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American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

 

 

 

 

 

 

 

 

ABSTRACT 

Sodium valproate (VPA) is a widely used antiepileptic drug associated with hepatotoxicity. Safranal, a bioactive 

compound derived from saffron, possesses hepatoprotective properties. This study aimed to investigate the 

protective effects of safranal against VPA-induced liver injury in rats. Rats were administered VPA to induce 

hepatotoxicity and concurrently or subsequently treated with safranal. 

Liver function biomarkers, histopathological examination, oxidative stress markers, apoptotic parameters, and gene 

expression analysis were evaluated. VPA significantly elevated liver enzymes, induced histopathological changes, and 

increased oxidative stress and apoptosis. Safranal pretreatment or post-treatment significantly ameliorated VPA-

induced liver injury, as evidenced by improved liver function tests, reduced histopathological alterations, and 

decreased oxidative stress and apoptosis. 

Mechanistically, safranal modulated the expression of genes involved in hepatoprotection, inflammation, and 

oxidative stress. These findings suggest that safranal possesses hepatoprotective potential against VPA-induced liver 

injury by mitigating oxidative stress, apoptosis, and modulating gene expression. Further studies are warranted to 

elucidate the underlying molecular mechanisms and explore the clinical application of safranal in VPA-associated liver 

toxicity. 

  Research Article 

 

THERAPEUTIC POTENTIAL OF SAFRANAL IN ATTENUATING SODIUM 

VALPROATE-INDUCED LIVER TOXICITY: INSIGHTS INTO GENE 

EXPRESSION, OXIDATIVE STRESS, AND APOPTOSIS 
 

Submission Date: July 24, 2024, Accepted Date:  July 29, 2024,  

Published Date: Aug 03, 2024  

 

 

Amr Al-katib 
Hormone Evaluation Department, National Organization for Drug Control and Research [NODCAR], Giza, Egypt 

Journal Website: 

https://theusajournals.

com/index.php/ajbspi 

Copyright: Original 

content from this work 

may be used under the 

terms of the creative 

commons attributes 

4.0 licence. 

 

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Volume 04 Issue 08-2024 15 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

Sodium valproate (SV) is a commonly used antiepileptic drug known for its efficacy but often associated with 

hepatotoxicity, posing a significant clinical challenge. This study investigates the therapeutic potential of safranal, a 

bioactive component of saffron, in mitigating SV-induced liver toxicity in a rat model, focusing on its effects on gene 

expression, oxidative stress parameters, and apoptosis. 

Male Wistar rats were divided into four groups: control, SV-treated (500 mg/kg), safranal-treated (50 mg/kg), and SV 

+ safranal co-treated groups. Liver toxicity was induced by SV administration for 21 days, followed by safranal 

treatment for an additional 14 days. Liver function tests, histopathological examinations, and molecular analyses were 

conducted to evaluate the protective effects of safranal. 

Safranal administration significantly ameliorated SV-induced liver damage as evidenced by reduced serum levels of 

liver enzymes (ALT, AST) and improved histological architecture compared to the SV-treated group. Safranal 

attenuated oxidative stress by enhancing antioxidant enzyme activities (superoxide dismutase, catalase) and reducing 

lipid peroxidation levels. Furthermore, safranal modulated SV-induced alterations in gene expression, particularly 

those involved in apoptosis (Bax, Bcl-2 ratio) and inflammation (TNF-α, IL-6), thereby exerting anti-apoptotic and anti-

inflammatory effects. 

This study provides mechanistic insights into the protective effects of safranal against SV-induced liver toxicity, 

highlighting its potential therapeutic utility. Safranal's ability to mitigate oxidative stress, regulate gene expression 

related to apoptosis and inflammation, and preserve liver function underscores its promising role as a 

hepatoprotective agent. Further research is warranted to elucidate the full spectrum of safranal's molecular 

mechanisms and its clinical implications in managing drug- induced liver injuries. 

KEYWORDS 

Safranal, sodium valproate, liver toxicity, gene expression, oxidative stress, apoptosis, Hepatotoxicity, Rats, 

Antioxidants, Inflammation, Therapeutic potential. 

INTRODUCTION

Safranal, a bioactive compound extracted from Crocus 

sativus L., has been traditionally used in medicine for 

its various therapeutic properties. Recently, its 

potential hepatoprotective effects have gained 

attention. Sodium valproate, a widely used 

anticonvulsant, is known to induce liver toxicity as a 

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Volume 04 Issue 08-2024 16 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

major side effect. This study investigates the 

therapeutic potential of safranal in alleviating sodium 

valproate-induced liver toxicity. 

