Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
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AMELIORATIVE ROLE OF SCHIFF-BASE DERIVED FROM PHENYL
ETHYL AMINE AGAINST SODIUM NITRATE TOXICITY IN
LABORATORY MALE RATS
Ibtihal Hassan Hatim , Rashad Fadhil Ghadhban* , Wasfi Aboud Al-Masoudi*
*Department of Physiology, Pharmacology and Biochemistry, College of Veterinary Medicine,
University of Basrah,
Corresponding Author: [email protected]
Keyword: Schiff base , Thyroid, Rats
ABSTRACT
This study was designed to Evaluate the biological activity of Schiff base derived from
phenyl ethyl amine produced novel compound used in this experiment. Thirty adult male rats
age (10-14) weeks (150-200) gm weights were included and separate randomly into 5 groups (6
rats / group) and treated for 21days intraperitoneally (I.P) as follows:- Group 1 (control):
0.5ml/day of DMSO daily ,Group 2: 18mg/kg of NaNO2, daily ,Group 3 94 mg/kg of phenyl
ethyl amine daily ,Group 4 18 mg/kg of NaNO2, then after one hour 0.5ml/day from 66.8mg/kg
of synthesis compound daily , Group 5: 0.5ml/day from 66.8mg/kg of synthesized compound.
According to finding Results there was significant ameliorative effects of Schiff base against
sodium nitrate toxicity in several physiological parameters as (R.B.C. count , Hb. concentration ,
PCV. ,W.B.C. count MID%, TSH,T3 andT4 levels ) which the result showed there were
significant decreased in this parameters in group 5 where administrate sodium nitrate and after
one hour novel compound in compared with group 2 sodium nitrate alone .
\
INTRODUCTION
Concentrate products of primary amines with carbonyl compounds are called Schiff bases
were first reported as Schiff in 1864 by (1) . according to important characteristic features in
catalysis. and biological activity, such as, antibacterial, antifungal activities Schiff bases have
been studied ( 2). Schiff bases metal complexes have been widely studied for the reason that,
they have anticancer and herbicidal effects . Schiff bases show clinical properties (3, 4). At
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
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191
higher doses Sodium nitrite (NaNO2 ) have toxic effect because of it exerts on red blood cells.
MtHb. levels below 2%. in mammals blood are normally, While levels exceed 70% usually
become fatal, by creating a lethal deficit of oxygen in cardiac muscle and the brain, and that lead
to rapid lack of oxygen to the brain and other vital organs and according respiratory failure this
goes to quickly death (5).
Severe metha-hemoglobinaemia are common sign in mammals that include shortness of
breath, cyanosis, lethargy, loss of consciousness and blue coloring of the skin mainly in high
blood supply areas like lips, gums, hands/paws and nose . There is various acute NaNO2 toxicity
data, however very limited are data available on risk of secondary poisoning (5, 6). It was
concluded that the biological and ameliorative action of this novel compound that derived from
phenyl ethyl amine and 2-hydroxy naphthaldehyde. against sodium nitrate toxic effect.
MATERIAL AND METHODS
The LD 50 of synthesized new compound was studied by the "up-and-down" procedure
on the mice that described by (7)
Experimental design
Thirty adult male rats age (10-14) weeks (150-200) gm weights were included and
separate into 5 groups (6 rats /group) randomly and treated for 21 days were injected
intraperitoneally (I.P) with:-Group 1 (control): 0.5ml/day of DMSO daily, Group 2: 18mg/kg of
NaNO2, daily, Group 3: 94 mg/kg of phenyl ethyl amine daily , Group 4: 18 mg/kg of NaNO2,
then after one hour injected with 0.5ml/day from 66.8 mg/kg of synthesis compound daily
,Group 5: 0.5ml/day from 66.8mg/kg of synthesized compound.
Finally, blood was obtained from the heart by cardiac puncture with a 10 ml disposable 22 G
needle syringe (8). Divided into two sections, 1ml was transferred to the tube contain anticoagulant
for hematological analysis, other part of blood was added in plain tube and centrifuge
for 15 minutes at 3000 rpm to extract the serum, which was collect to Eppendorf tube and store
at-20oC until used for biochemical and hormonal analysis.
