Effect of L-Arginine on Some Biochemical Markers of Metabolic Syndrome Associated with Brain Function in Female Wistar Rats
Metabolic syndrome (Mes) was associated with insulin resistance
and endothelial dysfunction. In particular, endothelial dysfunction was associated
with a significant reduction in nitric oxide, a metabolite of L-arginine (Arg).
Insulin resistance occurs following the failure of insulin to maintain glucose
balance or regulate appetite via signaling in the brain. Thus, this study investigated
the influence of Arg on some biochemical markers of Mes associated with the
brain function and on the brain histology of female Wistar rats. Two groups
of rats (n = 8) were exposed to a single dose of 60 mg kg-1 b.wt.
of Arg and 3 ml kg-1 b.wt. of distilled water respectively as treated
and control groups. Exposure was per oral (p.o) for twenty eight consecutive
days. Exposure to Arg evoked a significant increase (p<0.01) in aspartate
amino transferase (AST) activity (24.95±0.10 IU L-1) and ammonium
ion (NH4+) concentration (39.58±0.16 μg mL-1)
in the rats serum. It increased (p<0.01) the aspartate amino transferase
to alanine amino transferase (AST:ALT) ratio (0.37±0.01) of the rats.
Brain section of Arg-treated rats revealed degeneration, characterized by necrosis,
oedema and reduction of astrocytes. AST:ALT ratio had a significant positive
correlation (r = 0.01) with AST activity and NH4+ concentration.
The results suggest Arg-induced adverse influence on the studied markers of
Mes associated with the brain function. Hence, exposure to Arg may impair the
brain function and possibly, worsen Mes related to brain function of the rats.
Received: December 07, 2012;
Accepted: April 30, 2013;
Published: June 10, 2013
Metabolic syndrome (Mes) is a cluster of medical disorders. The syndrome is
characterized by obesity, insulin resistance (type 2 diabetes mellitus), atherogenic
dyslipidemia and hypertension (Deedwania and Gupta, 2006;
Gallagher et al., 2010; Mahajan
et al., 2010). Mes was associated further health risks in animals
(Azhar, 2010; Siddiqui, 2011;
Pelucchi et al., 2010; Rosato
et al., 2011; Capasso et al., 2010;
Mugnai, 2010). The prevalence of Mes is on the increase
and the pattern cuts across every age, location and gender (Gotto
et al., 2006; Grundy, 2008; Ijeh
et al., 2010; Bakoma et al., 2011).
However, female gender is an independent risk factor for the development of
Mes (Ravikiran et al., 2010). In addition, in
the females, Mes could result to polycystic ovary syndrome (Mathur,
2010) that may worsen infertility.
The pathophysiology of Mes was associated with endothelial dysfunction following
a significant reduction in nitric oxide, a metabolite of L-arginine (Garlichs
et al., 2000). Abnormal concentration of nitric oxide, NO, a vasodilator
molecule could result in pathologicl conditions (Lokhande
et al., 2006; McGrowder and Brown, 2007).
In addition, a decrease in ARG availability resulted in the reduction of the
biological activity of NO (Harisa, 2011) and in the
conversion of NO into peroxynitrites that could mediate cell damage (Subratty
et al., 2007). Furthermore, Mes was associated with insulin resistance,
the failure of insulin to maintain glucose balance that may result to type 2
diabetes and obesity (Ezeanyika and Egbuonu, 2011).
Insulin is the key hormone in the regulation of glucose homeostasis (Cohn
et al., 2005; Lann and LeRoith, 2007) and
appetite via. signaling in the brain (Gallagher et al.,
2010). Moreover, Arg could enhance the production and release of insulin
(Egbuonu, 2012). These suggest that Arg, a precursor
of Nitric Oxide (NO) (Moncada et al., 1991), may
affect Mes in animals via. possible alteration of their brain function.
L-Arg is commonly used in diets and drugs owing to its possible benefits in
animals (Egbuonu et al., 2012). However, Arg-induced
adverse response in rats was reported (Lokhande et al.,
2006; Nematbakhsh et al., 2008). Thus, this
study investigated the influence of L-arginine on some biochemical markers of
Mes associated with brain function in female Wistar albino rats. The study also
examined the effect of L-arginine on the brain histology of the rats. The choice
of female rats in this study derived from report that the female gender is an
independent risk factor for incidence of Mes (Ravikiran
et al., 2010) and that the prevalence of Mes is higher in the females
(Mangat et al., 2010; Kilic
et al., 2010; Titty et al., 2008)
where it could result to polycystic ovary syndrome (Mathur,
MATERIALS AND METHODS
Chemicals and reagents: The animal study was carried out between August
and September, 2010. Chemicals used in this study were procured from reputable
dealers in Nsukka, a University town in Enugu State, Nigeria. L-arginine is
a product of Sigma Chemical Company, St. Louis, U.S.A.
