Brain Disorders 13 (2024) 100109

Contents lists available at ScienceDirect

Brain Disorders
journal homepage: www.sciencedirect.com/journal/brain-disorders

Screening of anti-Parkinson activity of tannic acid via antioxidant and

neuroprotection in Wistar rats
Himani Badoni a, *, Sakshi Painuli b, Sachin Panwar c, Promila Sharma d, Prabhakar Semwal c, *
a
School of Applied and Life Sciences, Department of Biotechnology, Uttaranchal University, Premnagar, Dehradun, Uttarakhand, India
b
Uttarakhand Council for Biotechnology (UCB), Silk Park, Premnagar, Dehradun, 248007, Uttarakhand, India
c
Department of Biotechnology, Graphic Era Deemed to be University, Dehradun, 248002, Uttarakhand, India
d
Department of Microbiology, Graphic Era Deemed to be University, Dehradun, 248002, Uttarakhand, India

A R T I C L E I N F O A B S T R A C T

Keywords: Background: Inflammation in the brain is a severe pathological state to facilitate neurodegenerative disorders.
Anti-Parkinson Various inflammatory mediators, such as tumor necrosis factor-α (TNF-α), nitric oxide (NO), interleukin-1 (IL-1),
Catalepsy and prostaglandins, promote inflammation. The expression of these major inflammatory mediators is induced by
Oxidative stress
the activation of microglia and astrocytes. Diseases likewise Parkinson’s disease (PD), Alzheimer’s disease (AD)
Tannic acid
Molecular docking
and multiple sclerosis are caused by uncontrolled release of pro-inflammatory cytokines.
Methods: Acute (5, 50, and 300 mg kg− 1), subacute study (30, 100, and 300 mg kg− 1) toxicity in rats. In addition,
consequence of tannic acid (TA) on haloperidol stimulated catalepsy model of PD in Wistar rats (6–8 weeks) was
analysed. Toxicity study of TA has been done to identify the safer dose for experimental animals.
Results: In vivo antioxidant assays demonstrate the suppressed amount of oxidative stress caused due to lipid
peroxidation (LPO) and elevated amount of reduced glutathione (GSH),superoxide dismutase (SOD) and catalase
(CAT) after assessment with TA as compared to those in only haloperidol treated rats. TNF-α and NO amount
were too found to be reduced in rat model of PD when pretreated with TA. haematological analyses also
demonstrated the normal level of haemoglobin (Hb), Red blood cell (RBC) count, White blood cell(WBC) count,
lymphocyte count, granulocyte count, mean corpuscular volume (MCV) and platelet count in rats pretreated with
TA. Histopathological analysis of rat brain tissue showed neuroprotection in groups pretreated with TA. In
addition, ADMET results based on structure to activity calculation related to pharmacokinetics and toxicity
assessment revealed that TA had reasonably acceptable qualities. These attributes add to our understanding of
structural aspects that may boost the bioavailability of TA before going on to the early stages of medication
development.
Conclusion: Results obtained from the present study suggest that TA have potential to be extended as effective
curative candidate for PD and various neurodegenerative diseases.

1. Background Along with degeneration of neural cells, cognitive destruction and

depression also occur in PD [4,5].
Parkinson’s disease (PD) is featured due to result of a composite Numerous symptoms such as slowness of movement (bradykinesia),
interaction among environmental, genetic and pathogenic factors that rigidity, tremors, postural instability, difficulty in walking indepen­
influences the universal population of all over the world [1]. The disease dently, and behavioural issues are all indications of PD [6]. The etiology
influences ~1–3 % of the globally old above 60 years [1,2]. PD is an of PD is linked to the stimulation of microglia and astrocytes, in addition
infrequent progressive neurodegenerative disease. It is certified by to neuroinflammation. Additionally, it was reported that downregulated
dysfunction of neurotransmitter known as dopamine in the substantia mitochondrial activity, reactive oxygen species (ROS), and oxidative
nigra pars compacta (SNPc) [3]. Amid various factors, inflammation, stress produced by nitric oxide (NO) are participants in the pathogenesis
accumulation of free radicals, head trauma, oxidative stress and expo­ of Parkinson’s disease [7]. Neurodegeneration results from the activa­
sure to environmental toxins are frequent intermediaries of this disease. tion of microglial cells, which produce harmful substances including NO

* Corresponding authors.
E-mail addresses: himani318@gmail.com (H. Badoni), semwal.prabhakar@gmail.com (P. Semwal).

https://doi.org/10.1016/j.dscb.2023.100109

Available online 21 December 2023

2666-4593/© 2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
H. Badoni et al. Brain Disorders 13 (2024) 100109

