




































Highlights in BioScience
ISSN:2682-4043
DOI:10.36462/H.BioSci.202503

Research Article

Open Access

1 Department of Biology, Tbilisi State University,

Georgia.
2 Department of Biology, Ivane Javakhishvili

Tbilisi State University, Georgia.

* To whom correspondence should
be addressed: Temuri.Man-
tashashvili6037@ens.tsu.edu.ge

Editor: Hatem Zayed, Department of Biomedical
Science, College of Health Sciences, Qatar
University, Doha, Qatar.

Reviewer(s):
Hayder Tawfeeq, Middle Technical University,
Technical Instituteof Baqubah, Department of
Nursing, Dayala, Iraq.

Asmaa Hassan, Agricultural Genetic Engineering
Research Institute, Agriculture Research Center,
Giza, Egypt.

Received: February 12, 2025

Accepted: June 04, 2025

Published: June 20, 2025

Citation: Mantashashvili T, Nakaidze L,
Ananiashvili G, Burjanadze G, Koshoridze
N. L-arginine as a potential antidepressant: Effects
on cognitive function and antioxidant enzyme
activity in depressed rats. 2025 June 20;8:bs202503

Copyright: © 2025 Mantashashvili T et al.. This is
an open access article distributed under the terms
of the Creative Commons Attribution License,
which permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Data Availability Statement: All relevant data are
within the paper and supplementary materials.
Funding: The authors have no support or funding to
report.
Competing interests: The authors declare that they
have no competing interests.

L-arginine as a potential antidepressant: Effects on cognitive function
and antioxidant enzyme activity in depressed rats

Temuri Mantashashvili*1,2
>< �, Luka Nakaidze1,2

>< , Giorgi Ananiashvili1,2
>< , George

Burjanadze1,2
>< �, Nana Koshoridze1,2

>< �

Abstract

The potential antidepressant effects of dietary L-arginine (L-Arg) were investigated
in male white laboratory rats with corticosterone-induced depression. Daily
administration of L-Arg at a dose of 150 mg/kg for 14 consecutive days significantly
alleviated depressive-like behaviors and improved cognitive performance. Furthermore,
L-Arg supplementation restored serotonin levels in the prefrontal cortex and
hippocampus, which had been reduced following intraperitoneal corticosterone
injection. To evaluate the antioxidant properties of L-Arg, quantitative changes in
malondialdehyde (MDA) and nitric oxide (NO) levels were measured in the prefrontal
cortex and hippocampal cells of depressive rats following L-Arg administration. The
findings revealed that L-Arg normalized lipid peroxidation processes that had been
enhanced under depressive conditions. L-Arg treatment significantly reduced elevated
levels of these oxidative stress markers. Additionally, it increased the activity of
key antioxidant enzymes, including mitochondrial superoxide dismutase (SOD)
and catalase, whose activities had been suppressed in the depressive state. Kinetic
analysis of enzymatic reactions indicated that the increased activity of these antioxidant
enzymes in the brain cells of depressive rats was not due to structural modifications
of the enzymes, but rather to an increase in their abundance. This effect is likely
attributable to the activation of biosynthetic processes in brain cells triggered by L-Arg
administration.

Keywords: Depression, L-arginine, fluoxetine, antioxidant system, corticosterone

Introduction
Depression is a prevalent mental disorder with serious personal and socio-economic conse-

quences [1; 2]. It is characterized by a wide spectrum of symptoms that significantly impair quality

of life [3]. Despite extensive research efforts, the precise pathophysiology of depression and effective

treatment strategies remain incompletely understood. A growing body of evidence highlights the

role of oxidative stress in the pathogenesis of depression, marked by increased production of reactive

oxygen species (ROS) and diminished activity of antioxidant defense enzymes. Oxidative imbalance,

in turn, disrupts essential metabolic processes. Antioxidants are known to protect mitochondrial

structures and DNA from oxidative damage. During depression, mitochondrial dysfunction leads to