Statistical Analysis
Experiments data expressed as (Mean ±SD), and analyzed by One-way ANOVA using
computerized program Special Program for Statistical System (SPSS) version 21.0. least
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
Conference. College of Veterinary Medicine. University of Basrah. Iraq
192
significant difference test (LSD) to determine the significant differences between groups in
ANOVA-test (9).
RESULT
It seems from Table (1) that the RBC count, hemoglobin concentration (Hb), PCV, and
MCH decreased significantly (P≤0.05) in sodium nitrite compared as the control group.
However, RBC, Hb, PCV, MCHC, and MCH increased significantly (p≤0.05) in phenyl
ethylamine group, injection of synthesized compounds after one hour of NaNO2 increased RBC
a count (Hb), PCV, and MCH significantly (p≤0.05). In contrast, there was a decrease of MCHC
as compared with the NaNO2 group and control group. Injection of synthesized compounds
indicated that a substantially (p≤0.05) increases RBC count, hemoglobin conc., PCV% , MCHC,
and MCH level compared with the NaNO2 group.No significant difference was seen in treated
rats with (MCV)in all treated groups.
Table (1). Effects of different treatment on hematological parameters in adult male rat
(mean±SD).
Group RBCs
106/L
Hb
(g/dL)
PCV
103/L
MCH
(pg/cell)
MCHC
(g/dL)
MCV
(fL)
Control 6.40
± 0.35 a
12.66
±0.37 a
37.10
± 2.43 a
19.03
± 0.68 a
32.84
± 0.89 a
58.65
±0.85
a
NaNO2 5.67
± 0.66 b
9.39
±0.69 b
24.92
±1.04 b
16.82
± 1.03 b
30.82
± 0.82 b
54.58
±2.41a
Phenylethylamine 6.11
± 0.56 a
11.53
±0.89 a
36.15
±2.40 a
18.85
± 0.47 a
31.83
± 0.60 ab
59.33
±2.09a
NaNO2synthesized
compound
6.24
±0.75 a
11.53
±1.07 a
36.81
±3.52 a
18.46
± 0.81 a
31.30
±1.00 b
59.23
±2.99a
synthesized
compound
6.53
± 0.84 a
12.63
±1.50 a
39.13
±5.73 a
19.31
± 0.71 a
32.3
±0.87 a
59.53
±2.32a
*different letters denote signiicant P<0.05
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Total WBC count increased significantly (p≤0.05) in NaNO2 (group2) and phenyl
ethylamine (group3) when make comparison with the control group. injection of synthesized
compounds (group 5) alone or after an hour of injection NaNO2 (group4) was elevated but not
significant of WBC value than control groups. The administration novel compound (group5)
WBC value decreased significantly (p≤0.05) as compared with the (group2) group.
Simultaneously, there was a decrease in MID % in treated (groups 2 and 3) than control groups.
un- substantially changed was seen in granulocyte and lymphocytes value in male treated rats in
all treated groups. (Table 2),
Table (2). Effects of different treatment on WBC count in adult male rat. (mean ± SD) .
Group WBC
103/L
MID% GRAN% LYM%
Control
G1
10.15
± 1.04 b
15.38
± 3.57 a
36.71
±2.87 a
47.90
±4.14 a
NaNO2
G2
15.90
± 1.93 a
8.26
±1.85 b
40.00
±5.86 a
51.73
±6.80 a
Phenylethylamine
G3
15.51
± 1.77 a
6.03
±3.17 b
44.21
±7.65 a
49.75
±10.48 a
NaNO2+
synthesized
compound G4
11.67
± 0.83 b
6.08
±4.11 bc
41.30
±14.62 a
52.61
±18.44 a
synthesized
compound G5
10.23
± 1.14 b
5.78
±2.36 bc
44.03
±5.49 a
50.18
±7.19 a
*different letters denote signiicant P<0.05
Thyrotropin (TSH) level increase significantly (p≤0.05) in (group2) compared with all
treated groups and showed decrease but not substantial in (group3 4 and 5) while significant
reduction (p≤0.05) in groups (3. 4 and 5) is compared with NaNO2. Simultaneously, there were
non-significant changes between groups 3 and 4 also between groups 4 and 5. Table (3)
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Also, Table (3) showed that Triiodothyronine (T3) value increased in all groups except (group4)
there was an increased but not significant in comparison with the control group. No significant
difference was seen in Thyroxine level (T4) in all treated groups. Table (3) showed that
testosterone value increased significantly(p≤0.05) in (groups 3, 4, 5) compared with the control
group while there was an increase but not significant in (group2) than control group.