and some pro-inflammatory cytokines like TNF and interleukin-1 (IL-1). laboratory/house was retained at regular circumstances i.e., 22 ± 3 ◦ C,
Activation of microglial cells leads to the development of cytotoxic 12 h light and dark cycle was too retained. Wistar rats had open
factors such as NO, and some pro-inflammatory cytokines like TNF-α admittance to water and food.
and interleukin-1β (IL-1β), and therefore give rise to neurodegeneration
[8–10]. Medicinal plants having a variety of phytochemicals/ bioactive c. Ethical approval
compounds and these compounds lead to a finding of various novel
therapeutic agents [11–13]. Parkinson’s disease (PD), progressive All the experiments were performed after getting consent from the
supranuclear palsy (PSP), and essential tremor (ET) have all been ethical committee for animals of PBRI (Madhya Pradesh, India), with
studied to determine the significance of neutrophil-to-lymphocyte ratio protocol endorsement reference number PBRI/IAEC/PN-017.
(NLR) in the investigation of movement disorders. The findings indicate
that PSP has a higher NLR than PD [14]. 2.1. Experiments
Phytochemicals possesses different therapeutic properties like anti-
cancer, anti-aging, anti-bacterial, anti-oxidant and anti-hyperglycemic 2.1.1. Acute toxicity study
activities and various other activities [15–18]. These compounds
involve in various metabolic pathways or interfered in most of the 2.1.1.1. Dose administration. According to the Organisation for Eco­
metabolic pathways, and showed effective roles against numerous dis­ nomic Cooperation and Development (OECD)-423 rules acute oral
eases including neuropsychiatric disorders and neurodegenerative dis­ toxicity study was assessed. In support of each dose, a set of three male
eases [9,19].The most noteworthy class of bioactive components are Wistar rats weighing between 200 and 250 g were used as per OECD
tannins, alkaloids, flavonoids, terpenes, etc. Tannic acid (TA), is a guidelines. The dosage level of 5, 50, 300 mg kg− 1 were chosen for oral
mixture of galloyl glucose (majorly decagalloylglucose) or/and gal­ dose (Table 1). The drug was administered orally with the help of can­
loylquinic acid. Tannins are polyphenolic compounds, a versatile as­ nula, to the rats, which were starved all night with water ad libitum
sembly of phytochemicals which possess many health-related benefits prior to giving the drug. The measurement of body weight of the rats was
[16,20–27]. The occurrence of tannins is mostly noticed in stems and recorded prior to and after the treatment (Table 1). The Wistar rats were
bark, alongwith fruits and vegetables. Thus, intake of tannins is hugely taken in observation for lethal indications such as locomotion, convul­
on a daily basis with a difference in utilization rate from region to re­ sions, behavioural changes and mortality for first 72 h and then regu­
gion. It has been reported that intake of TA in various Indian provinces larly for subsequent 14 days [31].
varied from 1.5 to 2.5 g per day [28] and approximately 1 g per day in
the USA [29]. The molar mass of tannins up to 20,000 Daltons and their
2.1.1.2. Observation of toxicity signs. Fatal signs (cardiovascular signs,
chemical structure altered according to the source. Tannins allocation
respiratory pattern, general behaviour, reflexes, motor actions, along
and their concentration are diverse in different divisions likewise seeds,
with alteration in fur and skin) and death rate were assesses subsequent
leaves, fruits and roots [30]. Morphologically tannins are a light-yellow
to the dose administration at first day and one time daily subsequently
or white shapeless residue which possesses a biting taste with a weird
for fourteen days [32].
aroma. Tannins have been reported to have a strong antioxidant po­
tential due to which scientific community searches therapeutic potential
of TA. The antioxidant potential of tannins is capable in reducing 2.2. Sub-acute toxicity study
oxidative damage, which is a key feature of various disease such as
neurological disorders [30]. On the other hand, Tannins are present in 2.2.1. Treatments
numerous plants as a major bioactive component and previous studies In-vivo sub-acute toxicity analysis was executed as per the Organi­
prove the critical function of TA in the healing of Parkinson’s disease sation of Economic Cooperation and Development (OECD) standard
(PD). Therefore, TA is used in the present study. Due to these beneficial 407. A 28 days routine study provides information on the adverse/non-
effects of TA, the current study was conducted to assess and validate its adverse effects of repeated oral exposure, as well provides report on the
anti-Parkinson’s activity. selection of concentrations for experimental studies. Seven weeks old
male, Wistar rats were taken for subacute toxicity assessment. Animals
2. Materials and methods were arbitrarily distributed into four different groups and each group
contains 6 rats in it (Table 2). On the time of gavage weight of animals
a. Chemicals measured within the range of 200–250 g. The dose level of 30, 100 and
300 mg kg− 1 were selected for oral dose. The toxicity of TA was deter­
Potassium hydroxide, formalin, ethylenediaminetetraacetic acid mined [31]. TA were given by oral administration to the rats, those were
(Merck), acetonitrile (Merck), 5,5′- dithiobis-2-nitrobenzoic acid starved all night with water ad libitum prior to the administration of the
(DTNB) (Merck), iodine, acetic acid, hydrochloric acid, sodium sulphite TA. The weight of body was traced prior to and after administration of
(Sigma Aldrich), TA (Sigma Aldrich),distilled water, Methanol, ethanol, doses.
paraffin, normal saline (Sunpharma), haloperidol (Zydus), carbidopa
levodopa, (Sinemet), tween 20, thiobarbituric acid, phosphoric acid, 2.2.2. Haematological analyses
trichloroacetic acid, sodium phosphate monobasic, hydrogen peroxide, All animals were starved overnight prior to the end of study, before
sodium phosphate dibasic, sulphanilamide, Eosin and Haematoxylin, blood sampling. Weekly food as well water intake was recorded along
3,3′,5,5′-Tetramethylbenzidine (TMB), ELISA kit TNF-α(Sigma Aldrich, with body weight of Wistar rats. As well, simultaneous observation for
RAB0479) were obtained from the appropriate company dealer. The toxic symptom and mortality were done. On the 28th day, the blood
entire chemical and reagents of analytical grade were used in this study.
Table 1
b. Animals Various treatment groups for acute toxicity study.
Treatment Treatments Dosage
In this investigation, 60 healthy adult male Wistar rats were used. groups
These Wistar rats were kept in the animal laboratory/house of Pinnacle Group I Control animals 1 % Normal saline (NS)
Biomedical Research Institute (PBRI), Bhopal, India, five days prior to Group II Animals obtained TA dosage of 5 mg kg− 1 body weight, p.o.
the initiation of experimentation in order to adapt them. The other Group III Animals obtained TA dosage of 50 mg kg− 1 body weight p.o.
Group IV Animals obtained TA dosage of 300 mg kg− 1 body weight p.o
required condition such as requisite temperature of the animal