Concentration determination/justification: The test concentration, ARG
(60 mg kg-1 b.wt.), was based on the concentration used in earlier
studies (Alexander et al., 2004; Egbuonu
et al., 2010a, b,c)
in line with WHO reported daily oral intake of Arg (Marshal,
Animals and treatment: The female Wistar rats used in this study were
obtained from the animal house of the Faculty of Biological Sciences University
of Nigeria, Nsukka. The rats weighed 60-80 g, similar to weight range of rats
used by Amin and Nagy (2009). The animal study was according
to International, National and institutional guidelines for the care and use
of laboratory animals in Biomedical Research (CCAC, 1985;
WMA/APS, 2002) as approved by the Departmental adhoc
Ethical Committee, Department of Biochemistry University of Nigeria Nsukka,
The rats acclimatized for a week and thereafter were randomized into two groups
with sample size of eight rats each. Two groups of female Wistar albino rats
(n = 8) were exposed to a single dose of 60 mg kg-1 body weight (b.wt.)
of Arg and 3 mL kg-1 b.wt. of distilled water respectively as treated
and control groups. Exposure was per oral (p.o) for twenty eight consecutive
The rats were housed in a well-ventilated stainless steel cages at room temperature
(28±2°C) and tropical humid condition. They were maintained under
standard natural photoperiodic condition of twelve hours of light alternating
with twelve hours of darkness (i.e., a normal daylight/dark cycle). In compliance
with the ethical guidelines for treating laboratory animals, the rats were allowed
unrestricted access to tap water and standard rat chow (Grand Cereals and Oil
Mills Limited, Jos, Nigeria) for the experimental period.
Sample collection and preparation: Collection of the respective blood
sample of animals, sacrificed 24 h after the 28 days oral exposure, was by ophthalmic
venous plexus or retro orbital sinus venipuncture. This involved inserting a
sterile capillary tube into the medial canthus of the eye of the rat to puncture
the retro-bulbar plexus resulting to out flow of blood into clean non-anticoagulated
tube. Centrifugation of clotted blood at 3000 rpm for 10 min yielded the serum.
Thereafter, the serum (aspirated separately into stoppered polystyrene tubes)
was stored in a deep freezer for subsequent use in determining the aspartate
amino transferase activity and ammonium ion concentration. Organ specimen (brain)
excised from the sacrificed rats for histology was fixed in 10% formaldehyde
buffered saline (formal saline) until used.
Determination of parameters
Serum aspartate aminotransferase (AST) activity: The serum aspartate aminotransferase
(AST) activity assay was by the method of Reitman and Frankel
(1957). The method was based on the coupling of oxaloacetate (oxaloacetic
acid) formed from the aspartate aminotransferase catalysed reaction with chromogen
(2, 4-dinitrophenyl hydrazine) in alkaline medium to yield colored hydrazone
that was measured colorimetrically at 540 nm.
Serum ammonium ion (NH4+) concentration: Determination
of ammonium ion concentration was by colorimetric method as described in AOAC
(2005). This based on the principle of colorimetric estimation at 480 nm
of ammonia, distilled after alkalinization, by nesslerizaton or titrimetry.
Calculation of the diagnostic ratio: AST:ALT ratio was calculated from
the corresponding parameters obtained in the same study. However, alanine amino
transfrase activity was not reported here.
Organ histology: Organ specimen (brain) promptly excised from the sacrificed
rats for histological examination were fixed in 10% formaldehyde buffered saline
(formal saline) until used as reported (Egbuonu et al.,
2010c). In brief, after dehydration (in graded levels (70-100%) of alcohol),
clearing (in xylene impregnated with paraffin wax) and sectioning (at 5 microns
thickness using rotary microtone) the sections were floated on a water bath
maintained at a temperature of 2-3°C below melting point of the paraffin
wax. Thereafter, drying of the sections was performed on a hot plate maintained
at a temperature of 2-3°C above the melting point of the paraffin followed
by staining and mounting of the sections using haematoxylin and eosin.
Statistical analysis: Analysis of data to determine significant difference
in mean was by Students t-test
using the Statistical Package for the Social Sciences (SPSS) for Windows (version
16.0; SPSS Inc., Chicago, IL., USA). Results were expressed as mean and standard
deviation (Mean±SD) of eight rats per group at significance level of
p<0.01. Furthermore, correlation of the results for possible association
among the studied parameters was by Pearsons
bivarate method (r = 0.01).
Serum aspartate aminotransferase (AST) activity: A significant increase
(p<0.01) in the serum AST activity was recorded in the Arg-treated rats (24.95±0.10
IU L-1). This represents an increase by 8.95 % (Fig.
Serum aspartate aminotransferase to alanine aminotransferase (AST:ALT) ratio:
The computed serum AST:ALT ratio increased (p<0.01) in Arg-fed rats (0.37±0.01)
relative to control, representing an increase by 32.14 % relative to control
Serum ammonium ion (NH4+) concentration: As depicted
in Fig. 3, the serum NH4+ ion concentration
in Arg-treated rats increased (p<0.01) (39.58±0.16 μg mL-1)
above that of the control rats. This represents an increase of 8.05% relative
||Correlations of AST:ALT ratio, serum AST activity and ammonium
|**: Correlation is significant at the 0.01 level (2-tailed)
Correlation outcome: As revealed in Table 1, AST:ALT
ratio had a significant positive correlation (r = 0.01) with AST activity (0.980)
and ammonium ion concentration (0.957).