Table (3). Effects of different treatment on thyroid hormones in adult male rat. (mean ± SD).
Group TSH
μlU/ml
T3
ng/dl
T4
μg/dl
Testosterone
pg/ml
Control(DMSO)
G1
1.8
± 0.24 b
0.91
± 0.10 b
7.80
±0.60 a
1.12
± 0.19 a
NaNO2
G2
3.03
±0.52 a
1.22
±0.13 a
8.25
±1.60 a
1.36
±0.08 ab
Phenylethylamine
G3
1.86
±0.15 b
1.15
± 0.12 a
7.65
±1.33 a
1.59
± 0.10 a
NaNO2+Synthesis
compound G4
1.69
±0.09 b
1.06
± 0.17 ab
7.99
±0.55 a
1.61
±0.34 a
Synthesized
compound G5
1.79
±0.16 b
1.19
± 0.21 a
6.76
±0.49 a
1.54
± 0.28 a
*different letters denote signiicant P<0.05
DISCUSSION
The results findings in a table (1) were consistent with previous research (10, 11) on the
decrease in RBCs, while the other hematological outcomes, including the percentage of PCV,
MCH, and MCHC, were not consistent with the work (12)
Nitrite created free radicals, such as lipid peroxidation products, which react with lipid
bilayer sulfhydryl groups erythrocyte membrane protein components change its structure.
Besides, nitrite-promoted Ca2 + influx stimulates phospholipases in blood cells, which raises the
proportion of phospholipids in the cell membrane to a rigid frame (13, 14).
Nitrites believed to transform hemoglobin's ferrous ion (Fe+2) to ferric ion (Fe+3) both in
vivo and in vitro (12). This conversion can explain the lowering of hemoglobin levels. Nitrite
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
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administration tends to lead to hypoxia of the hematopoietic tissue, resulting in a long-term (21
days in the current study) decrease in blood hemoglobin levels. Different animals have reported
reducing hemoglobin due to nitrate treatment (14).
According to this experiment, in treated rats, NaNO2 causes macrocytic hypochromic
anemia. It may result from NaNO2's harmful effect on the bone marrow, liver, and spleen, and it
is compatible with this finding (11). It may be the reason for a percentage rise in PCV (15). The
PCV value is known to depend on the RBC structure.
Sodium nitrite causes oxidative damage to type meta globulin, which induces
modifications and oxidation of ferrous ions in oxyhemoglobin (15, 16). Another mechanism for
decreasing hematological values was expressed as reductions in erythropoietin hormone secreted
from kidney tissues due to their damage by reducing RBC production (17).
Erythrocytes are highly susceptible to oxidative damage than other cells due to the
high cellular concentration of oxygen; also, hemoglobin is considered potentially as a powerful
promoter for the oxidative processes (18).
The results show that the injection of phenyl ethylamine group3 causes a significant
increase in the RBC count, MCHC, and increase in MCH, whereas no significant difference
observed in packed cell volume and MCV compared with the control group.
It seems from the table (1) that the RBC count, Hb, MCV, MCH MCHC, and PCV did
not change by the injection of NaNO2 and then injected with synthesized compound after one
hour to rats. Hence, it gives evidence that the synthesized compound, when injected after one
hour NaNO2, has ameliorative effects that reduce the harmful effects of NaNO2 when compared
with the control group.
Because of its low toxicity to humans and animals, the synthesized compound (group5)
raises the RBC can be known to be one of the most common solvents used experimentally (19).