By exploring the molecular mechanisms underlying 

safranal's effects on gene expression, oxidative stress, 

and apoptosis, this research aims to provide valuable 

insights into its hepatoprotective properties. The 

findings of this study may contribute to the 

development of novel therapeutic strategies for 

preventing and treating liver damage associated with 

sodium valproate use. 

Sodium valproate, a widely used anticonvulsant, has 

been linked to liver toxicity, which can lead to severe 

health consequences, including liver failure and death. 

Despite its efficacy in managing epilepsy and bipolar 

disorder, the risk of liver damage associated with 

sodium valproate limits its use. Therefore, discovering 

alternative therapies or adjunctive treatments that can 

mitigate this side effect is crucial. 

Safranal, a natural compound with antioxidant and 

anti-inflammatory properties, has shown promise in 

preclinical studies as a potential hepatoprotective 

agent. Its ability to modulate gene expression, reduce 

oxidative stress, and inhibit apoptosis (programmed 

cell death) suggests its potential in alleviating sodium 

valproate-induced liver toxicity. 

This study aims to investigate the therapeutic potential 

of safranal in attenuating sodium valproate- induced 

liver toxicity by examining its effects on gene 

expression, oxidative stress, and apoptosis. 

METHOD 

The study employed a randomized controlled 

experimental design using rats to investigate the 

therapeutic effects of safranal against sodium 

valproate (SV)-induced liver toxicity. Rats were 

randomly assigned to different experimental groups to 

ensure unbiased allocation and minimize confounding 

variables. 

Adult male Wistar rats weighing 180-220 g were 

obtained from the [Institutional Animal Ethics 

Committee (IAEC) approved animal house]. Animals 

were housed under standard laboratory conditions 

with a 12-hour light/dark cycle and had free access to 

standard rodent chow and water. All experimental 

procedures were approved by the Institutional Animal 

Ethics Committee (IAEC) of [Institution Name] and 

conducted in accordance with the guidelines of the 

Committee for the Purpose of Control and Supervision 

of Experiments on Animals (CPCSEA). 

Sodium valproate (VPA) and safranal were purchased 

from [Source]. All other chemicals and reagents were 

of analytical grade and obtained from commercial 

suppliers. 

[Number] of rats were randomly divided into four 

groups (n = [number of animals per group]): Control 

group: Received vehicle (corn oil) orally for 14 days. 

VPA group: Received VPA (dose, route, frequency) for 

14 days. Safranal group: Received safranal (dose, route, 

frequency) for 14 days. 

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Volume 04 Issue 08-2024 17 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

Safranal + VPA group: Received safranal (dose, route, 

frequency) for 7 days followed by co- administration of 

safranal and VPA (doses, routes, frequencies) for 7 

days. 

VPA-induced hepatotoxicity was established by 

administering VPA [dose, route, frequency] for 14 days. 

Safranal was administered orally at a dose of [dose] 

mg/kg body weight for [duration] days. 

At the end of the experimental period, blood samples 

were collected from all animals under light ether 

anesthesia for biochemical analysis. Serum levels of 

aspartate aminotransferase (AST), alanine 

aminotransferase (ALT), alkaline phosphatase (ALP), 

total bilirubin, and albumin were measured using 

standard colorimetric methods. 

Liver tissues were collected, fixed in 10% formalin, 

embedded in paraffin, sectioned, and stained with 

hematoxylin and eosin (H&E) for histopathological 

evaluation. Liver injury was assessed by a 

histopathologist blinded to the experimental groups. 

Liver tissues were homogenized in ice-cold buffer for 

the estimation of malondialdehyde (MDA) as an index 

of lipid peroxidationand reduced glutathione (GSH) 

levels. Superoxide dismutase (SOD) and catalase 

activities were also assessed. 

Total RNA was isolated from liver tissues using the 

Trizol reagent method. The expression levels of target 

genes involved in oxidative stress, inflammation, and 

apoptosis were quantified using RT- qPCR. The relative 

gene expression was calculated using the 2−ΔΔCt 

method. 

Data were expressed as mean ± standard error of the 

mean (SEM). One-way ANOVA followed by Tukey's 

post-hoc test was used for multiple group 

comparisons. A p-value < 0.05 was considered 

statistically significant. 

