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Ann. psychophysiol. 
ISSN 2412-3188 (Online)|2410-1354 (Print) 

APP| Published By AEIRC| https://doi.org/10.29052/2412-3188.v9.i2.2022.76-84 

Original Article 

6-AF Evaluation of Neuroprotective Activity
against Cd- Induced Oxidative Stress and
Degenerative Brain Disease including PD in
Mice
Waqar Ahmad Khan1 , Shahid Ali Shah1 , & Shamsher Khan2

1Sarhad University of Science & Information Technology, Peshawar -Pakistan 
2University of Engineering and Technology, Peshawar-Pakistan 

Abstract 
Background: The neurotoxicity caused by Cadmium (Cd) has been researched 
internationally. Since it has a wide range of unfavorable effects on people, it is 
believed to be one of the primary tissue-inducing target agents. Using adult male 
albino mice, the therapeutic potential of 6-AF to reduce memory impairment, 
neurodegeneration, and neuroinflammation caused by Cadmium Chloride 
(CdCl2) was evaluated in the current study for the first time. 
Methodology: The male adult mice were distributed into 4 sub-groups; Control, 
Cd treated (1 mg/kg thrice weeks), Cd (1 mg/kg 3 weeks) + 6-AF (30 mg/kg 3 a 
week for last 2 weeks) and 6-AF treated (30 mg/kg thrice a week for the last two 
weeks). After the initial seven-day Cdcl2 dosing cycle, the 6-Aminoflavone was 
administered interpretively intravenously for the following around 14 days (three 
per week). After receiving Cdcl2 injections for 30 days, behavior tests were 
conducted. Western blot analysis was performed after the hippocampus was 
extracted, and the results were then used to develop the X-rays.  
Results: Our results demonstrate that 6-AF significantly enhanced behavior as 
assessed by the Y-maze and Morris Water Maze (MWM) and that this 
enhancement was followed by an inhibition of phospho C-Jun N Terminal Kinase 
(p-JNK) and its downstream signaling, including tumor necrosis factor-alpha 
(TNF-alpha), Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-
KB), and Poly (ADP-ribose In addition, 6-AF also reduced the expression of NRF-
2 proteins in adult mice exposed to oxidative stress caused by cadmium chloride. 
Conclusion: 6-AF is an effective neuroprotective drug in disorders causing 
neurodegeneration. 

Keywords 
CdCl2, Neuro-inflammation, 6-AF, Phospho-JNK ,NRF-2,Parkonsion 

disease. 

Citation: Khan WA, Shah SA, Khan S. 6-
AF Evaluation of Neuroprotective Activity 
against Cd- Induced Oxidative Stress and 
Degenerative Brain Disease including PD 
in  Mice. APP. 2022; 9(2): 76-84 

Corresponding Author Email: 
waqarahmadkhan1990@gmail.com 

DOI: 10.29052/2412-3188.v9.i2.2022.76-84 

Received 16/09/2022 

Accepted 26/10/2022 

Published 01/12/2022 

Copyright © The Author(s). 2022. This 
open-access article is distributed under the 
terms of the Creative Commons 
Attribution 4.0 International License, 
which permits unrestricted use, 
distribution, and reproduction in any 
medium, provided the original author and 
source are credited.  

Funding: The author(s) received no 
specific funding for this work. 

Conflicts of Interests: The authors have 
declared that no competing interests 
exist. 

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Introduction 
Neurodegeneration is a process where 
neurons gradually degenerate or die. This 
can lead to a decline in brain function and 
various neurological symptoms, including 
problems with movement, thinking, and 
behavior. At the same time, 
neurodegenerative diseases are conditions 
characterized by progressive damage to the 
neurons in the brain and nervous system1. 

Parkinson's disease (PD), a late-onset 
neurodegenerative disorder, is characterized 
by an extensive and progressive loss of 
dopaminergic neuronal cells in the 
substantia nigra compacta and the 
accumulation of Lewy bodies, which are 
intracellular inclusions comprised of -
synuclein2,3. Parkinson's patients' post-
mortem brain tests reveal lysosomal 
consumption and autophagosome 
accumulation, which may indicate impaired 
autophagic clearance. The proteasome, 
chaperone-mediated autophagy, and macro-
autophagy can contaminate 4-synuclein4,5. 
Following the critical role of autophagy in -
synuclein Lewy bodies, several 
investigations have demonstrated that 
pharmacological and genetic stimulation of 
autophagy reduces -synuclein aggregation 
and disease pathogenesis6,7.  

