# Serum Insulin-Like Growth Factor-1 and Nitric Oxide Levels in Parkinson's Disease

Authors: Deniz Tuncel; Fatma Inanc Tolun; Ismail Toru
Journal: Mediators of Inflammation
 (2009)

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## Abstract

The aim of this study was to investigate the role of circulating growth hormone (GH), insulin growth factor-1 (IGF-1), IGF binding protein-3 (IGFBP-3), and nitric oxide (NO) concentrations in the patients suffering from Parkinson's disease (PD). The study groups were consisted of 25 patients with PD and 25 matched healthy subjects as a control. The NO level of patients in PD group (2.3±0.4 μmol/L) was significantly lower than that in the control group (2.8±0.6 μmol/L) (P:.011). Although there were no statistically significant differences in the GH, IGF-1, and IGF BP-3 levels among the two groups, in this preliminary study, we found low NO and mildly elevated IGF-1 levels in the patients with PD. The results may be associated with adaptation or protective mechanisms in the neurodegenerative disease processes such as seen in the PD. Further studies should be carried out to confirm our results.


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## Body

## 1. Introduction

Parkinson’s disease (PD) is a common neurodegenerative disorder that can
cause significant disability and decline in the
quality of life. It is not a single entity simply resulting from a dopaminergic
deficit, rather most likely caused by a combination of genetic predisposition
and environmental factors. Mitochondrial dysfunction has been proposed as a general
basic mechanism underlying the neurodegeneration seen in PD [1, 2]. This
condition is related to increased
free radical production, oxidative stress, and decreased ATP production, that
leads to increased intracellular calcium concentration, excitotoxicity, and
nitric oxide related cellular damage [1, 3, 4].Nitric oxide (NO) has varied physiological roles in the nervous system,
including morphogenesis and developmental synaptic plasticity. However, in the pathological
conditions, it could contribute to the oxidative stress and neurodegeneration
[4, 5]. Clinical findings, evidences from experimental models, and postmortem
studies revealed a connection of NO with the selective degeneration of
dopaminergic neurons in the PD [4, 6]. Formation of NO can be regulated via the
GH-IGF-1 system,
but the cellular mechanism for this regulation is unknown [7]. Growth hormone
(GH) exerts much of its biological activity by stimulating the production of (IGF-1),
which is synthesized in nearly every tissue including the central nervous
system. Insulin and IGF-1 have metabolic,
neurotrophic, neuromodulatory, and neuroendocrine important functions in the brain. Studies among older people suggest
that the GH-IGF-1 axis activity is reduced with age [7–9]. Thus, IGF-1 deficiency may be involved in the
pathogenesis of age-related neurodegenerative diseases and might be relevant to
the etiology of PD [8–10].To further reveal the pathophysiological processes that were seen in the PD, we
aimed to investigate the role of circulating GH, IGF-1, IGFBP-3, and NO
concentrations in the PD patients in comparison with healthy subjects.


## 2. Materials and Methods

After receiving approval from the Hospital’s Ethics Committee,
we recruited patients from the out-patient clinic of our Neurology Department. All
subjects had signed written informed consent before participation. A
neurologist performed physical examination of each patient and noted the
patient history. All PD patients showed rest tremor, rigidity, bradykinesia,
and postural instability. These features with any one had begun displayed
asymmetry. Patients with Parkinsonism, stroke, and
dementia were excluded from the study. The patients with PD and healthy control
groups were consisted of nonsmokers
without other neurodegenerative, chronic, or infectious diseases. There were 25
patients in the PD group and 25 matched healthy subjects in the control group. The
revision of Hoehn and Yahr staging scale was used to estimate the disease
severity [11]. All of the PD patients were under the treatment with anti-PD
drugs.Venous blood samples were collected at 8 AM and 9 AM after an overnight fasting period. Within 1
hour after blood taking, the blood was centrifuged at 4000 rpm for 10 minutes,
and the serum was stored at−70°C until analyzed. Stored sera were assayed for
IGF-1, IGFBP-3, and GH
by an automated chemiluminescent assay system (IMMULITE 2000, Diagnostic
Products Corp., Los Angeles, Calif, USA). Serum nitric
oxide measurement was performed using the Griess method for detection of
nitrite levels [12].Statistical assessments were carried out with SPSS 10.0 packet
program. All data were given as mean±standard deviation (SD). The
results were analyzed
using the Mann-Whitney U-test.
A P-value of less than .05 was considered statistically significant.