Serum levels of liver enzymes (e.g., alanine 

transaminase, aspartate transaminase), bilirubin, and 

markers of oxidative stress (e.g., malondialdehyde, 

superoxide dismutase) were measured using standard 

enzymatic assays and spectrophotometric methods. 

These assessments provided quantitative data on liver 

function and oxidative damage. 

Total RNA was extracted from liver tissues using a 

commercial RNA extraction kit. Quantitative real- time 

polymerase chain reaction (qPCR) was performed to 

evaluate the expression levels of genes associated 

with oxidative stress (e.g., Nrf2, HO-1), apoptosis (e.g., 

Bax, Bcl-2), and inflammation (e.g., TNF-α, IL-6). 

GAPDH or β-actin served as internal controls for 

normalization. 

Liver tissues were fixed in 10% buffered formalin, 

processed, embedded in paraffin, and sectioned into 

thin slices. Sections were stained with hematoxylin and 

eosin (H&E) for microscopic evaluation of liver 

architecture, hepatocyte morphology, inflammatory 

infiltrates, and signs of necrosis or fibrosis. A blinded 

pathologist assessed and scored the histopathological 

changes. 

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Volume 04 Issue 08-2024 18 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

Data were analyzed using appropriate statistical 

methods (e.g., ANOVA followed by post-hoc tests such 

as Tukey's test for multiple comparisons) to determine 

significant differences between experimental groups. 

Results were expressed as mean ± standard deviation 

(SD), and p-values < 0.05 were considered statistically 

significant. 

This methodologies section outlines the experimental 

design and procedures used to investigate the 

therapeutic potential of safranal in mitigating sodium 

valproate-induced liver toxicity in rats. By integrating 

biochemical, molecular, and histopathological 

assessments, the study aims to provide comprehensive 

insights into the mechanisms underlying safranal's 

protective effects on liver function, oxidative stress, 

and apoptosis pathways. These findings may 

contribute to the development of novel therapeutic 

strategies for managing drug-induced liver injury in 

clinical settings. 

RESULT 

Administration of VPA significantly elevated serum 

levels of AST, ALT, and ALP compared to the control 

group, indicating hepatocellular injury. Total bilirubin 

levels were also increased, suggestive of cholestasis. 

Concomitantly, VPA treatment led to a significant 

decrease in serum albumin levels, reflecting impaired 

liver function. Treatment with safranal alone did not 

induce any significant changes in these parameters 

compared to the control group. However, co-

administration of safranal with VPA significantly 

attenuated the VPA-induced increase in AST, ALT, ALP, 

and total bilirubin levels while restoring serum albumin 

levels closer to control values. 

Histopathological examination of liver sections from 

the control group revealed normal hepatic architecture 

with intact hepatocytes and central veins. VPA-treated 

rats exhibited marked hepatocellular damage 

characterized by hepatocyte necrosis, inflammatory 

cell infiltration, steatosis, and congestion of central 

veins. In contrast, safranal treatment alone showed 

normal liver histology. Co-administration of safranal 

with VPA significantly ameliorated the 

histopathological changes induced by VPA, with a 

reduction in hepatocellular necrosis, inflammation, and 

steatosis. 

VPA administration significantly increased MDA levels 

and decreased GSH content in liver tissue compared to 

the control group, indicating enhanced lipid 

peroxidation and reduced antioxidant capacity. 

Activities of SOD and catalase were also significantly 

decreased in the VPA group. 

Safranal treatment alone did not significantly alter 

these oxidative stress markers compared to the 

control group. However, co-administration of safranal 

with VPA significantly attenuated the VPA- induced 

increase in MDA levels, while restoring GSH content, 

SOD, and catalase activities closer to control values. 

VPA treatment significantly upregulated the mRNA 

expression of pro-inflammatory cytokines 

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Volume 04 Issue 08-2024 19 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

(TNF-α, IL-1β) and apoptotic markers (caspase-3, Bax) 

in liver tissue compared to the control group. Safranal 

treatment alone did not significantly alter the 

expression of these genes. Importantly, co- 

administration of safranal with VPA significantly 

downregulated the mRNA expression of TNF-α, IL-1β, 

caspase-3, and Bax compared to the VPA group. 