Several PD-related proteins, in addition to -
synuclein, are directly involved in the 
autophagy pathway. The quality encodes the 
Lysosomal Trans Film ATPase protein8. PD-
related mutations in ATP13A2 lead to 
defects in lysosomal acidification, which 
reduce autophagosome clearance and 
accumulate a-synuclein9,10. Other proteins 
identified with PD Loss-of-work 
modifications in prompted putative kinase-
1, PTEN protein gene coding, and PARK2 
are also known to cause autosomal-passive 
type PD and -synuclein11-13. The prodded 
putative kinase-1 gene genes for a 

threonine/serine protein kinase transmitted 
in the outer mitochondrial film14. These 
proteins regulate mitophagy, a process that 
results in mitochondrial damage. 

Cadmium (Cd) is a common industrial 
pollutant and environmental contaminant 
released mainly by burning fossil fuels, 
refining metal from municipal waste, and 
smoking cigarettes15. When Cd enters the 
atmosphere and a living thing, it has various 
adverse effects related to Cd damage15. 
Human exposure to Cd damages and affects 
body organs like the liver, bone, testicles, 
kidney, and cerebrum and can result in 
cancer, tumors, etc16,17. Due to its ability to 
pass the (BBB), Cd can cause damage to 
nerve cells and the cerebrum. It also results 
in a defective nervous system that impairs 
vascular functioning, neurological disorders 
in the brain, and learning difficulties in 
addition to PD18. 
Additionally, Cd increased the generation of 
free radicals, which led to oxidative stress 
and protein and phospholipid degradation 
(DNA)19. Additionally, it is claimed that Cd 
is to blame for developing 
neurodegenerative disorders like AD17. 
Cadmium also replaces copper and iron in 
the protein's structure20. These unbound 
metals result in oxidative stress through 
Fenton chemistry processes, which causes 
cancer to develop in various organ systems 
and systems of a living organism. 
Consequently, cadmium is regarded as a 
class of human carcinogens21. 

In contrast, Polyphenols called flavonoids 
are found in foods including fruits, 
vegetables, herbs, tea, wine, and other 
organic and natural items. They stand out for 
having a wide-ranging understanding of 
that medication. Flavonoids work as breast 
cancer chemotherapeutic agents. The 
function of 6-Amino Flavone in cancer 
chemoprevention. 6-AF works in a variety of 
ways, including by inactivating carcinogens. 



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The 6-Aminoflavones have a strong anti-
breast cancer effect. In cancer, the 6-AF are 
incredibly active. Studies have also shown 
that 6-AF's antioxidant activities are 
vigorous; as a result, 6-Aminoflavone was 
used in the current investigation to test its 
effectiveness against reactive radicals in a 
mouse model 22-24.  

The above evidence suggests that heavy 
metals like cadmium severely harm the 
health of humans, and it is one of the leading 
causes of neurological disorders, including 
PD, AD, and HD. Therefore, this study aims 
to determine the remedial action to lessen 
and defeat this harmful disease by 
investigating the brain damage and 
poisoning effects of cadmium chloride in 
mice. Moreover, we also investigate how 6-
AF activity reduces Cd-induced 
neuroinflammation, and we further 
hypothesize to identify a treatment for the 
oxidative stress brought on by Cd toxicity.  

Methodology 
Mice weighing between 26-30g were 
collected for this experimental study. These 
mice were bought from the Peshawar 
Veterinary Research Institute. These mice 
were kept in a 23–24 degrees Celsius 
chamber, with 12-hour cycles of light and 12-
hour cycles of darkness. The (NMRC), 
associated with the chemistry department, 
SUIT Peshawar, conducted this 
experimental study. The committee of the 
Centre oversaw carried out the research 
activities.  

The male adult mice were distributed into 
4 sub-groups as given under 

1. Control (Normal) mice. Cd treated (1
mg/kg thrice weeks).

2. Cd (1 mg/kg 3 weeks) + 6-AF (30 mg/kg
3 a week for last 2 weeks).

3. 6-AF treated (30 mg/kg thrice a week for
the last two weeks).