Because it has a high affinity with hydroxyl radicals and modulates the antioxidant enzyme
system in the body, the synthesized compound can also serve as an anti-inflammatory, anticoagulant
reactive oxygen species scavenger activity. Increases the activity of blood antioxidant
enzymes, i.e., (glucose-6-phosphate dehydrogenase (G6PDH) and glutathione peroxidase ( GPx),
to shield the cells from hyper production of reactive oxygen species (20). The hydroxyl radical is
Basrah Journal of Veterinary Research,Vol.19, No.3, 2020. Proceeding of the 17th International
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also neutralized and reduces cellular toxicity as one of the most toxic side products of superoxide
production (21).
The findings indicate a sustainable increase in total leukocyte count after animal injection
with sodium nitrate. The increases in the overall and differential count of leukocytes may be due
to the inflammatory reaction to sodium nitrite; this causes the development of a high number of
bone marrow cells, accompanied by the release of significant amounts of possible oxidant agents
that may trigger damage to the tissues and cells around them (22).
The current findings do not agree with (23), which indicates a substantial decrease in the
overall leukocytes’ count of the group treated with sodium nitrite than the control group.
The phenyl ethylamine effect on WBC was a little increased in the treated rats than the
control. The trace amine receptors that β-phenyl ethylamine is known to influence (TAAR1 and
2) appear to be expressed on leukocytes, and trace amino acids appear to control leukocyte
migration concentration, which is relevant even without nutritional supplementation (24).
Including both T and B cells and the activation by β-phenyl ethylamine of both receptors and the
cause chemotaxis of immune cell, This is a dose that is already lower at rest than human plasma,
therefore below physiological thresholds and thus tends to be important physiologically. Similar
actions have also been found with T1AM (3-Monoiodothyronamine) and tyramine trace amines
(25).
While there was an increase in WBC but not significantly in (groups 4 and 5)The effect
of the synthesized compound on the hematopoietic system and blood indices tended to enhance
the destructive impact of sodium nitrite compared to the graduated dosage, which may be
attributed to the effects of the novel compound as an anti-inflammatory agent and antioxidant
activity, Also, there was a significant decrease in MID (Basophile, Eosinophile, and monocytes)
when treated by NaNO2 and phenyl ethylamine, group4 (NaNO2+synthesized compound) and
group 5(synthesized compound) than control and other groups. As explained in the study,
synthesized compounds reported inhibiting lipid peroxidation in this study. This defense defined
the ability of the synthesized compound to scavenge free radicals and, at the same time, spare
other antioxidants from oxidation, suggesting the power of a synthesized compound to
counteract the deleterious effect of nitrite overdose by shielding blood parameters and blood
indices from oxidative damage caused by free radicals (26, 27).
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A significant increase in Thyrotropin (TSH) T3and T4 after injected rats with NaNO2
than in all other treated groups; Such data indicate NaNO2, which causing blocked protein
synthesis, fast break down, increased rate of Free amino acids, and lowering protein turnover,
and this will require stimulation of thyroid and adrenal glands (28, 29),
Thyrotropin (TSH) and Triiodothyronine and Thyroxine (T4)value decrease in group
(NaNO2 + synthesized compound) and synthesized compound group than the NaNO2 group by
the effect on the thyroid gland which may cause enlargement of the thyroid gland and cause
hypothyroidism,through inhibiting iodine absorption through tyrosine thyroglobulin residue and
thereby ending the thyroid hormone, (T3 ) and (T4), biosynthesis ( 30, 31).
Increased serum testosterone in (Group 2) NaNO2 resulted from elevated hypoxia as a
result of the influence of NaNO2 hydrogen peroxide-induced oxidative stress in rats, resulting in
testicular degeneration (32, 33, 43).
The table showed that testosterone value increases significantly in group3 (phenyl
ethylamine) compared with the control group. This increase in phenyl ethylamine injection was
also apparent in the concentration of testosterone relative to NaNO2.
Synthesized compound expected to decrease these harmful effects of (NaNO2) when
injected after one hour from NaNO2 injection, and its effects were apparent where seminiferous
tubules and epididymis tubules have somewhat retained to their typical histological architecture,
increased spermatogenic cells, and increased the number of mature spermatozoa in epididymis
tubules (23).
Ethics
All animal experiments are subjected to established stander ethics in the Veterinary Medicine
College of Basrah University.
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