## 3. Results

There were 25 patients (20 males, 5 females) in the PD group with
a mean age of67.9±9.4 years, and 25 healthy subjects (20 males, 5 females) in
the control group with a mean age of 64.3±8 years. Age and sex distributions of
patients and control groups were similar (P>.05).
The mean Hoehn and Yahr stage was 3, and the duration of PD was 4.9±3.1 years (see
Table 1). NO, IGF-1, and IGFBP-3 levels in
serum of PD patients showed no correlation with the duration and severity of the
disease (measured by the Hoehn and Yahr staging scale).Table 1
Age, sex, and clinic features of the patients with PD and healthy controls.
PatientsControlsAge (years)mean±SD67.9±9.464.3±8SexMale (n)2020Female (n)55Hoehn  and Yahr scoremean±SD3±1Duration of illnessmen±SD4.9±3.1The NO level
of patients in PD group (2.3±0.4 μmol/L)
was significantly lower than that in the control group (2.8±0.6 μmol/L) (P:.011). However, there were no statistically significant
differences in the GH, IGF-1, IGFBP-3
levels among the patient and the control group (P>.05) (see Table 2).Table 2
Nitric oxide, growth hormone, insulin-like growth factor-1, and insulin-like growth factor BP-3 levels of the patients with PD and healthy controls.
PatientsControlsNitric oxide (μmol/L)mean±SD2.3±0,42.8±0.6*Growth hormone (ng/mL)mean±SD0.9±0.90.7±1.2Insulin-like  growth
factor-1 (ng/mL)(mean±SD)132±42113±51Insulin-like  growth
factor BP-3 (μg/mL)(mean±SD)3.4±0.83.7±1P*:.011, P:.52, P:.087,
P:.19, respectively.


## 4. Discussion

Mitochondria are critical regulators of cell death and
have been implicated as an important player in the death of dopaminergic
neurons in PD. NO has been suggested to contribute, via impairment of
mitochondrial function, to the neurodegenerative process [1, 3, 4]. It has
previously been shown that formation of NO can be regulated via the GH-IGF-1 system, and this
system may prevent the NO-mediated neuronal damage. But, the cellular mechanism
for this regulation is unknown [9]. We found that the NO level of patients in
the PD group was significantly lower than that in controls. Although
statistically not significant, IGF-1 levels were mildly elevated in the
patients with PD. These changes may be considered to reflect local adaptive and
protective responses to an underlying pathological derangement [3, 5, 9, 13].The excess of NO could contribute to the formation of free radicals that
could be involved in the death of dopaminergic neurons, leading to the
development of PD symptoms [4]. Studies on nitrite
and nitrate measurements in the cerebrospinal fluid (CSF) of PD patients have
been contradictory, as there
was no change [14–16], increase [17, 18], or
decrease [19, 20]. On the other hand, some studies showed that CSF and
plasma nitrate levels did not correlate with age at onset, duration, scores of
the unified Parkinson's disease rating scales, and Hoehn and Yahr staging in
the patients group [15, 16]. NO-mediated neurotoxic
and neuroprotective effects seem to be dependent on its oxidative/reductive
status, and the exact contribution to neurodegeneration is still not completely
understood. An involvement of NO in the protective effect may occur via
adaptive mechanisms. Therefore, the excessive NO synthesized in the course of
adaptation is stored against the detrimental effects [4–6, 13]. We found that the nitric oxide level of patients in the PD
group was significantly
reduced than that in controls. The possible explanations for these low levels
may be a defective NO-dependent adaptation mechanism or the exhaustion of NO
storage in the course of PD. However, we found
no significant correlation between these levels and the duration of disease and Hoehn and Yahr staging.Growth hormone exerts much of its biological activity by stimulating the
production of IGF-1, which is synthesized in nearly every tissue including the
central nervous system and bounds to IGFBP-3. The GH-IGF-1 axis activity is
reduced with age. Various studies showed that declining levels of serum IGF-1
contribute to age-associated brain impairments and neurodegenerative diseases
such as PD and Alzheimer’s [9, 21]. Also, IGF-I has recently been found of
potential therapeutically use in different neurodegenerative conditions. Substantia
nigra is one of the regions in the human brain, where a considerable density of
IGF-1 receptors is evident. IGF-1 increases the survival of neurons in the
brain stem and rescues embryonic DA neurons from programmed cell death [9, 22, 23]. It is found that serum IGF-1 levels are
variable in the different diseases [9]. There
were no statistically significant differences in the IGF-1 and IGFBP-3 levels among our patient and control groups. After a pathological condition develops, IGF-1 levels increase to protect affected
neurons and to adapt
to an underlying pathological process. This mechanism may explain the mildly
elevated IGF-1 levels [9].Our study has some limitations; our patient group is rather
small and had a male predominance. The results of this preliminary study must
be confirmed in larger patient groups with different age and sex distributions.As a conclusion,
there are few data about the role of NO on
IGF-1, IGFBP-3 gene
expression, and serum levels in PD. In this
preliminary study, we found that there were low NO and mildly elevated IGF-1 levels in the patients. The results may be
associated with adaptation or protective mechanisms in the neurodegenerative
diseases process such as PD. Further studies should be carried out to confirm these
results.



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