All animals were handled with extreme care. 
Adult albino mice received Cd injections for 
three weeks. After the initial seven-day 
Cdcl2 dosing cycle, the 6-Aminoflavone will 
be administered interpretively 
intravenously for the following around 14 
days (three per week). After receiving Cdcl2 
injections for 30 days, behavior tests were 
conducted. 6-AF, indicated in the study's 
instructions, contributed to the successful 
outcome of the neuroprotective agent drug. 
6-Amino Flavone repaired adult albino
mice's memory impairment caused by
cadmium.

The Y-Maze test was also conducted. A 120-
degree angle is formed by the three arms of 
the Y-maze, which measure 50 by 10 by 20 
cm3 (LxWxH). Mice were given a 10-minute 
window to become used to their new 
surroundings. The mouse was then kept in 
the maze's center for 8 minutes while it was 
free to explore. Track was kept on the mice's 
total arm entries and consecutive triplet 
counts, and the percentage of alternations 
was calculated using the formula [successive 
triplet sets/total arm entries 2] times 100. 
Working memory performance in the spatial 
domain was positively linked with the 
percentage of alternations. 

Morris Water Maze (MWM) was used to 
examine the hippocampus region's role in 
long-term spatial learning. For the first three 
days, the mice were trained twice daily. The 
mice's 60-second escape delay in locating the 
submerged platform was then observed. If 
the mice could not locate the platform on 
their own, they were manually guided there 
and made to stay there for 10 seconds. Up 
until day 5, this procedure was followed, and 
each day's data (seconds) for the three 
experimental groups were separate. The 



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mice were given two days to recuperate 
before being subjected to a probe test. 

Western blot analysis was performed, and 
the hippocampus was extracted and placed 
in an ice-cold 1:1 RNA-to-PBS solution. T-
PER (Thermo Scientific) solution for tissue 
extraction protein reagent was used to 
homogenize the hippocampus component. 
A semi-dry trans-blot technique transferred 
the proteins to the PVDF membrane (Bio-
Rad). They were followed by secondary 
antibodies that were HRP-conjugated 
against mice from Santa Cruz, California, 
USA. The results were then used to develop 
the X-rays.  

Result 
The results show that Cadmium chloride 

induced a significantly high expression of p-

JNK in the brain homogenates of mice. On 

the other hand, we also injected 6-Amino 

flavone for two weeks after cd induces p-

JNK activation to know its inhibitory ability 

of p-JNK proteins, as shown in figure 1. Our 

outcomes revealed that 6- Amino Flavone 

significantly reversed the expression of 

phospho-JNK in the brain of albino mice.

Figure 1: 6-AF inhibited phospho-JNK activation in Cdcl2 Induced adult albino Mice brain. 

Downregulated signal activation in adult albino mice is observed when injected with another 

neuroprotective drug 6-AF, for the last two weeks. This suggests that 6-Amino Flavone 

dramatically altered the expression of TNF expression in the brains of albino mice. One of the 

frequent mediators of neuroinflammation is TNF-α. 



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Figure 2: 6-AF inhibited Tumor necrosis factor TNF-α Neuroinflammation in Cdcl2  Induced 

Mice 

Figure 3 shows the immunoblots of NF-κB and β-actin along with their histogram for all 4 

experimental groups (n=4/group). Western analysis reveals that cadmium chloride dramatically 

raises NF-B expression in the brain of adult albino mice. After two weeks of 6-Amino Flavone 

injection, the brains of adult albino mice showed decreased NF-B expression. 

Figure 3: 6-AF inhibited NF-κB and instigated by Cd in adult male mice brains. 

The outcome demonstrates that in the adult albino mouse brain, the Caspase-3 signal is up-

regulated and activated by Cd. Figure 4 shows the 6-AF decreased Caspase-3 down-regulated 



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expression in the brain of albino mice. This demonstrates that quercetin treatment improves the 

morphology of mice's neurodegenerating hippocampus following Cd exposure. 

Figure 4: 6-AF inhibited Caspase-3 proteins in Cdcl2 Administered Mice 

As shown in our results, 6-AF diagrammatically reduced the expression of the PARP-1 protein 

(Figure 5). This suggests that Caspase-3, Caspase-9, and PARP-1 protein levels decreased in 

response to Cd, and the levels of cleaved Caspase-3, Caspase-9, Caspase-8, and FasL proteins rose 

dose-dependently. While N-acetylcysteine successfully prevented these changes. 