2
H. Badoni et al. Brain Disorders 13 (2024) 100109

Table 2 and suspended 70 cm above a foam pad, with the forelimbs propped for
Various treatment groups for subacute toxicity study. weight bearing. The time, in seconds was recorded until the rat was
Treatment Treatments Dosage knocked down. The duration (in seconds) earlier to the rat knock down
groups was noted. If the rat does not resist for a while and fell immediately, a
Group I Control group 1 % Normal saline (NS) for 28 zero score was credited, and the 60 s were the latency period to score
Days more than zero. Three readings were taken for each trail session [34].
Group II Animals received TA 30 mg kg− 1 body weight, p.o. for
28 days. 2.3.3. Tardive dyskinesia test
Group III Animals administered 100 mg kg− 1 body weight p.o. for
with TA 28 days.
It is a type of vacuous grinding exercise (VCM) in rats. At the day of
Group IV Animals obtained TA 300 mg kg− 1 body weight p.o. for scheduled experiment, the Wistar rats were positioned in isolation in a
28 days. little polypropylene coop of measurement 30 × 20 × 30 cm, to assess the
level of oral dyskinesia. Prior to the behavioural assessment, Wistar rats
were permitted to acclimatize for 10 min in the environment of cage. To
sample was taken and collected from experimental animals by retro
perform this experiment, monitoring of oral dyskinesias was assigned by
orbital puncture. Blood samples were taken in a EDTA (Ethyl­
placing mirrors under the floor and behind the barricade at the rearmost
enediaminetetraacetic acid) containing tube, EDTA is an anticoagulant,
part of the cage while the animals were well away from the observer’s
to prevent clot formation. Further blood samples were used to determine
eyes. Behavioural frames of oral dyskinesia were recorded uninter­
various parameters like count of RBCs, WBCs, platelets, lymphocytes,
ruptedly for up to five minutes [35].
granulocytes, haemoglobin estimation and mean corpuscular volume
(MCV) by span diagnostic (Model number: PE6400) fully automated
2.4. Analysis of biochemical markers
haematology analyzer.
a. Dissection
2.3. Neurobehavioral studies
Finally at the completion of experiment, animals were euthanized by
2.3.1. Catalepsy test impalement under gentle anesthesia. After the death of animals, brains
Dopamine receptors are blocked after treatment with haloperidol were detached instantly, forebrain was taken for further study, and
(HP), which accelerates the turnover of dopamine. As a result of their cerebellum was disposed of.
metabolism, this may cause the production of ROS. HP administration
also causes the generation of free radicals and is linked to a marked b. Preparation of brain homogenate
decline in antioxidant levels [33]. Male adult Wistar rats (6 weeks,
200–250 g) were distributed into four different groups, every group Separated brain tissue samples were placed on ice and cleaned with
includes 6 animals. Control animal group (Group I) received 1 % normal chilled isotonic saline to eradicate blood traces. Homogenized tissue (10
saline (NS). Second group (Group II) administered with haloperidol only % w/v) was ended with phosphate buffer (0.1 M, pH 7.4). The ho­
and marked as cataleptic control group without any drug treatment. mogenized samples were centrifuged at 10,000 g for 15 min and an
Next group (Group III) was treated with TA (30 mg kg− 1 body weight). aliquot of the supernatant was secured for further evaluation.
As a positive control in the experiment, a different group (Group IV) is
given a merger of Levodopa (100 mg kg− 1 body weight, i.p.) and car­ 2.4.1. Assay for malondialdehyde (MDA) activity
bidopa (25 mg kg− 1 body weight, i.p.) (Table 3). Drugs were given orally The quantity of malondialdehyde obtained was taken as secondary
for a time period of four days, on the subsequent fifth day, after 30 min measurement of lipid peroxidation and quantified by response with
of treatment with TA, catalepsy was induced by haloperidol (i.p.) at a thiobarbituric acid (TBA) [36]. In brief, 1 mL supernatant collection
dosage of 1 mg kg− 1 body weight. To perform physiological studies a tubes or aliquots of homogenized samples were added to conical test
quiet room is taken with no outside intervention. The catalepsy score tubes. Then 3 ml, TBA reagent (0.38 % (w/w) with 0.25 M hydrochloric
was recorded in continuous gap of 30 min intended for an entire time of acid (HCl) and 15 % trichloroacetic acid (TCA) was added to the aliquot.
two hours. At the last day (5th day) of catalepsy experiment, Wistar rats Further, the mixed solution was shaken, placed in an ice bath for 15 min,
were euthanized by means of cervical displacement, at the same time the and then cooled. Subsequently chilling the solution, it was centrifuged at
entire brain was sliced up instantly and cleaned in chilled saline to 3500 g for 10 min. Additionally, top activity was obtained and quanti­
eradicate every blood traces. Subsequently, the brains were weighed to fied by spectrophotometry at 532 nm. All readings were obtained in
prepare tissue homogenate (10 %) and used to measure the LPO, GSH, triplicate. The resulting values obtained were deliberated as nano­
catalase and SOD activities. In addition to this neuroinflammatory moles/mg of protein.
markers, TNF-α, Nitric oxide level were assessed. MDA concentrations were measured by the formula: -
Conc.of MDA = Abs532 × 100 × VT/(1.56 × 105) × WT × VU. (1)
2.3.2. Hang test
This test has been done to examine muscle potency and motor neuron Here, Abs532 is absorbance at 532 nm, VT, total volume of mixture,
consistency. Wistar rats were strung between two 30 cm bars on a pole 1.56 × 105, molar extinction coefficient WT, weight of dissected brain,
and VU, aliquot capacity.
Table 3
Various treatment groups. 2.4.2. Assay for superoxide dismutase (SOD) activity
Superoxide dismutase (SOD) assay was performed as per the meth­
Treatment Treatments Dosage
odology illustrated by Beyer and Fridovich (1987) [37]. The supernatant
groups
(0.1 mL) was assorted with 1 × 10− 4 M EDTA (0.1 mL), plus carbonate
Group I Control group 1 % Normal saline (NS) for 5 days.
buffer (0.5 mL, pH 9.7), along 1 mM epinephrine (1 mL). The absor­
Group II Animals received dosage of 1 mg kg− 1 body weight (i.
Haloperidol p.). bance of produced adrenochrome was taken at 480 nm for next 3 min on
Group III Animals administered 30 mg kg− 1 body weight p.o. for 5 spectrophotometer. The obtained quantity of enzyme action was
with TA days. measured in U/min/mg. The required concentration used for the
Group IV Animals received L + C 100 + 25 mg kg− 1 body weight p.o. obstruction of chromogen creation by 50 % in one min below the pre­
for 5 days.
defined assay circumstances is termed as one unit of enzyme activity.

3
H. Badoni et al. Brain Disorders 13 (2024) 100109

2.4.3. Assay for catalase (CAT) activity nitrosating agent and act in response with sulfanilic acid to create the
Catalase activity in the sample was evaluated by the methodology of diazonium ion. Finally formed ion is then combined with N-(1-naphthyl)
Aebi, 1984 [38]. The experiment combination comprises of tissue ho­ ethylenediamine to shape the azo-derivative of chromophore that ab­
mogenate supernatant (0.05 mL, 10 %) plus 50 mM of phosphate buffer sorbs light at 540–570 nm. Same volume of brain homogenate and
(1.95 mL, pH 7.0) in a cuvette (3 mL). To this, 1 mL hydrogen peroxide Griess reagent were used in this assay, followed by 10 min incubation at
(30 mM) was combined and alteration in optical density were tracked normal room temperature and the Optical density (OD) was taken at
for 30 s at 240 nm at 15 s break. The sample catalase activity was 546 nm using ELISA plate reader (BioRad). The level of nitrite in the
measured by means of the millimolar extinction coefficient of H2O2 supernatant was analysed using standard curve and expressed in µM
(0.071 mmol cm− 1) and deliberated as micromoles of H2O2 oxi­ gm− 1 wet tissue.
dized/minute/milligram protein:
CATactivity = δO.D./E × Vol.of Sample(mL) × mgof protein (2) 2.6. Histopathological studies
Here, δO.D. is variation in absorbance/minute; E: extinction coeffi­
cient of H2O2 (0.071 mmol cm− 1). Wistar rat brains isolated from control rats and treatment groups
were set with formalin (10 %) furthermore implanted in paraffin wax,
2.4.4. Assay for reduced glutathione activity (GSH) further the isolated brain tissue was sliced into longitudinal section (5
To assess reduced glutathione activity, 10 % TCA (1 ml) was µm width). For histopathological observation, tissue segments were
precipitated with one mL of tissue homogenate. To the supernatant of stained with two dyes namely, hemotoxylin and eosin [43].
treated sample, phosphate solution (4 mL) plus DTNB (0.5 mL) mixture
were added. Then, optical density was taken and recorded at 412 nm
[39]. The obtained results were articulated as nM of reduced gluta­ 2.7. Induced fit docking
thione/mg of protein:
For molecular docking studies, the ligand and protein must have a
GSHactivity = Y − 0.00314/0.0314 × DF/BT × VU (3) three-dimensional structure. The 3D crystal structures of TNF-alpha
Here Y, A412 of tissue homogenate, DF, dilution factor, BT, ho­ (PDB ID:2AZ5) and Nitric oxide synthase (PDB ID:2FLQ) were
mogenate (brain tissue), VU, is aliquot volume. retrieved from the protein data bank (PDB) at www.rcsb.org. The Open
Babel software was used to convert the SMILE format to the PDB format.
2.5. Estimation of neuroinflammatory markers The chemical structure of ligand molecule was retrieved from PubChem.
The molecular docking process were performed by using AutoDock vina.
To the obtained sample tissue homogenate, HCl–butanol (5 ml) was Using the AutoDock tools, a grid box (120, 120, 120) centred at (X =
added and centrifuged at 2000 rpm for 10 min. Further, supernatant was − 7.045, Y = 70.074, Z = 23.999) for the TNF-alpha and (120, 120, 120)
isolated with heptanes (2.5 mL) plus HCl (0.31 mL) and robustly shaken. centred at (X = − 15.176, Y = 72.127, Z = 26.191) for the Nitric oxide
Afterward, this blend was centrifuged at 2000 rpm for 10 min. For was utilised as search space in docking studies. BIOVIA Discovery Studio
quantification of the neuroinflammatory markers lower aqueous phase 2020 were used to visualise the interaction of the protein ligand
was taken [40–42]. complex.