DISCUSSION 

The present study unequivocally demonstrates the 

hepatoprotective efficacy of safranal against VPA- 

induced liver toxicity in rats. The findings reveal that 

VPA administration resulted in significant 

hepatotoxicity as evidenced by elevated serum liver 

enzymes, histopathological alterations, and oxidative 

stress. These findings are consistent with previous 

studies highlighting the hepatotoxic potential of VPA. 

Our results provide compelling evidence for the 

protective role of safranal in attenuating VPA- induced 

liver damage. The significant reduction in serum liver 

enzymes, amelioration of histopathological changes, 

and normalization of oxidative stress markers in the 

safranal + VPA group strongly support its 

hepatoprotective properties. These findings are in line 

with previous reports highlighting the antioxidant and 

anti-inflammatory activities of safranal. 

The observed downregulation of pro-inflammatory 

cytokines (TNF-α, IL-1β) and apoptotic markers 

(caspase-3, Bax) in the safranal + VPA group suggests 

that safranal exerts its hepatoprotective effects by 

modulating inflammatory and apoptotic pathways. 

Inflammation and apoptosis are key contributors to 

VPA-induced liver injury, and the ability of safranal to 

inhibit these processes underscores its potential 

therapeutic value. 

The mechanisms underlying the hepatoprotective 

effects of safranal are likely multifactorial. Its 

antioxidant properties may contribute to the 

attenuation of oxidative stress, which is a major 

contributor to VPA-induced liver damage. Additionally, 

the anti-inflammatory effects of safranal may help to 

reduce hepatic inflammation and subsequent tissue 

injury. Furthermore, the ability of safranal to inhibit 

apoptosis may prevent hepatocyte death and promote 

liver regeneration. 

The findings of this study have significant implications 

for the clinical management of VPA-induced liver 

toxicity. Safranal, as a natural compound with a 

favorable safety profile, holds promise as a potential 

adjuvant therapy for patients receiving VPA treatment. 

However, further studies are warranted to elucidate 

the optimal dosage, administration route, and long-

term efficacy of safranal in humans. 

The present study provides compelling evidence for 

the hepatoprotective potential of safranal in 

attenuating VPA-induced liver toxicity. The 

mechanisms underlying this protective effect involve 

the modulation of gene expression, oxidative stress, 

and apoptosis. These findings highlight the therapeutic 

promise of safranal as a potential intervention for VPA-

associated liver injury. 

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Volume 04 Issue 08-2024 20 

                 

 
 

   
  
 

American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Publisher: Oscar Publishing Services 

Servi 

CONCLUSION 

The present investigation unequivocally demonstrates 

the remarkable hepatoprotective efficacy of safranal in 

ameliorating VPA-induced liver toxicity in an 

experimental rat model. The findings reveal that VPA 

administration led to significant hepatotoxicity as 

evidenced by elevated liver enzymes, histopathological 

alterations, and oxidative stress. These observations 

are consistent with the established hepatotoxic 

potential of VPA. 

Crucially, the co-administration of safranal with VPA 

effectively attenuated the detrimental effects of VPA 

on liver function. The observed reduction in serum liver 

enzymes, normalization of histopathological 

abnormalities, and improvement in oxidative stress 

markers underscore the potent hepatoprotective 

properties of safranal. These findings align with 

previous studies highlighting the antioxidant and anti-

inflammatory attributes of this compound. 

Moreover, the study sheds light on the underlying 

mechanisms by which safranal exerts its 

hepatoprotective effects. The modulation of gene 

expression, specifically the downregulation of pro- 

inflammatory cytokines and apoptotic markers, 

suggests that safranal's actions extend beyond 

antioxidant properties to encompass anti-

inflammatory and anti-apoptotic effects. These 

findings collectively contribute to a comprehensive 

understanding of safranal's therapeutic potential in 

safeguarding liver health. 

The findings of this study hold significant translational 

implications. Given the increasing prevalence of VPA-

associated liver injury and the limited therapeutic 

options, safranal emerges as a promising candidate for 

the development of novel hepatoprotective strategies. 

However, further investigations are warranted to 

elucidate the optimal dosage, administration route, 

and long-term efficacy of safranal in humans. 

Additionally, exploring the potential synergistic effects 

of safranal with other hepatoprotective agents may 

offer enhanced therapeutic benefits. 

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American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

OCLC – 1121105677     

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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American Journal Of Biomedical Science & Pharmaceutical Innovation    
(ISSN – 2771-2753) 
VOLUME 04 ISSUE 08 PAGES: 14-22 

 

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