ATP deficiency, impairing neuronal function and contributing to what is often referred to as “cellular

energy depression” [4; 5]. Hormonal dysregulation, particularly involving the hypothalamic-pituitary-

adrenal (HPA) axis, also plays a critical role in depression. Activation of this system can promote

free radical production. For example, elevated cortisol levels observed in depressed patients may

be caused by oxidative damage to receptor systems or reduced cytochrome P450 activity, both of

which can be linked to oxidative stress [6; 7]. However, despite continued investigation, the primary

initiating mechanism of depression remains elusive. Most currently available antidepressants target

monoaminergic pathways in the brain, acting primarily as enzyme inhibitors that prevent neuro-

transmitter degradation or block their reuptake. Nevertheless, these drugs are often associated with

limited efficacy, a delayed onset of therapeutic action (typically 2–3 weeks or more), and various

adverse effects [8; 9]. These limitations have led to a search for novel antidepressants that act through

alternative mechanisms. In the late 1990s, interest grew around agents such as ketamine, which

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https://creativecommons.org/licenses/by/4.0/
mailto:Temuri.Mantashashvili6037@ens.tsu.edu.ge
https://orcid.org/0000-0002-9738-1027
mailto:luka.nakaidze155@ens.tsu.edu.ge
mailto:giorgi.ananiashvili342@ens.tsu.edu.ge
mailto:giorgi.burjanadze@tsu.ge
http://orcid.org/0000-0002-5404-0644
mailto:nana.koshoridze@tsu.ge
http://orcid.org/0000-0001-7324-1495
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Mantashashvili T et al., 2025 L-arginine as a potential antidepressant: Effects on cognitive function

Figure 1. Scheme of studying the effect of exogenous L-arginine on depression

induced by corticosterone administration.

modulate the glutamatergic system [10; 11]. The rapid antide-
pressant action of ketamine has been attributed to activation of
the mTOR signaling pathway in the hypothalamus and prefrontal
cortex. However, the clinical utility of ketamine is limited by
its side effect profile [12; 13]. Given this context, the identifi-
cation of new compounds with antidepressant effects and fewer
adverse outcomes is of significant interest. One such candidate
is the amino acid L-arginine. Dietary L-arginine is absorbed in
the small intestine and distributed throughout the body. It is
metabolized along several pathways: converted into ornithine
and urea, acts as a nitrogen donor, participates in transamination,
and facilitates the elimination of protein catabolites. Ornithine,
a metabolic product of L-arginine, serves as a precursor for the
synthesis of collagen and polyamines [14; 15]. In parallel, ni-
tric oxide (NO), synthesized from L-arginine, functions as a key
signaling molecule involved in vasodilation, synaptic plasticity,
learning and memory, and the modulation of neuronal activity
during stress and anxiety [16; 17].

Importantly, L-arginine has also been reported to exhibit
antioxidant properties [18; 19]. It downregulates oxidative stress,
at least in part, by enhancing the antioxidant system through
upregulation of related enzymes. For example: L-arginine has
been shown to stimulate glutathione synthesis and activate the
Nrf2 pathway, contributing to a robust antioxidant response [20].
Based on this background, the present study aimed to investigate
the effects of exogenous L-arginine on depressive-like behaviors
in a rat model, to evaluate its potential antidepressant activity,
and to elucidate the molecular mechanisms underlying its action.

Materials and Methods
Ethics approval

The study protocol was approved by the Institutional Review
Board of Ivane Javakhishvili Tbilisi State University. All proce-

Figure 2. Study of corticosterone-induced depressive state in rats using the free

swim test (FST) and tail-flick test (TST).

dures were conducted in accordance with the guidelines for the
care and use of laboratory animals (N58/187). The experimental
work was performed at the Department of Biology, Faculty of
Exact and Natural Sciences, in close collaboration with the Chair
of Biochemistry.