2.5.1. Quantification of TNF-α

2.8. Pharmacokinetics and toxicity risk assessment
An antibody specific estimation was done by using rat TNF-α. Rat
TNF-α antibodycoated 96-well plate was used in this assay. Standard and
The ADMET characteristics are critical in deciding if a medication
sample of 100 μL was added to relevant wells. Wells were enclosed
will be a successful drug candidate. SWISS ADME tool (http://www.
properly and incubated for 2.5 h at normal room temperature. Then
swissadme.ch/) was used to determine compound ADMET profiles.
solution was decanted and rinsed four times with wash solution (1x).
The compound TA have reduced gastrointestinal absorption, other
Each well was rinsed with wash buffer (300 μL). Liquid was completely
compounds rapidly absorbed in the abdomen and epithelium. The
removed at each step. Wash buffer was discarded by aspirating subse­
compound TA have affinity for P-glycoprotein. The TA had a skin
quent to last wash step. The 96- well plate was upturned and blotted
penetration value greater than − 1.0, indicating that they were easily
beside fresh paper sheets. Then, 1x biotinylated antibody (100 μL) was
absorbed via the skin.
added to every well along with mild shaking for 1 h at room tempera­
ture. Further, solution was decanted and rinsed. Again, ready solution of
Streptavidin (100 μL) was poured to every compartment and left at room 3. Statistical analyses
temperature for forty-five minutes with mild trembling. Then, solution
was disposed of and rinsed. To each well, 3,3′,5,5′-Tetramethylbenzidine The entire experiments were performed thrice for independent ob­
(TMB) of 100 μL was poured and incubated for 30 min in dark (R.T.) servations. Records from the laboratory experiments were evaluated
with mild shaking. Lastly, in each well stop solution of 50 μL was added. individually. To assess each experiment, all the readings were subjected
Optical density was recorded using ELISA plate reader at 450 nm to one way ANOVA (analysis of variance) using SigmaStat®3.5 Software
immediately. tracked by Bonferroni t-test (p < 0.001). Data were expressed as mean ±
SEM.
2.5.2. Quantification of NO
Aggregation of nitrite in the supernatant is a signal of oxidative stress 4. Results
developing in the brain which occurs due to nitric oxide (NO) produc­
tion. NO was spectrophotometrically assessed by using Griess reagent 4.1. Acute toxicity study
(0.1 % N-1-napththyl ethyleneamine dihydrochloride, 1 % sulphanila­
mide and 2.5 % phosphoric acid). NO assay actuates nitric oxide con­ The results of acute toxicity experiment showed TA is safe and sound
centration depends on the alteration of nitrate to nitrite. Further, at various doses used in treatment and no mortality was noticed at the
reaction is pursued by colorimetric identification of nitrite, that is a dose of 300 mg kg− 1 of TA when dose given orally. As a result, 30 mg
product of the Griess Reaction, an azo dye. This two-step diazotization kg− 1was taken as the beneficial dose and variations was created by
reaction is initiated with acidification of NO2 that generates a taking 5 mg kg− 1as lower dose and 300 mg kg− 1as higher dose (Table 4).

4
H. Badoni et al. Brain Disorders 13 (2024) 100109

Table 4 4.4. Effect of TA on haloperidol stimulated Parkinson’s disease model

Acute toxicity study of TA at various dose levels.
Drug Dose Signs of toxicity Effect Mortality 4.4.1. Effects of TA on haloperidol stimulated Parkinson’s disease in hang
treatment (mgkg− 1) observed test
TA 5 No signs was None 0/3 TA (TA) treatment significantly declined the drop time when judge
observed against to the control animals. Persistent oral treatment of (30 mg kg− 1)
30 No signs was None 0/3 noteworthy (p < 0.001) augmented the drop time when contrast to
observed haloperidol treated group from day 1 to 5. Levodopa + Carbidopa (100
300 No signs was None 0/3
observed
+ 25 mg kg− 1) significantly (p < 0.001) augmented the drop time as
contrast to haloperidol treated group. Treatment with TA (30 mg kg− 1)
does not illustrate any significant changes (Fig. 3A).
4.2. Sub-acute toxicity study
4.4.2. Effect of TA on haloperidol stimulated Parkinson’s disease in tardive
The subacute toxicity of TA at various doses administered to the dyskinesia
Wistar rats, did not generate any toxicity signs or lethality in the entire The haloperidol treated group was observed to be significantly
treatment groups. Moreover, it was observed that no significant alter­ delayed (p < 0.001) in burst and munching movement as contrast to the
ations take place in food and water use in Wistar rats administered sub- control group (Fig. 3). In the Levo + Carbidopa (100 + 25 mg kg− 1)
acutely by replicated oral doses of the aqueous extract (5, 30, or 300 mg tested animal group and the candidate drug TA at doses (30 mg kg− 1)
kg− 1). Together, the control and treatment groups were observed fit significantly declined (p < 0.001) burst and munching activity was
during entire experiment the 28-day period and on the completion of the analysed as contrast to the haloperidol tested group (Fig. 3B).
experiment (Fig. 1).
4.4.3. Effect of TA on LPO, SOD, CAT, and GSH levels
4.3. Neurobehavioral studies Treatment with TA results in noteworthy alterations in tested
biochemical parameters as contrast to the control group. Inoculation of
4.3.1. Effect of TA on haloperidol induced catalepsy TA provoked oxidative stress, as specified by augmented LPO (MDA)
Persistent oral treatment of TA (30 mg kg− 1) displayed noteworthy activity, along with declined SOD, CAT and GSH activity when contrast
(p < 0.001) changes as contrast to control group (Fig. 2). to control group in brain tissues. TA (30 mg kg− 1), p.o.) treatment
illustrated significant (p < 0.001) decline in MDA activity contrast to
haloperidol treated groups. In the same way, every day administration
of (30 mg kg− 1TA) inhibits the enhancement in SOD and CAT activity
with haloperidol tested group. Prior treatment with TA (30 mg kg− 1)
notably (p < 0.001) augmented activity of GSH in the brain tissues as

