Ibotenic Acid-Induced Hematological Disorders in Rat Model of Alzheimer's Disease
The present study was conducted in order to investigate the effects of right-unilateral lesion of substantia nigra neurons by means of Ibotenic acid, a cholinergic-selective neurotoxin, on hematological parameters in rats. Thirty male Wistar rats weighing 200±50 g at the start of the experiment were used. The substantia nigra was right-unilateral lesioned by stereotaxic microinjections of ibotonic acid. Seven days after neurosurgery, we assessed the total number of White Blood Cells (WBC), the total number of Red Blood Cells (RBC), Red Cell Distribution (RDW), platelet and hemoglobin level and the erythrocyte indexes (Mean Cell Volume, (MCV), Mean Cell Hemoglobin,(MCH), Mean Cell Hemoglobin Concentration (MCHC)). Ibotenic acid treatment induced a highly significantly decrease of white blood cells, followed by significant decrease in red blood cells and hemoglobin level comparative with sham-operated rats. Also in the ibotenic acid-lesioned rats the erythrocyte indexes (Mean Cell Volume, MCV; Mean Cell Hemoglobin, MCH were significantly decreased comparative with sham-operated rats. By contrast, platelets, mean cell hemoglobin concentration and red blood cell distribution width were significantly increased in the ibotonic-acid lesioned rat versus sham-operated animals. On the whole, the obtained data indicate the important role of the central nerves system in the regulation of erythrocyte dynamics.
Alzheimer's Disease (AD) is characterized by degenerative changes in the brain
(Etienne et al., 1986) and the impairment of
learning and memory function (Miranda et al., 2003).
It is widely accepted that learning and memory are deeply associated with the
functional activity of the cholinergic system in the Central Nervous System
(CNS). The basal Fore Brain (BF) provides the major source of cholinergic in
put to the neocortex and hippocampus (Miranda et al.,
2003) and the cholinergic neurons in the Nucleus Basalis of Mynert (NBM)
are markedly degenerated in AD (Etienne et al., 1986).
Because the Nucleus Basalis Magnocelluralis (NBM) in the rat is analogous to
the NBM in humans, the NBM-lesioned rat has been regarded as an animal model
for cholinergic dysfunction in the cerebral cortex of patients with AD (Wu
et al., 2005). The NBM-lesioned rat shows decreases in cholinergic
markers, such as acetylcholine (ACh) release (Meyer et
al., 1987) and choline acetyltransferase (ChAT) activity (Arendash
et al., 1987), in the cerebral cortex and shows learning and memory
impairment (Salamone et al., 1984). In AD the
principal neurochemical abnormality is the alteration of the cholinergic system
in the Central Nervous System (CNS) (Zatta et al.,
2002; Kaizer et al., 2005).
Hematopoiesis, the dynamic process of blood cell production and development,
is characterized by a continuous, robust turnover of cells. The hematopoietic
system, which consists of the Bone Marrow (BM), liver, spleen, lymph nodes and
thymus, provides leukocytes, erythrocytes and platelets through a complex network
of tissues, organs, stem cells and regulatory factors (Huang
and Liu, 2009).
However, the mechanism causing anemia associated with autonomic dysfunction
is not well explained. Catecholamines and their corresponding receptors are
widely distributed in both the central and peripheral nervous system. Besides
their vasoactive effect (Siarakas et al., 1997),
catecholamines have been known to be involved in different forms of learning
and memory (Hefco et al., 2003; Spreng
et al., 2001). Immune cell types associated with innate immunity
such as natural killer cells, neutrophils and macrophages are the potential
subjects to be regulated by catecholamines because these cells express functional
β2- and/or α-adrenergic receptors (Dent et
The processes of hematopoiesis in the bone marrow are regulated by a variety
of factors including those produced by the stromal elements, the developing
hematopoietic cells themselves and by exogenous substances, such as hormones
and neurotransmitters, like acetylcholine. In particular, cutting nerves which
enter the hip bones influenced erythropoiesis, while injecting nicotine inside
the bone induced changes in the processes controlled by the autonomic nervous
system (Desforges, 1984). These data demonstrated the
role of the bone marrow innervation in hematopoiesis and the presence of nicotinic
acetylcholine receptors within the bone marrow. This view was further supported
by the recent studies of nicotine-stimulated changes in hematopoiesis (Khaldoyanidi
et al., 2001; Serobyan et al., 2005).