Animals and housing conditions
Adult male white laboratory rats (weighing 100 ± 15 g) were

obtained from the animal facility of the A. Natishvili Institute
of Morphology, Tbilisi State University (Tbilisi, Georgia). Prior
to the experiment, the rats underwent a 7-day acclimatization
period to the vivarium conditions. Animals were housed under
standard laboratory conditions: a 12 h light/dark cycle, ambient
temperature of 22 ± 1◦C, and relative humidity of 47 ± 2%. Food
and water were provided ad libitum. The animals were randomly
assigned to four experimental groups (n = 15 per group; Figure
1):

• Group I (G1) received daily intraperitoneal injections of
100 µL 100% Dimethyl Sulfoxide (DMSO) (sc-358801,
Santa Cruz Biotechnology, Inc., Europe) for 14 consecutive
days and served as the vehicle control group.

• Group II (G2) received daily intraperitoneal injections of
corticosterone (20 mg/kg) (sc-300391, Santa Cruz Biotech-
nology, Inc., Europe) for 14 consecutive days to induce
depressive-like behavior.

• Group III (G3) received corticosterone as described for
G2 during the first 14 days, followed by daily oral adminis-
tration of L-arginine (150 mg/kg) (sc-391662, Santa Cruz
Biotechnology, Inc., Europe) for an additional 14 days.

• Group IV (G4) received corticosterone as described for
G2 during the first 14 days, followed by daily oral admin-
istration of fluoxetine (10 mg/kg) (sc-279166, Santa Cruz
Biotechnology, Inc., Europe) for the next 14 days.

Behavioral assessments and biochemical analysis
To assess the emotional state and depression-like behavior

of the experimental animals, the open-field test (OFT), forced

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Mantashashvili T et al., 2025 L-arginine as a potential antidepressant: Effects on cognitive function

Table 1. Changes in some physiological parameters of experimental animals under the influence of dietary L-arginine under conditions of corticosterone-induced

depression.

Behavioural parameters I group II group III group IV group
Crossed cells 255.5 ± 15.5 73.7 ± 18.7∗ 280.57 ± 20.8## 270.97 ± 22.4###

Number of positions in
the centre 2.89 ± 0.5 0.4 ± 0.1∗∗ 2.757 ± 0.8### 2.607 ± 0.3###

Vertical posture 3.97 ± 0.7 0.5 ± 0.1∗∗∗ 6.97 ± 2.5### 5.557 ± 1.9###

Vertical posture with
wall touching 13.5 ± 3.1 6.9 ± 1.1∗∗ 1.8 ± 0.3### 2.0 ± 0.4###

Duration of freezing
(sec) 32.8 ± 3.8 127.7 ± 12.4∗∗∗ 40.3 ± 4.6### 38.8 ± 5.2###

Duration of grooming
(sec) 18.9 ± 3.5 9.7 ± 2.9∗∗∗ 16.2 ± 3.1## 17.7 ± 2.4###

Defecation 2.5 ± 0.4 3.7 ± 0.9∗ 1.7 ± 0.1# 2.3 ± 0.1#

The duration of immobility
in the FST (sec) 160.0 ± 15.1 210.6 ± 30.7∗∗ 100.5 ± 15.5## 140.9 ± 30.8##

The duration of immobility
in the TST (sec) 50.5 ± 9.6 225.0 ± 25.9∗∗∗ 144.8 ± 35.8## 145.3 ± 47.4###

Data are shown as mean ± SD; ∗, the difference compared to control; #, the difference compared to
CORT-induced depression; ∗,# , p < 0.05; ∗∗,## , p < 0.01; ∗∗∗,### , p < 0.001

swim test (FST), and tail suspension test (TST) were performed
Figure 2. These tests were conducted in accordance with the
methodology described by [15]. In the FST, rats were placed in a
cylinder filled with water for a total duration of 6 minutes, while
in the TST, the animals were suspended by the tail for 5 minutes.
A corticosterone solution (20 mg/mL) was freshly prepared each
day in 100% dimethyl sulfoxide (DMSO) and administered in-
traperitoneally at a dose of 20 mg/kg, as outlined in Figure 1.
The concentrations of nitric oxide (NO) and malondialdehyde
(MDA), along with the enzymatic activities of superoxide dismu-
tase (SOD) and catalase, were measured spectrophotometrically
following previously described methods [16].