Fig. 1. Effects of TA. A. Weekly water intake, B. Food intake and, C. Body weight. Values are in Mean ± SEM (n = 6). The differences in the mean values among the
groups are greater than would be expected by chance; here is a statistically significant difference (p < 0.001).

5
H. Badoni et al. Brain Disorders 13 (2024) 100109

Fig. 2. Effect of TA on haloperidol induced catalepsy in Wistar rats. Values are in Mean ± SEM (n = 6). The differences in the mean values among the groups are
greater than would be expected by chance (p < 0.001).

Fig. 3. Effect of TA on A. Hang test and B. Tardive dyskinesia test in Wistar rats. Values are in Mean ± SEM (n = 6). The differences in the mean values among the
groups are greater than would be expected by chance; here is a statistically significant difference (p < 0.001).

contrast to haloperidol tested animals, therefore avoiding the drop in as contrast to the vehicle control group. The Wistar rat groups, treated
GSH stimulated via haloperidol (Fig. 4). with Levodopa + Carbidopa (100 + 25 mg kg− 1) and the experimental
drug TA at doses (30 mg kg− 1), it was observed that there is a note­
4.4.4. Effect of TA on TNF- α, nitric oxide(NO) activity worthy decrease (p < 0.001) in TNF-α and NO activity as contrast to the
Results showed that groups treated with haloperidol were signifi­ haloperidol treated animals (Fig. 5).
cantly increased (p < 0.001) TNF-α and NO activity in haloperidol group

Fig. 4. Effect of TA on biochemical parameters A.LPO, B. SOD, C.GSH, D. CAT on Wistar rats. Values are in Mean ± SEM (n = 6). The differences in the mean values
among the groups are greater than would be expected by chance (p < 0.001).

6
H. Badoni et al. Brain Disorders 13 (2024) 100109

Fig. 5. Effect of TA. A. TNF- α, B. Nitric oxide (NO) activity in Wistar rats. Values are in Mean ± SEM (n = 6). The differences in the mean values among the groups
are greater than would be expected by chance; here is a statistically significant difference (p < 0.001).

4.4.5. Effect of TA on haematological profile of normal and TA treated indicated by dashed lines (Fig. 8). While, two-dimensional diagram of
animals TA docking with Nitric oxide, and the interactions corresponding the
There was observed significant alterations in haematological pa­ amino acids of protein and ligand are indicated by dashed lines (Fig. 8).
rameters (HGB, RBC, WBC, LYM, GRAN, MCV, PLT) in haloperidol
treated group as contrast to normal group (Table 5). 5. Discussion

4.4.6. Effect of TA on histopathological alterations in treated and untreated Parkinson’s disease is generally characterized by a persistent
animals neurodegenerative disorder in which there is reduction in dopaminergic
The results obtained for histopathological experiment illustrated that neurons of the substantia nigra pars compacta (SNpc). The PD patho­
neurotoxin, namely, haloperidol, caused obvious hypertrophic alter­ genesis cascade comprises of protein buildup similar to a-synuclein,
ations, permeation of neutrophils, enlarged intracellular space, dimin­ apoptosis, oxidative stress, neuronal excitotoxicity and mitochondrial
ished compactness of cells, hemorrhage, changes in construction and dysfunction. The vital pathological mechanism for PD is oxidative stress.
neuronal damage that results into cell death (Fig. 6). SNpc is extra susceptible to reactive oxygen species (ROS) because it has
large quantity of dopamine. A large amount of ROS is generated by
4.5. Molecular docking studies catabolism of dopamine via monoamine oxidase-B, which is involved in
rotation of Fenton-type free radical producing reactions associated with
The molecular interaction investigation revealed that TA has − 8.2 ferric elements found in abundance in the nigral cells. In the CNS of the
Kcal mol− 1 binding affinity with receptor TNF-alpha and − 8.4 kcal animals has glioma, the levels of nitrite, thiobarbituric acid reactive
mol− 1 binding energy with receptor Nitric oxide. While the molecular substance (TBARS), ROS increased one hand, and, on the other hand
interaction revealed that Haloperidol has − 8.4 kcal mol− 1 binding en­ thiol (SH), CAT and superoxide dismutase (SOD) activities were
ergy with receptor Nitric oxide and − 7.7 kcal mol− 1 against TNF-alpha declined; It was observed that TA treatment drop off the TBARS and ROS
(Table 6, Fig. 7). levels and reimpose the activity of SOD. The serum sample examination
of the animal groups has glioma, showed downregulation of ATP hy­
4.6. ADMET profile drolysis; again, TA treatment reinstate this factor. Furthermore, it has
been reported that ROS levels upregulated and the SH and SOD activity
The ADMET profiling based on structure to activity calculation downregulated by glioma embed; treatment with TA improved nitrite
related to pharmacokinetics and toxicity assessment revealed that TA levels and undo SOD activity. On the whole, results imply that TA is an
had reasonably acceptable qualities (Table 7). imperative target in the cure of GB, as it regulates purinergic and redox
A two-dimensional diagram of TA docking with TNF-alpha, and the systems [44].
interactions corresponding the amino acids of protein and ligand are The current study concludes the consequences of TA in neurotoxin
(haloperidol) provoked Parkinson disease in Wistar rats. As reported by
Table 5 various literature, catalepsy induced by Haloperidol is mostly under­
Effect of TA in haematological profile of normal and haloperidol treated rats. standable animal model of PD. Haloperidol an anti-psychotic drug,
Values are in Mean ± SEM (n = 6). The differences in the mean values among the serves a therapeutic model of PD by interrupting by the accumulation of
treatment groups are greater than would be expected by chance; here is a sta­ catecholamine’s intracellularly, follow-on dopamine reduction in nerve
tistically significant difference (p < 0.001). endings. The current research showed that, haloperidol (1 mg kg− 1, i.p.)
Hematology Control Haloperidol TA L+C prompt considerable catalepsy in Wistar rats as the time consumed on
parameters block was increased as evaluated against vehicle treated animals. TA
HGB(g/dL) 15 ± 0.22 9.12 ± 0.86 7.65 ± 10.47 ± administration significantly diminished the catalepsy symptoms in rats
2.25 1.06 treated with haloperidol in dose reliant mode. Mitochondrial dysfunc­
RBC(10 £ 6/ul) 6.37 ± 4.77 ± 0.33 3.90 ± 5.59 ± 0.53 tion leads to oxidative stress which was produced as an effect of mainly
0.57 0.96
mitochondrial complex-1 destruction that take part in imperative
WBC(10 £ 3) 11.18 ± 4.42 ± 1.08 4.77 ± 10.88 ±
1.05 2.16 0.88 element in the pathogenic cascade of PD. The level of oxidative stress
LYM(10 £ 3/ul) 16.04 ± 4.86 ± 0.25 11.27 ± 13.57 ± was calculated via levels of LPO, SOD, CAT and GSH in the brain tissue.
3.50 1.44 0.15 As well neuroinflammatory markers (TNF-α, and Nitric oxide) level was
GRAN(10 £ 3/ul) 28.97 ± 12.67 ± 19.34 ± 24.87 ± evaluated.
1.46 0.58 0.41 0.35
Haloperidol causes an elevation in the generation of free radicals and
MCV(fL) 65.96 ± 52.34 ± 59.65 ± 60.32 ±
3.56 0.67 1.44 0.56 hydrogen peroxide [45,46]. Production of ROS by non-enzymatic
PLT(10 £ 3/ul) 188.5 ± 71.5 ± 8.34 100.7 ± 134.45 ± degradation of haloperidol or direct blockage of complex I and com­
9.76 9.34 7.25 plex IV of the mitochondrial electron transport chain [46–48]. The