Figure 5: 6-AF inhibited PARP-1 proteins expression in Cd Mice 



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Discussion 
Cdcl2 is a well-familiar agent to induce 
phospho-JNK activation15. In a recent study, 
we injected CdCl2 intraperitoneally for three 
weeks into adult albino mice. And aims to 
determine the remedial action to lessen and 
defeat harmful neurological disorders. 
Studies suggest that Cdcl2 has been shown 
to be a hazardous metal that enters the body 
directly and harms cells. Cd can throw off 
oxidative equilibrium. In mice treated with 
Cd, it results in a loss of motor function and 
damages the DNA in cells and the structural 
integrity of the cerebellum25.  

One of the most prevalent 
neurodegenerative disease mediators is JNK. 
Our findings are consistent with earlier 
research because Chen et al. also showed 
that cadmium could cause the 
phosphorylation of the JNK protein in 
mouse brain tissue. According to a study, the 
celastrol neuroprotective pharmacological 
agent Cd caused neuron cell death by 
phosphorylating JNK and targeting the 
PTEN-Akt/mammalian target of the 
Rapamycin network15. According to our 
findings, cholesterol may protect against 
Cadmium-induced neurodegenerative 
diseases. The researcher showed that active 
p-JNK is critically involved in disease
development after Traumatic Brain Injury
and that inhibition of p-JNK with SP600125 is
highly efficient for slowing disease
progression by reducing multiple
pathological features in Traumatic Brain
Injury mice brains and regulating cognitive
dysfunction26.

Cadmium Chloride was administered 
intraperitoneally to the male mice for a week 
thrice to induce neurodegeneration and 
neuroinflammation in adult albino mice and 
then treated with 6-Amino flavone for two 
weeks. When compared to mice exposed to 
Cd, immunohistochemical investigation 

shows that in earlier studies, mice that had 
been pre-treated with (SME) showed a 
decrease in the amount of TNF- appearing as 
a protein. Our findings are consistent with 
those of Elkhadragy et al., who also suggest 
that Cd can cause the tumor necrosis factor 
protein to be expressed in the mouse brain27. 

Our findings reveal that cadmium chloride 
dramatically raises NF-B expression in the 
brain of adult albino mice. Previous research 
indicated higher amounts of inflammatory 
cytokines, including NF-B and -Actin 
proteins, were also significantly found. 
Notably, research on (Nrf-2) silencing and 
(NF-B) has shown that Cadcl2 can trigger the 
NF-B in the brain of albino male mice28. 
Studies of nuclear factor-B (NF-B) inhibition 
and nuclear factor-2 erythroid-2 (Nrf-2) gene 
silencing demonstrate that caffeine produces 
neuroprotection via Nrf-2- and (NF-B) 
dependent pathways, respectively, in the 
HT-22 and BV-2 cell lines28. 

It is also demonstrated that quercetin 
treatment improves the morphology of 
mice's neurodegenerating hippocampus 
following Cd exposure. According to Chong 
et al., synuclein causes cell death in a 
dopaminergic neuronal model of 
Parkinson's disease by increasing oxidative 
stress, increasing Cd uptake, changing 
caspase-9 and caspase-3 activation, and 
decreasing the neuroprotective effect of Akt. 
This is in response to acute Cadmium 
exposure29. According to previous research, 
oxidative stress, mitochondrial damage, and 
Cd-induced cell death are all caused by 
parthanatos and the MAPK signaling 
pathway. JNK1/2 and p38 are implicated in 
parthanatos, which also synergistically affect 
apoptosis when paired with oxidative 
stress30. 

Even though the current study focused on 6-
AF's neuroprotective and memory-
improving effects in mice exposed to Cd. The 



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only concentration of 6-AF employed as a 
neuroprotective agent in this investigation. 
However, it is advised to use alternative 
concentrations of 6-AF in future research on 
animal models of neurodegenerative 
disorders. It is also advised to thoroughly 
investigate the 6-AF in vitro model of cell 
culture to better understand its usefulness as 
a medication. 

Conclusion 
According to this study, 6-AF is a 
neuroprotective drug that reduces Cd-
induced toxicity in an animal model. It has 
been demonstrated that 6-AF works in vivo 
to reverse the memory deficits caused by Cd 
while lowering neuroinflammation and 
being a natural, safe, and accessible 
therapeutic agent. This work also 
demonstrated the molecular mechanism by 
which 6-AF in Cd causes neurological 
disease. 