Statistical analysis
The obtained data were statistically analyzed using the SPSS

software (version 23; SPSS Inc., Chicago, IL, USA). One-way
ANOVA was employed in order to evaluate differences among
the groups in physiological and biochemical parameters. When
appropriate, either Tukeys HSD or Games-Howell post hoc tests
were used to determine specific group differences. The results
are presented as mean ± standard deviation (SD), and p-values
less than 0.05 were considered statistically significant.

Results
Behavioral effects of L-arginine in a corticosterone-induced
depression model

Corticosterone-induced depression significantly altered sev-
eral important behavioral parameters in rats. Compared to the
control group, the animals exposed to corticosterone exhibited
clearly reduced exploratory activity, diminished cognitive func-
tion, and heightened anxiety-like behavior. Specifically, these
animals demonstrated a marked and consistent decrease in the
number of box crossings (by approximately 70%) and center
entries (by about 80%). Conversely, the duration of freezing be-
haviora commonly used and widely accepted indicator of fearin-
creased by nearly 280%, thereby highlighting a substantial rise in
anxiety levels Table 1. Furthermore, the forced swim test (FST)
further supported the observed behavioral benefits of L-arginine,
clearly showing a significant reduction in immobility time af-
ter treatment Figure 1. This particular outcome is consistent
with an established antidepressant-like effect. A very similar
trend was also observed in the tail suspension test (TST), where
L-arginine administration significantly improved performance
metrics compared to the untreated depressive group.

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Mantashashvili T et al., 2025 L-arginine as a potential antidepressant: Effects on cognitive function

Figure 3. Effect of L-arginine on nitric oxide and malondialdehyde content in

prefrontal cortex and hippocampal cells of depressed.

Figure 4. Effect of L-arginine on superoxide dismutase and catalase activity in

prefrontal cortex and hippocampal cells of depressed individuals.

Effect of L-arginine on the hormonal status of depressed animals
Impact on serotonergic activity

Quantitative analysis of serotonin levels in the prefrontal
cortex revealed a marked decline (approximately 28%) in corti-
costerone treated rats relative to controls Figure 2A. However,
L-arginine supplementation led to a substantial increase (approx-
imately 35%) in serotonin concentration compared to the un-
treated depressive group Figure 3A. Similar recovery patterns
were observed in the hippocampus Table 2, indicating that L-
arginine may exert its antidepressant effects at least in part via
the restoration of monoaminergic neurotransmission. The results
obtained also show that administration of the serotonin reuptake
inhibitor fluoxetine produced similar effects in the depressed
group of animals.

Effect of L-arginine on nitric oxide and malondialdehyde levels in
the brain cells of depressed animals

Studies have shown a significant increase in nitric oxide levels
in the prefrontal cortex and hippocampus of depressed individu-
als. However, 14-day administration of L-arginine to depressed
animals significantly reduced these levels by approximately 30%
and 35%, respectively Figure 3 A and B. Similar effects were
observed with fluoxetine treatment.

Changes in malondialdehyde levels
Alterations were also observed in malondialdehyde (MDA)

levels. As shown in Figure 3 C and D, corticosterone-induced

depression is associated with an increased concentration of mal-
ondialdehyde in both the prefrontal cortex and hippocampal brain
cells. However, L-arginine administration led to a reduction in
its levels by approximately 20% in the prefrontal cortex and
about 30% in the hippocampus. These findings suggest that
corticosterone-induced depression is accompanied by increased
lipid peroxidation, which decreases and approaches control lev-
els following L-arginine treatment. As with previous parameters,
fluoxetine administration similarly reduced malondialdehyde con-
tent.

Effect of L-arginine on the activity of antioxidant enzymes in
depressed animals

The activities of key antioxidant enzymes superoxide dismu-
tase (SOD) and catalasewere evaluated across the experimental
groups, as presented in Figure 4. As shown in Figure 4A, SOD
activity in the prefrontal cortex of depressed animals was signifi-
cantly decreased (approximately 51%) compared to the control
group. However, after 14 days of L-arginine administration, en-
zyme activity significantly increased and approached the control
values. Similar trends were observed in the hippocampus Figure
4 B, although overall SOD activity in this region was lower than
in the cortex across all groups.