7
H. Badoni et al. Brain Disorders 13 (2024) 100109

Fig. 6. Histopathology. (A) Control group rats treated with normal saline showed regular brain construction, (B) Rats administered with (L + C) + Halo showed
minimum variations in neuronal cell integrity, (C) Rats administered with haloperidol only, showed degeneration and vacuolation of neurons, (D) TA + Halo treated
rats showed minimum changes in neuronal cell populations.

alpha and Nitric oxide in this study, which could explain the anti­
Table 6
parkinsonian activity of the compound.
Table showing binding energy (kcalmol− 1) of docked protein TNF-alpha and
Furthermore, the ADMET profile of TA was anticipated to provide a
nitric oxide.
safe and highly effective medication for Parkinson’s disease when
Compounds Binding affinity (kcal mol− 1) Binding affinity (kcal mol− 1)
compared with carbidopa and levodopa. Natural antioxidants, these
with TNF-alpha with nitric oxide
phytochemicals are also important in the prevention and treatment of
TA − 8.2 − 8.4 various metabolic illnesses. The application of in silico approaches in this
Haloperidol 7.7 8.4
work retrieved molecular infrastructures, which are critical to compre­
− −
Carbidopa − 5.7 − 5.5
Levodopa − 5.4 − 5.4 hend oral bioavailability of phytochemicals. The Swiss ADME web tool
has provided in silico models to evaluate the bioavailability, toxicity, and
absorption of TA [50].
resulting ROS generation from the breakdown of haloperidol leads to
lipid peroxidation, protein denaturation and elevation of glutathione 6. Conclusion and future perspective
levels found in Parkinson’s patients [43,49–54].
Molecular docking is a powerful method for simulating ligand- As per the findings of current study, we are concluding that TA
receptor interactions, including binding mode, complexation, and showed antioxidant potential and possess capability to attenuate Par­
ligand-receptor interactions. Induced Fit docking also takes into account kinson’s disease in Haloperidol induced catalepsy model. Additionally,
the receptor’s flexibility or the re-arrangement of residues to exactly results also support declination in neuroinflammatory markers (TNF-α
create the conformation upon ligand binding, reducing false positivity and NO) by TA. Moreover, molecular docking studies and ADMET pro­
during simulation. TA showed a high affinity for the active sites of TNF- file assessment confirmed the usage of TA and provided a new approach

Fig. 7. Docking interaction of TA and 2AZ5.

8
H. Badoni et al. Brain Disorders 13 (2024) 100109

Table 7
ADMET profile of compounds.
Compound name ADMET
(a) (b) (c) (d) (e) (f) (g) (h) (i)

Haloperidol High Yes No No No No Yes Yes − 5.54

Levodopa High No No No No No No No − 9.45
Carbidopa High No No No No No No No − 9.22
TA Low No Yes No No No No No − 10.00

(a) GI absorption (b) BBB permeant (c) Pgp substrate (d) CYP1A2 inhibitor (e) CYP2C19 inhibitor (f) CYP2C9 inhibitor (g) CYP2D6 inhibitor (h) CYP3A4 inhibitor (i)
log Kp (cm/s).

Fig. 8. Docking interaction of TA and 2FLQ.

for the creation of novel anti-parkinsonian drug aspirants derived from Permission to reproduce material from other sources
natural sources that are compatible with the human body.
The present study showed the efficacy of tannins as a promising Not applicable
candidate in the treatment of Parkinson’s disease. Future tannin
research must focus on the elaboration of these described benefits at the Clinical trial registration
subcellular and molecular levels in order to obtain clinical acceptance of
all their health-promoting benefits from detailed in-vitro, in-vivo, and Not applicable
preclinical studies. The prevention and treatment of neurodegenerative
diseases (PD, AD, etc.) with complex mechanisms require novel targeted
CRediT authorship contribution statement
therapeutic strategies. Additionally, a thorough investigation of tannins’
risk assessment and safety evaluation in relation to their potential
Himani Badoni: Conceptualization, Data curation, Formal analysis,
pharmaceutical usage in neurodegenerative illnesses is required.
Investigation. Sakshi Painuli: Formal analysis, Investigation, Writing –
original draft. Sachin Panwar: Formal analysis, Software. Promila
Authors contribution
Sharma: Writing – review & editing. Prabhakar Semwal: Writing –
review & editing.
All authors have read and agreed to the published version of the
manuscript.
Declaration of Competing Interest
Funding statement
The authors declare that they have no known competing financial
Not applicable interests or personal relationships that could have appeared to influence
the work reported in this paper.
Data availability statement
Acknowledgement
The data presented in this study are available upon request.
Not Applicable.
Ethics approval statement

All the experiments were performed after getting consent from the References
ethical committee for animals of PBRI (Madhya Pradesh, India), with
[1] N. Ball, Chandra S TeoW-P, J Chapman, Parkinson’s disease and the environment,
protocol endorsement reference number PBRI/IAEC/PN-017. Front. Neurol. 10 (2019) 218, https://doi.org/10.3389/fneur.2019.00218.
[2] L. Hirsch, N. Jette, A. Frolkis, T. Steeves, T. Pringsheim, The incidence of
Patient consent statement Parkinson’s disease: a systematic review and meta-analysis, Neuroepidemiology 46
(2016) 292–300, https://doi.org/10.1159/000445751.
[3] M.J. Farrer, Genetics of Parkinson disease: paradigm shifts and future prospects,
Not applicable Nat. Rev. Genetics 7 (2006) 306–318.