Histomorphology of the brain: Brain sections of the control rats showed
typical brain histology, with population of normal cells (Fig.
||Influence of distilled water (DW) and ARG on serum AST activity
||Effect of distilled water (DW) and ARG on serum AST:ALT ratio
||Effect of distilled water (DW) and ARG on serum ammonium ion
concentration of rats
||Brain section of control (Group A) rat showing typical histology,
with lots of Astrocytes (arrow heads). H and E stains, x400
||Brain section of rats exposed to Arg (Group B) showing moderate
necrosis, oedema and reduction of astrocytes (arrow heads). H and E stains
Sections collected from rats treated with Arg (Group B) showed moderate oedema.
The population of astrocytes was moserately reduced (Fig. 5).
Metabolic syndrome (Mes) predisposes animals to further health risks (Lerman-Garber
et al., 2010; Szosland, 2010; De
Flines and Scheen, 2010; Brietzke, 2010; Zambon
et al., 2010). The association of Mes pathogenesis with a significant
reduction in NO availability (Garlichs et al., 2000)
suggested that Arg, through its major precursor role in NO synthesis (Moncada
et al., 1991), may improve Mes. Indeed, Arg improved the renal function
markers of metabolic syndrome (Egbuonu and Ezeanyika, 2013).
However, Arg worsened the markers of Mes related to lipid metabolism (Egbuonu
and Ezeanyika, 2012), warranting this study to ascertain the effect of Arg
on some biochemical markers of metabolic syndrome associated with the brain
function of female rats.
Elevated serum AST activity may indicate damage to other high metabolic organs
besides the liver (Bush 1991; Egbuonu
et al., 2012). Arg ingestion to rats elicited a significant increase
(p<0.01) in AST activity of the rats serum, indicating altered function
of high metabolic organs. The observation is consistent with that of earlier
study in male rats (Egbuonu et al., 2010c), adduced
to adverse influence on high metabolic organs including the brain (Egbuonu
et al., 2010b).
A reduced serum aspartate aminotransferase to alanine aminotransferase (AST:ALT)
ratio was associated with enhanced insulin resistance (Hanley
et al., 2005) and incidence of Mes (Tzima et
al., 2009; Sidorenkov et al., 2010). Consistent
with earlier study in male rats (Egbuonu et al.,
2010c), exposing the female rats to Arg increased their computed AST:ALT
ratio, precluding liver damage as the source of increased AST activity in this
study and suggesting suppressed insulin resistance or Mes. Women with Mes had
lower AST:ALT ratios than those without (Tzima et al.,
2009). Thus, exposeing female rats to Arg may improve Mes related to reduced
AST:ALT ratio in the female rats.
By contrast with control, Arg ingestion to the rats increased (p<0.01) the
serum ammonium (NH4+) ion concentration, indicating adverse
influence on the brain (Lichter-Konecki et al.,
2008). Ammonium ion build up may result in oedema, increased extracellular
concentration of glutamate and energy depletion in the brain (Rodrigo
et al., 2009). With buildup in the blood, ammonium ion may traverse
the blood brain barrier and in the brain, its conversion to glutamate via. glutamate
dehydrogenase depletes α-ketoglutarate ultimately halting citric acid cycle
activity resulting to reduced energy production and brain damage. Furthermore,
NH4+ could combine with glutamate in a glutamine synthetase
catalyzed reaction to produce glutamine, which as an osmolyte could elicit direct
osmotic effect on the brain resulting to brain swelling or oedema. Consistent
with this study (Zhao et al., 2003) arginine
exacerbated oedema in mice. However, contrary to this study, Kondoh
et al. (2010) demonstrated the protective effect of arginine against
cerebral oedema. The observed increase in ammonium ion concentration in the
ARG-treated group is a significant shortcoming of possible Arg benefit on MES
hence, deserves follow up.
Histomorphologic alterations in organs were the most consistent treatment-related
changes and in concert with anthropometric and biochemical results may give
a clear picture of physiological function of animals (Egbuonu
et al., 2010c). Agent-induced physiological and biochemical disturbances
(Adeniran et al., 2006), as well as alterations
in liver and kidney histology (Farrag and Shalby, 2007;
Egbuonu et al., 2010c) have been reported. In
support of this study, the brain section of female rats exposed to Arg showed
degenerative changes characterized by necrosis and oedema. Pearsons correlation
analysis indicated that AST:ALT ratio correlated positively (r = 0.01) with
AST activity and ammonium ion. This may suggest concerted Arg-induced adverse
response on these markers in the female rats (Egbuonu and
In conclusion, the results suggest Arg-induced adverse influence on the studied
markers of Mes associated with brain function. Hence, exposure to Arg may impair
the brain function and possibly, worsen Mes related to brain function of the
rats. The finding of this study may limit the possible potential use of Arg
in managing MES in animals hence, warrants further investigation.
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