Nicotinic acetylcholine receptors (nicotinic receptors) are ligand-gated ion
channels mediating synaptic transmission in nerve and muscle cells. They are
composed of several types of alpha and beta subunits forming either homomeric
or heteromeric functionally distinct receptor subtypes (Paterson
and Nordberg, 2000). Nicotinic receptors are also present in many non-excitable
cells, such as skin keratinocytes (Arredondo et al.,
2003), respiratory tract epithelial cells, vascular endothelium (Conti-Fine
et al., 2000) and most of the blood cells: leukocytes (Cormier
et al., 2004), lymphocytes (Kawashima and Fujii,
2003), macrophages (Wang et al., 2003) and
erythrocytes (Bennekou, 1993), where their functions
are quite different from those in muscles or neurons. In summary, the primary
goal of this study was to evaluate whether disorders hematopoiesis regulation
via Nucleus Basalis Magnocelluralis (NBM) neuron lesion may induce hematological
MATERIALS AND METHODS
This research was conducted from June 2008 to June 2009.
Animals and Surgery
Thirty male inbreed Wistar rats, weighing 250-300 g and housed with free
access to food and water. They were maintained in a 12 h light/dark cycle with
lights on at 6:00 am at constant temperature (25°C). The animals were divided
into three equal number groups (n = 15): Control, sham operated (ShO) and ibotenic
acid (IBO). The rats were not found to have other causes of anemia, the nutritional
state was adequate and no evidence of any hemorrhagic and thrombotic disorder.
Neurosurgery and Drug Administration
On the day of surgery, the animals were anesthetized with ketamine/xylazine
(50 mg kg-1, i.p.) and placed in a stereotaxic apparatus (Kopf).
The incisor bar was set -0.16 mm posterior and ±0.40 mm lateral to the
bregma and -0.55 mm below the top of the skull (Ahmed et
al., 2004; Paxinos and Watson, 2007; Yamamoto
et al., 2003) to reach the nucleus basalis magnocellularis. Rats
received unilateral infusions of 0.5 μL volume of vehicle (NaCl 0.9%) or
ibotenic acid (8 μg μL-1) using a 5 μL Hamilton syringe.
The injection was given over a period of 5 min and the needle was left in the
injection site for a further 5 min. After behavioral tasks, rats were sacrificed
for neurochemical analysis. The protocol concerning this research is in accordance
with the guidelines of the committee on the care and use of Experimental Animal
Resources, School of Medicine, Ahwaz Jondishapour University of Medical Sciences,
Ahwaz, Iran. Hematological parameters were assayed 1 week after the neurosurgery.
Morris Water Maze Task
Training in the maze taken place during the light phase of the cycle between
8:00 am and 5:00 pm. A circular pool was used as described by Morris with some
modification (Widy-Tyszekoeiwecz et al., 2002).
It was a black circular pool (120 cm in diameter and 80 cm in height) filled
with tap water (27±2°C) with a depth 60 cm. The maze was divided
geographically into four equal size quadrants and release points were designed
in each quadrant as North (N), East (E), South (S) and West (W). A hidden circular
escape platform (12 cm in diameter), was emerged 2 cm below the water level
and was located in the center of the northeast quadrant. Some fixed visual cues
including computer, desk, shelves, posters and illumination lights were placed
on the walls around the pool. A camera was positioned above the center of the
pool that was connected to a computer to record the animal motions. An automated
tracking system (Radiab ver. 2, Tehran, Iran) was used to measure the escape
latency, swimming distance and speed.
Twenty four hours after the last infusion of GH (8th day) animals were subjected
to the training procedure of one session of four trials (block) daily for four
consecutive days in the water maze. In each trial, the animals were allowed
60 sec to find the platform, after then were allowed to remain there for 30
sec, if did not find the platform within 60 sec animals were gently guided to
the platform. After the completion of a trial, animals were returned to a holding
cage for an intertrial interval of 60 sec. After 24 h of the last trial, platform
was removed and rats were released from Southwest as a probe trial (consisted
of a 60 sec free swim period) and the time spent in the target quadrant was
recorded (Alaeia et al., 2008). The behavioral
test include calculation of path length, escape latency, swimming speed and
Blood Sampling Protocol
One week after neurosurgery, blood samples were withdrawn from lateral tail
vein via the Biotrol sampling catheter from 15 sham operated and 15 ibotenic
acid-treated rats. Blood samples (0.5 mL approximately/sample) were collected
in vials containing EDTA for hematological investigations. Hematological parameters
were assayed by a COULTER® Ac•T 5diff CP-precision
instrument for hematology research. In order to rule out the iron deficiency
anemia, the standard discrimination indices were calculated by using red blood
cell indices as in our previous study (Keikhaei et al.,
At the end of the experiment, all rats were sacrificed with an overdose
of sodium pentobarbital (100 mg kg-1 i.p.) followed by a transcardial
infusion of 0.9% saline and a 10% formalin solution. The brains were removed
and placed in a 30% sucrose/formalin solution. The brains were frozen and cut
into coronal sections (50 μm) using a freezing microtome and stained with
crystal violet for verification of the point of the syringe needle. Only experimental
data from lesions correctly located in the substantia nigra were used for statistical
Data Presentations and Statistical Analysis
Statistical analysis was performed with SPSS software (v. 12.0; SPSS Inc.,
Chicago, IL, USA). Results were expressed as Mean±SEM. Because the data
were not normally distributed, the non-parametric statistic Mann-Whitney U-test
was employed. Results were considered significant if p<0.05. The number of
observation was 30.
