IGF Binding Protein 3 Levels in Patients With Acute Cerebral Ischemic Injury
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.
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Abstract |
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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
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 loss4 ; 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.
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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 (1500g, 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).
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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
).
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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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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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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 al11 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 Bondy24 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 al25 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 hormone–stimulated 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.
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Selected Abbreviations and Acronyms |
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Received February 28, 1997; revision received May 2, 1997; accepted May 16, 1997.
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