9
H. Badoni et al. Brain Disorders 13 (2024) 100109

[4] A. Sarrafchi, M. Bahmani, H. Shirzad, M. Rafieian-Kopaei, Oxidative stress and [29] H.P. Makkar, P. Siddhuraju, K Becker, Tannins. Plant Secondary Metabolites,
Parkinson’s disease: new hopes in treatment with herbal antioxidants, Curr. Pharm. Springer, 2007, pp. 67–81.
Des. 22 (2016) 238–246. [30] G. Hussain, J. Huang, A. Rasul, H. Anwar, A. Imran, J. Maqbool, A. Razzaq, N. Aziz,
[5] M. Oguru, H. Tachibana, K. Toda, B. Okuda, N. Oka, Apathy and depression in E.U.H. Makhdoom, M. Konuk, et al., Putative roles of plant-derived tannins in
Parkinson disease, J. Geriatr. Psychiatry Neurol. 23 (2010) 35–41, https://doi.org/ neurodegenerative and neuropsychiatry disorders: an updated review, Molecules
10.1177/0891988709351834. 24 (2019) 2213.
[6] J. Jankovic, Parkinson’s disease: clinical features and diagnosis, J. Neurol. [31] K. Jaijoy, N. Soonthornchareonnon, N. Lertprasertsuke, A. Panthong,
Neurosurg. Psychiatry 79 (2008) 368–376, https://doi.org/10.1136/ S. Sireeratawong, Acute and chronic oral toxicity of standardized water extract
jnnp.2007.131045. from the fruit of Phyllanthus emblica Linn, Int. J. Appl. Res. Nat. Prod. 3 (2010)
[7] G.S. Gaki, A.G. Papavassiliou, Oxidative stress-induced signaling pathways 48–58.
implicated in the pathogenesis of Parkinson’s disease, Neuromolecular Med. 16 [32] Chan, P.K.; O’Hara, G.P.; Hayes, A.W. Principles and methods for acute and
(2014) 217–230, https://doi.org/10.1007/s12017-014-8294-x. subchronic toxicity. In Principles and Methods of Toxicology, Hayes, A.W., Ed.; NY:
[8] F. Magrinelli, A. Picelli, P. Tocco, A. Federico, L. Roncari, N. Smania, G. Zanette, Raven Press: New York, 1982; Volume 12, pp. 17–19.
S. Tamburin, Pathophysiology of motor dysfunction in Parkinson’s disease as the [33] A. Kabra, U.S. Baghel, C. Hano, N. Martins, M. Khalid, R. Sharma, Neuroprotective
rationale for drug treatment and rehabilitation, Parkinsons Dis. 2016 (2016), potential of Myrica esulenta in haloperidol induced Parkinson’s disease,
9832839, https://doi.org/10.1155/2016/9832839. J. Ayurveda Integr. Med. 11 (2020) 448–454, https://doi.org/10.1016/j.
[9] G. Hussain, A. Rasul, H. Anwar, N. Aziz, A. Razzaq, W. Wei, M. Ali, J. Li, X. Li, Role jaim.2020.06.007.
of plant derived alkaloids and their mechanism in neurodegenerative disorders, Int. [34] B. Nishchal, S. Rai, M. Prabhu, S.D. Ullal, S. Rajeswari, H. Gopalakrishna, Effect of
J. Biol. Sci. 14 (2018) 341–357, https://doi.org/10.7150/ijbs.23247. Tribulus terrestris on haloperidol-induced catalepsy in mice, Indian J. Pharm. Sci.
[10] A. Rauf, H. Badoni, T. Abu-Izneid, A. Olatunde, M.M. Rahman, S. Painuli, 76 (2014) 564.
P. Semwal, P. Wilairatana, M.S. Mubarak, Neuroinflammatory markers: key [35] H. Jia, Z. Liu, X. Li, Z. Feng, J. Hao, X. Li, W. Shen, H. Zhang, J. Liu, Synergistic
indicators in the pathology of neurodegenerative diseases, Molecules 27 (2022) anti-Parkinsonism activity of high doses of B vitamins in a chronic cellular model,
3194. Neurobiol. Aging 31 (2010) 636–646, https://doi.org/10.1016/j.
[11] P. Semwal, S. Painuli, Antioxidant, antimicrobial, and GC-MS profiling of neurobiolaging.2008.05.031.
Saussurea obvallata (Brahma Kamal) from Uttarakhand Himalaya, Clin. [36] H. Ohkawa, N. Ohishi, K. Yagi, Assay for lipid peroxides in animal tissues by
Phytoscience 5 (2019) 1–11. thiobarbituric acid reaction, Anal. Biochem. 95 (1979) 351–358, https://doi.org/
[12] Y. Taheri, H.A.R. Suleria, N. Martins, O. Sytar, A. Beyatli, B. Yeskaliyeva, 10.1016/0003-2697(79)90738-3.
G. Seitimova, B. Salehi, P. Semwal, S. Painuli, Myricetin bioactive effects: moving [37] W.F. Beyer Jr., I Fridovich, Assaying for superoxide dismutase activity: some large
from preclinical evidence to potential clinical applications, BMC Complement. consequences of minor changes in conditions, Anal. Biochem. 161 (1987) 559–566,
Med. Ther. 20 (2020) 1–14. https://doi.org/10.1016/0003-2697(87)90489-1.
[13] B. Salehi, N. Cruz-Martins, M. Butnariu, I. Sarac, I.-C. Bagiu, S.M. Ezzat, J. Wang, [38] H. Aebi, Catalase in vitro, Methods Enzymol. 105 (1984) 121–126, https://doi.org/
A. Koay, H. Sheridan, C.O. Adetunji, Hesperetin’s health potential: moving from 10.1016/s0076-6879(84)05016-3.
preclinical to clinical evidence and bioavailability issues, to upcoming strategies to [39] I. Rahman, A. Kode, S.K. Biswas, Assay for quantitative determination of
overcome current limitations, Crit. Rev. Food Sci. Nutr. (2021) 1–16. glutathione and glutathione disulfide levels using enzymatic recycling method,
[14] P. Alster, N. Madetko, A. Friedman, Neutrophil-to-lymphocyte ratio (NLR) at Nat. Protoc. 1 (2006) 3159–3165, https://doi.org/10.1038/nprot.2006.378.