RESULTS AND DISCUSSION
Experimental data were registered 1 week after the ibotenic acid administration
(Table 1). Comparing the swimming path length between the
various groups did not indicate any differences during 4 days spatial training
in water maze (p>0.05). Path length in each session in ibotenic acid-lesioned
group was longer than control group significantly (p<0.01). Comparing the
escape latency between the various non-lesioned groups did not indicate any
differences during four days spatial training in water maze (p>0.05). Time
required to find and locate on escape platform in each session in ibotenic acid-lesioned
group was more than control group significantly (p<0.01). Total escape latency
was increased in ibotenic acid-lesioned group after 4 days training significantly
comparing to control (p<0.001). Comparing the swimming speed between the
various groups did not indicate any differences during four days spatial training
in water maze (p>0.05). The percent of time spent in goal quarter while escape
platform removed during probe trial 24 h after 4 days training, decreased significantly
in ibotenic acid-lesioned group (p<0.001) when comparing to control group.
||Demographic variables of study groups with their U and p-values
|©: Significant increase in values of variable among the ibotenic
acid exposed group (IBO). *Significant decrease in values of variable among
the sham operated group (ShO). £: Non significant difference. **p-values
between control and ShO groups, ***p-values between control and IBO groups,
NS: Not significant
||Differential value for each discrimination index in differentiation
between non iron deficiency and iron deficiency anemia
|IDA: Iron deficiency anemia, NIDA: Non Iron deficiency anemia
We have calculated the different indices for ibotenic acid-lesioned rats individually.
The differential value for each discrimination index in differentiation between
non iron deficiency and iron deficiency anemia are shown in Table
2. In the ibotenic acid-lesioned rats, we observed a significant decrease
in the total number of white blood cells (p<0.001), Mean Cell Volume (MCV)
(p<0.05), red blood cells (p<0.05) and hemoglobin level (p<0.05) (Fig.
1A-E), compared with the sham-operated groups. Ibotenic
acid significantly increased Red Cell Distribution Width (RDW) (p<0.05),
platelet (p<0.05) and Mean Cell Hemoglobin Concentration (MCHC) (p<0.05)
compared with sham-operated groups (Fig. 2A-C).
In case of this three increased values, the high level was observed comparing
to sham-operated group, but the values was also decreased comparing to control
group (Fig. 2).
Beard et al. (1997) suggested that anemia increases
the risk of Alzheimer's disease, although the mechanism remains to be elucidated.
In addition, anemia can lead to other neurologic symptoms, such as headaches,
loss of concentration and depression (Katz et al.,
1993). It is well recognized that the immune response is under the influence
of a variety of neural or neuroendocrine mechanisms. Much less studied is the
possible influence of these mechanisms on hematopoiesis. Earlier studies reported
that the central dopaminergic system has a crucial role in regulation of the
immune processes as well as hematopoiesis (Nanda et al.,
2005; Pacheco-Lopez et al., 2003). In the
present study, we used a procedure of chemical sympathectomy by lesioning the
basalis magnocellularis with ibotenic acid. By means of this particularly electrolytic
lesion, we observed a significant decrease in hematological parameters registered
1 week after ibotenic acid administration, tested by the total number of leukocytes,
erythrocytes, hemoglobin level and the erythrocyte indexes (MCV and MCH). Interestingly,
we observed increase in platelet numbers, Red Dell Width (RDW) distribution
and other erythrocyte index (MCHC) in ibotenic acid-lesioned rats comparing
to sham operated group. We demonstrated that rats treated with ibotenic acid
showed anemia. In addition, since the WBC significantly decreased during ibotenic
acid-induced anemia, the effect of ibotenic acid in this experiment may be specific
for erythropoiesis, as well as for bone morrow suppression.
In this study, we also demonstrated the low hemoglobin associated with AD which
was in agreement with study done by Pandav et al.