Acknowledgment 
The Authors would like to thank their 
Supervisor, Professor Dr. Shahid Ali Shah, 
for their continuous assistance. And would 
also like to show their gratitude to their 
college classmates for their helpful advice on 
chemicals and equipment. 

References 
1. Przedborski, S., Vila, M., & Jackson-Lewis, V.

Series Introduction: Neurodegeneration:
What is it and where are we?. J Clin Investig.
2003;111(1):3-10.

2. Thomas B. Parkinson’s disease: from
molecular pathways in disease to therapeutic
approaches. Antioxid Redox Signal.
2009;11:2077–2082.

3. Mizuno Y, Hattori N, Kubo S, Sato S, Nishioka
K, Hatano T, Tomiyama H, Funayama M,
Machida Y, Mochizuki H. Progress in the
pathogenesis and genetics of Parkinson’s
disease. Philos Trans R Soc Lond B.
2008;363:2215–2227.

4. Vogiatzi, T., Xilouri, M., Vekrellis, K., &
Stefanis, L. Wild type α-synuclein is degraded
by chaperone-mediated autophagy and
macroautophagy in neuronal cells. J Biol
Chem. 2008;283(35):23542-23556.

5. Webb, J. L., Ravikumar, B., Atkins, J., Skepper,
J. N., & Rubinsztein, D. C. α-Synuclein is
degraded by both autophagy and the
proteasome. J Biol Chem. 2003;278(27):25009-
25013.

6. Spencer, B., Potkar, R., Trejo, M., Rockenstein,
E., Patrick, C., Gindi, R., ... & Masliah, E.
Beclin 1 gene transfer activates autophagy and
ameliorates the neurodegenerative pathology
in α-synuclein models of Parkinson's and
Lewy body diseases. J Neurosci.
2009;29(43):13578-13588.

7. Nah J, Yuan J, and Jung YK. Autophagy in
neurodegenerative diseases: from mechanism
to therapeutic approach. Mol Cells.
2015;38:381–389.

8. Dehay B, Martinez-Vicente M, Caldwell GA,
Caldwell KA, Yue Z, Cookson MR, Klein C,
Vila M, Bezard E. Lysosomal impairment in
Parkinson’s disease. Mov Disord.
2013;28(6):725-32.

9. Ramirez A, Heimbach A, Grundemann J,
Stiller B, Hampshire D, Cid LP, Goebel I,
Mubaidin AF, Wriekat AL, Roeper J, AlDin A,
Hillmer AM, Karsak M, Liss B, Ravikumar B,
Vacher C, Berger Z, Davies JE, Luo S, Oroz
LG, Scaravilli F, Easton DF, Duden R, O’Kane
CJ, Rubinsztein DC. Inhibition of mTOR
induces autophagy and reduces the toxicity of
polyglutamine expansions in fly and mouse
models of Huntington disease. Nature Genet.
2004;36:585–595.

10. Dehay, B., Ramirez, A., Martinez-Vicente, M.,
Perier, C., Canron, M. H., Doudnikoff, E., ... &
Bezard, E. Loss of P-type ATPase
ATP13A2/PARK9 function induces general
lysosomal deficiency and leads to Parkinson
disease neurodegeneration. Proc Natl Acad
Sci. 2012;109(24):96119616.

11. Lesage, S., & Brice, A. Parkinson's disease:
from monogenic forms to genetic
susceptibility factors. Human Mol Genet.
2009;18(R1):R48-R59.

12. Kitada T, Asakawa S, Hattori N, Matsumine
H, Yamamura Y, Minoshima S, Yokochi M,
Mizuno Y, Shimizu N. Mutations in the
parkin gene cause autosomal recessive



84 

ISSN 2412-3188 (Online)| 2410-1354 (Print) 

APP| Published By AEIRC| Volume 9 Issue 2 

juvenile parkinsonism. Nature. 1998;392:605–
608. 

13. Valente, E. M., Abou-Sleiman, P. M., Caputo,
V., Muqit, M. M., Harvey, K., Gispert, S., ... &
Wood, N. W. Hereditary early-onset
Parkinson's disease caused by mutations in
PINK1. Sci. 2004;304(5674):1158-1160.

14. Vives-Bauza, C., Zhou, C., Huang, Y., Cui, M.,
De Vries, R. L., Kim, J., ... & Przedborski, S.
PINK1-dependent recruitment of Parkin to
mitochondria in mitophagy. Proc Natl Acad
Sci. 2010;107(1):378-383.