Comparable patterns were noted for catalase activity. In the
prefrontal cortex Figure 4C, catalase activity was reduced by
approximately 47% in the depressed group, while L-arginine ad-
ministration resulted in a 60% increase. Similar effects were also
observed in the hippocampal cells Figure 4D. Importantly, fluox-
etine treatment led to changes comparable to those observed with
L-arginine. These results indicate that corticosterone-induced
depression leads to decreased activity of antioxidant enzymes
(SOD and catalase), while dietary L-arginine supplementation
restores their activity.

Table 2. Quantitative changes in serotonin levels in the prefrontal cortex and

hippocampus cells of depressed rats after receiving L-arginine.

Group Prefrontal cortex Hippocampus
I group 55.7 ± 9.8 58.9 ± 8.6

II group 38.3 ±6.3∗∗∗ 40.2 ±5.7∗∗

III group 60.8 ±12.5## 50.0 ±5.5#

IV group 68.5 ±12.8### 52.7 ±7.4##

Data are shown as mean ± SD; ∗, the difference com-
pared to control; #, the difference compared to CORT-
induced depression; ∗,# , p < 0.05; ∗∗,## , p < 0.01;
∗∗∗,### , p < 0.001.

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Mantashashvili T et al., 2025 L-arginine as a potential antidepressant: Effects on cognitive function

Figure 5. Effect of exogenous L-arginine on superoxide dismutase Vmax and

Km in depressed rats.

Figure 6. Effect of exogenous L-arginine on catalase Vmax and Km in depressed

rats.

Notes: On the ordinate axis 1/V; on the abscissa axis substrate concentration

(mM).

Kinetics of SOD and catalase and the effect of L-arginine
To investigate the mechanisms underlying enzyme activity

changes, kinetic parameters were assessed. As shown in Figure 5
A, the maximum velocity (Vmax) of SOD in the prefrontal cortex
was decreased in the depressed group (Group II) compared to the
control. However, Vmax increased in Groups III and IV (arginine-
and fluoxetine-treated groups, respectively). Interestingly, the
Michaelis constant (Km), indicating the enzyme’s affinity for its
substrate, remained nearly unchanged across all groups. Similar
results were observed in the hippocampus Figure 5 B. (Note: On
the ordinate axis 1/V; on the abscissa axis substrate concentra-
tion (mM)).

Similar results were obtained in the study of the kinetic pa-
rameters of the enzyme catalase. In particular, only the maximum
velocity of the enzyme changed, while the affinity of the enzyme
for the substrate (H2O2) remained the same Figure 6.

Discussion
This study aimed to investigate the effect of exogenous L-

arginine on corticosterone-induced depression in albino rats.
Our findings demonstrate that daily administration of L-arginine
(150 mg/kg) for 14 days leads to improvements in behavioral
and physiological parameters associated with depression. No-
tably, the open-field test results showed enhanced locomotor
activity Table 1 , while improvements in forced swim test (FST)
and tail suspension test (TST) parameters further supported its

antidepressant-like effects, in agreement with existing literature
[21]. Serotonin, a key neurotransmitter, plays a critical role in
the pathophysiology of depression, as evidenced by the efficacy
of selective serotonin reuptake inhibitors (SSRIs) [8; 9; 22]. To
clarify the mechanism underlying the observed effects, we mea-
sured serotonin levels in the prefrontal cortex and hippocampus.
L-arginine supplementation significantly increased serotonin lev-
els in both regions, closely resembling the effects of fluoxetine
Table 2. This suggests that the antidepressant-like activity of
L-arginine may be, at least in part, serotonin-mediated. Sero-
tonin also exhibits strong antioxidant properties. A decrease in
serotonin levels, as observed in depression, is associated with
reduced antioxidant defense and elevated oxidative stress markers
such as malondialdehyde (MDA) and nitric oxide (NO), along
with decreased activity of antioxidant enzymes like glutathione
peroxidase, superoxide dismutase (SOD), and catalase Hence,
restoring serotonin levelseither pharmacologically (e.g., fluox-
etine) or via L-arginine supplementationcan reduce oxidative
stress in the brain [22; 23; 24].