(2004). McCaddon et al. (2004) showed thathemoglobin
and platelet counts fell only slightly with increasing dementia duration, but
there were no other changes in hematological indices. In particular, macrocytosis
and red cell distribution width were unrelated to disease duration and no patients
were anemic. Present result not only showed the significant decrease in hemoglobin
and other hematological indices also increase in red cell distribution width.
||(A) The effect of the chemical lesion with ibotenic acid on
total number of leukocytes (**p<0.03 vs. control group), (B) total number
of erythrocytes (**p<0.01 vs. control group), (C) hemoglobin level (**p<0.02
vs. control group), (D) mean cell volume (**p<0.04 vs. control group)
and (E) mean cell volume (**p<0.04 vs. control group) all tested one
week after lesion; *all p-values of control vs. sham-operated group (p>0.05).
Values are Mean±SEM (n = 15 per group)
The regulation of the hematopoietic system is achieved at three levels: (1)
at the cellular level of bone marrow stroma, (2) at the humoral level by cytokines
and (3) by catecholamines and other neuroendocrine factors. Sympathetic nerve
endings and bone marrow cells are the main source of bone marrow catecholamines
(Felten, 1993; Maestroni, 1998;
Hoogduijn et al., 2006).
||(A) The effect of the chemical lesion with ibotenic acid on
increased mean cell hemoglobin concentration (**p<0. 04 vs. sham-operated
group), (B) platelet (**p<0.03 vs. sham-operated group) and (C) red cell
distribution width (p<0.03 vs. sham-operated group) all tested one week
after lesion; *all p-values of control vs. sham-operated group (p>0.05).
Values are Mean±SEM (n = 15 per group)
Among the catecholamines, a substantial amount of dopamine was detected in
bone marrow (Marino et al., 1997). Bone marrow
catecholamines originate from sympathetic nerve fibers and from hematopoietic
cells directly. Catecholamines of neural origin show a circadian rhythmicity.
Adrenoceptors present on bone marrow cells include the 1-subtype, which seems
to mediate the catecholaminergic ShO of hematopoiesis.
Kaizer et al. (2008) have suggested that AChE
activity in erythrocytes may be considered a marker of easy access of the central
cholinergic status. Many researches showed that the bone marrow acetylcholine
can be released by the stromal elements affecting generation and differentiation
of blood cells. In the cited work nicotine affected hematopoiesis supportive
stromal microenvironment, interfering with the stem cell homing. Later it was
shown that nicotinic receptors are expressed in the very hematopoietic cell
precursors (Serobyan et al., 2007; Koval
et al., 2008).
It has been well documented that there are α- and β-adrenergic receptors
on the surface of the erythrocytes. However, β-receptors are more important
in erythropoiesis. Administration of an α-adrenergic stimulant did not
elicit the erythropoietic effect, whereas a β-adrenergic stimulant induced
erythropoiesis in an in vitro culture of erythroid progenitor cells (Mladenovic
and Adamson, 1984). Since β-adrenergic receptors are abundant on the
surface of erythrocytes, the effect of α-adrenergic blocking agents has
often been investigated using erythrocytes (Miklavc et
al., 1989; Hritcu, 2006). In accordance with
these findings, in our present study we observed some abnormalities of hematopoiesis
after electrolytic lesion of the central dopaminergic neurons from the substantia
nigra by means of ibotenic acid. Ibotenic acid is a useful chemical agent for
inducing neurogenic anemia.
Serum levels of methylmalonic acid rise in B12 deficiency, whereas homocysteine
levels rise in both folate and B12 deficiency (Andres et
al., 2008). Hematological features of B12 and folate deficiencies include
anemia, macrocytosis, thrombocytopenia, neutropenia and neutrophil hypersegmentation.
Recently elevated serum homocysteine in patients with Alzheimer's Disease (AD)
has been described (McCaddon et al., 1998). Other
studies have confirmed this observation and suggested that elevated homocysteine
is a risk factor for cognitive decline and dementia (McCaddon
et al., 2001, 2002; Seshadri
et al., 2002; Seshadri, 2006; Schulz,
In conclusion, this study confirms earlier observations of increased plasma
homocysteine and reduced serum folate levels in patients with clinically diagnosed
AD, Hb and platelet counts fell only slightly with increasing dementia duration,
also there were other changes in hematological indices; macrocytosis and RDW
in particular were related to disease duration and there were anemic subjects.
Thus, in present study sample, low Hb and RBC indices may have increased susceptibility
to AD. The potential role of this changes in hematological parameters in increasing
risk of AD should be explored prospectively, in both developed and developing
countries, considering its high prevalence in older adults and the intriguing
possibility that low Hb and RBC indices could be a modifiable risk factor.
This study (PRC44) was supported by Ahwaz Jondishapour University of Medical
Sciences, Ahwaz, Iran.
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