15. Chen L, Liu L, Huang S. Cadmium activates
the mitogenactivated protein kinase (MAPK)
pathway via induction of reactive oxygen
species and inhibition of protein
phosphatases 2A and 5. Free Radic Biol Med.
2008;45:1035–1044.

16. Oliveira, H., Lopes, T., Almeida, T., Pereira,
M. D. L., & Santos, C. Cadmium-induced
genetic instability in mice testis. Human Expt
Toxicol. 2012;31(12):1228-1236.

17. Åkesson, A., Bjellerup, P., Lundh, T., Lidfeldt,
J., Nerbrand, C., Samsioe, G., & Vahter, M.
Cadmium-induced effects on bone in a
population-based study of women. Environ
Health Perspect. 2006;114(6):830-834.

18. Manca, D., Ricard, A. C., Van Tra, H., &
Chevalier, G. Relation between lipid
peroxidation and inflammation in the
pulmonary toxicity of cadmium. Arch
Toxicol. 1994;68(6):364-369.

19. Torra, M., To-Figueras, J., Rodamilans, M.,
Brunet, M., & Corbella, J. Cadmium and zinc
relationships in the liver and kidney of
humans exposed to environmental cadmium.
Sci Total Environ. 1995;170(1-2):53-57.

20. Wang, B., & Du, Y. Cadmium and its
neurotoxic effects. Oxid Med Cell Longev.
2013;2013:1-12.

21. Son, Y. O., Wang, X., Hitron, J. A., Zhang, Z.,
Cheng, S., Budhraja, A., ... & Shi, X. Cadmium
induces autophagy through ROS-dependent
activation of the LKB1–AMPK signaling in
skin epidermal cells. Toxicol Appl Pharmacol.
2011;255(3):287-296.

22. Panche, A. N., Diwan, A. D., & Chandra, S. R.
Flavonoids: an overview. Journal of
nutritional science. 2016.

23. Iwashina, T. Flavonoid properties of five
families newly incorporated into the order
Caryophyllales. Bull Natl Mus Nat Sci.
2013;39:25-51.

24. Moorkoth, S. Synthesis and anti-cancer
activity of novel thiazolidinone analogs of 6-
aminoflavone. Chem Pharm Bull. 2015;c15-
00454.

25. PM, M. M., Shahi, M. H., Tayyab, M., Farheen,
S., Khanam, N., Tabassum, S., & Ali, A.
Cadmium‐induced neurodegeneration and
activation of noncanonical sonic hedgehog
pathway in rat cerebellum. J Biochem Mol
Toxicol. 2019;33(4):e22274

26. Rehman, S. U., Ahmad, A., Yoon, G. H., Khan,
M., Abid, M. N., & Kim, M. O. Inhibition of c-
Jun N-terminal kinase protects against brain
damage and improves learning and memory
after traumatic brain injury in adult mice.
Cereb Cortex. 2018;28(8):2854-2872.

27. Elkhadragy, M. F., Kassab, R. B., Metwally, D.,
Almeer, R. S., Abdel-Gaber, R., AlOlayan, E.
M., ... & Abdel Moneim, A. E. Protective
effects of Fragaria ananassa methanolic
extract in a rat model of cadmium chloride-
induced neurotoxicity. Biosci Rep.
2018;38(6):BSR20180861.

28. Khan, A., Ikram, M., Muhammad, T., Park, J.,
& Kim, M. O. Caffeine modulates cadmium-
induced oxidative stress, neuroinflammation,
and cognitive impairments by regulating Nrf-
2/HO-1 in vivo and in vitro. J Clin Med.
2019;8(5):680.

29. Chong, W., Jiménez, J., McIIvin, M., Saito, M.
A., & Kwakye, G. F. αSynuclein Enhances
Cadmium Uptake and Neurotoxicity via
Oxidative Stress and Caspase Activated Cell
Death Mechanisms in a Dopaminergic Cell
Model of Parkinson’s Disease. Neurotox Res.
2017;32(2):231-246.

30. Luo, T., Yuan, Y., Yu, Q., Liu, G., Long, M.,
Zhang, K., ... & Liu, Z. PARP-1 overexpression
contributes to Cadmium-induced death in rat
proximal tubular cells via parthanatos and the
MAPK signalling pathway. Sci rep.
2017;7(1):1-13.

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