In this study, we observed decreased MDA and NO levels
following L-arginine administration Figure 3, suggesting a re-
duction in lipid peroxidation and nitrosative stress. These re-
sults support the notion that the antidepressant-like effect of
L-arginine is mediated not only by serotonin enhancement but
also by attenuation of oxidative stress [25]. Furthermore, we
evaluated the impact of L-arginine on antioxidant enzyme ac-
tivity. Corticosterone-induced depression significantly reduced
SOD and catalase activities Figure 4, consistent with previous re-
ports [26; 27]. L-arginine administration restored these activities,
comparable to the effects observed with fluoxetine. To under-
stand the mechanism behind these changes, we analyzed kinetic
parameters (Vmax and Km) of SOD and catalase.

In corticosterone-treated rats, both Vmax and substrate affinity
(Km) of the enzymes were reduced. However, L-arginine and
fluoxetine treatments produced divergent outcomes. Fluoxetine
increased both Vmax and substrate affinity Figure 5, suggesting al-
terations in both enzyme expression and structure. These findings
align with literature indicating that fluoxetines antioxidant effects
may extend beyond serotonin modulation, potentially involving
direct ROS scavenging [28; 29].

Conversely, L-arginine administration led to increased Vmax

without altering Km, indicating an upregulation in enzyme quan-
tity rather than structural modifications. These changes suggest
that L-arginine stimulates enzyme synthesis Figures 5, 6, en-
hancing antioxidant capacity via increased enzyme availability
rather than altered binding properties. Mitochondrial dysfunc-
tion and ATP depletion are well-documented in depression and
contribute to impaired neuronal function and synaptic plasticity.
L-arginine is a precursor for several metabolites, including cre-
atine, which plays a crucial role in energy metabolism [30; 31].
Therefore, the observed effects of L-arginine may also be linked
to its role in restoring cellular energy homeostasis, which is often
compromised during depression.

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Mantashashvili T et al., 2025 L-arginine as a potential antidepressant: Effects on cognitive function

Conclusion
Depression is a prevalent and debilitating psychiatric disor-

der with profound implications for individual well-being and
societal productivity. The current study provides compelling
evidence for the antidepressant-like effects of L-arginine in a
corticosterone-induced model of depression. L-arginine sup-
plementation significantly improved behavioral parameters and
increased serotonin levels in key brain regions affected by depres-
sion. It also demonstrated potent antioxidant effects, as evidenced
by reduced levels of oxidative stress markers (NO, MDA) and
restored activities of crucial antioxidant enzymes (SOD and cata-
lase). Kinetic analyses revealed that L-arginine enhances enzyme
activity primarily by increasing enzyme synthesis, contrasting
with the dual structural and quantitative effects observed with flu-
oxetine. Collectively, these findings suggest that L-arginine exerts
its antidepressant-like effects through a dual mechanism involv-
ing both serotonin-mediated neurotransmission and improved
antioxidant defense. Given its natural origin and multifaceted
biological effects, L-arginine may serve as a promising adjunct
or alternative to conventional antidepressant therapy. Further re-
search is warranted to elucidate its precise molecular mechanisms
and evaluate its clinical potential.

Acknowledgements
The designated project is done with the financial support

of the Shota Rustaveli Georgian National Science Foundation
(Grant #FR-23-7525). Any idea contained in this publication is
the authors’ property and may not represent the opinion of the
foundation.

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Highlights in BioScience Page 7 of 7 June 2025|Volume 8

http://bioscience.highlightsin.org/

	Abstract
	Introduction
	Materials and Methods
	Ethics approval
	Animals and housing conditions
	Behavioral assessments and biochemical analysis
	Statistical analysis

	Results
	Behavioral effects of L-arginine in a corticosterone-induced depression model
	Effect of L-arginine on the hormonal status of depressed animals
	Effect of L-arginine on nitric oxide and malondialdehyde levels in the brain cells of depressed animals
	Changes in malondialdehyde levels
	Effect of L-arginine on the activity of antioxidant enzymes in depressed animals
	Kinetics of SOD and catalase and the effect of L-arginine

	Discussion
	Conclusion
	Acknowledgements