boundaries of progressive supranuclear palsy syndrome (PSPS) and corticobasal [40] U. Saleem, R. Akhtar, F. Anwar, M.A. Shah, Z. Chaudary, M. Ayaz, B. Ahmad,
syndrome (CBS), Neurol. Neurochir. Pol. 55 (1) (2021) 97–101, https://doi.org/ Neuroprotective potential of Malva neglecta is mediated via down-regulation of
10.5603/PJNNS.a2020.0097. cholinesterase and modulation of oxidative stress markers, Metab. Brain Dis. 36
[15] N. Aziz, A. Rasul, S.A. Malik, H. Anwar, A. Imran, A. Razzaq, A. Shaukat, S. (2021) 889–900, https://doi.org/10.1007/s11011-021-00683-x.
K. Shahid Kamran, J.G. de Aguilar, T. Sun, et al., Supplementation of Cannabis [41] M. Sanawar, U. Saleem, F. Anwar, S. Nazir, M.F. Akhtar, B. Ahmad, T. Ismail,
sativa L. leaf powder accelerates functional recovery and ameliorates haemoglobin Investigation of anti-Parkinson activity of dicyclomine, Int. J. Neurosci. (2020)
level following an induced injury to sciatic nerve in mouse model, Pak. J. Pharm. 1–14, https://doi.org/10.1080/00207454.2020.1815732.
Sci. 32 (2019) 785–792. [42] D.G.T. Parambi, U. Saleem, M.A. Shah, F. Anwar, B. Ahmad, A. Manzar, A. Itzaz,
[16] D.O. Kennedy, E.L. Wightman, Herbal extracts and phytochemicals: plant S. Harilal, M.S. Uddin, H. Kim, et al., Exploring the therapeutic potentials of highly
secondary metabolites and the enhancement of human brain function, Adv. Nutr. 2 selective oxygenated chalcone based MAO-B inhibitors in a haloperidol-induced
(2011) 32–50, https://doi.org/10.3945/an.110.000117. murine model of Parkinson’s disease, Neurochem. Res. 45 (2020) 2786–2799,
[17] S. Painuli, P. Semwal, N. Cruz-Martins, R.K. Bachheti, Medicinal plants of https://doi.org/10.1007/s11064-020-03130-y.
Himalayan forests. Non-Timber Forest Products, Springer, 2021, pp. 175–212. [43] C. Rajaram, K.R. Reddy, K.B.C. Sekhar, Neuroprotective activity of Tephrosia
[18] P. Semwal, S. Painuli, H. Badoni, R.K. Bacheti, Screening of phytoconstituents and purpurea against haloperidol induced Parkinson disease model, Pharmacologia 6
antibacterial activity of leaves and bark of Quercus leucotrichophora A. Camus (4) (2015) 125–130.
from Uttarakhand Himalaya, Clin. Phytoscience 4 (2018) 1–6. [44] E. Brglez Mojzer, M. Knez Hrnčič, M. Škerget, Ž. Knez, U. Bren, Polyphenols:
[19] G. Hussain, J. Huang, A. Rasul, H. Anwar, A. Imran, J. Maqbool, A. Razzaq, N. Aziz, extraction methods, antioxidative action, bioavailability and anticarcinogenic
E.U.H. Makhdoom, M. Konuk, et al., Putative roles of plant-derived tannins in effects, Molecules 21 (2016), https://doi.org/10.3390/molecules21070901.
neurodegenerative and neuropsychiatry disorders: an updated review, Molecules [45] G. Cohen, R.E. Heikkila, The generation of hydrogen peroxide, superoxide radical,
24 (2019), https://doi.org/10.3390/molecules24122213. and hydroxyl radical by 6-hydroxydopamine, dialuric acid, and related cytotoxic
[20] G. Sathishkumar, G. Kasi, K. Zhang, E.-T. Kang, L. Xu, Y. Yu, Recent progress in TA- agents, J. Biol. Chem. 249 (1974) 2447–2452.
driven antimicrobial/antifouling surface coating strategies, J. Mater. Chem. B [46] D.G. Graham, S.M. Tiffany, W.R. Bell Jr., W.F Gutknecht, Autoxidation versus
(2022). covalent binding of quinones as the mechanism of toxicity of dopamine, 6-
[21] L. Alechinsky, F. Favreau, P. Cechova, S. Inal, P.A. Faye, C. Ory, R. Thuillier, hydroxydopamine, and related compounds toward C1300 neuroblastoma cells in
B. Barrou, P. Trouillas, J. Guillard, et al., TA improves renal function recovery after vitro, Mol. Pharmacol. 14 (1978) 644–653.
renal warm ischemia-reperfusion in a rat model, Biomolecules 10 (2020), https:// [47] Y. Glinka, M. Gassen, M.B. Youdim, Mechanism of 6-hydroxydopamine
doi.org/10.3390/biom10030439. neurotoxicity, J. Neural Transm. Suppl. 50 (1997) 55–66, https://doi.org/
[22] N. Braidy, B.E. Jugder, A. Poljak, T. Jayasena, S.M. Nabavi, P. Sachdev, R. Grant, 10.1007/978-3-7091-6842-4_7.
Molecular targets of TA in Alzheimer’s disease, Curr. Alzheimer Res. 14 (2017) [48] Y.Y. Glinka, M.B. Youdim, Inhibition of mitochondrial complexes I and IV by 6-
861–869, https://doi.org/10.2174/1567205014666170206163158. hydroxydopamine, Eur. J. Pharmacol. 292 (1995) 329–332, https://doi.org/
[23] K.T. Chung, T.Y. Wong, C.I. Wei, Y.W. Huang, Y. Lin, Tannins and human health: a 10.1016/0926-6917(95)90040-3.
review, Crit. Rev. Food Sci. Nutr. 38 (1998) 421–464, https://doi.org/10.1080/ [49] P. Jenner, C.W. Olanow, Understanding cell death in Parkinson’s disease, Ann.
10408699891274273. Neurol. 44 (1998) S72–S84, https://doi.org/10.1002/ana.410440712.
[24] Z. Guo, W. Xie, J. Lu, X. Guo, J. Xu, W. Xu, Y. Chi, N. Takuya, H. Wu, L. Zhao, TA- [50] S. Panwar, M. Thapliyal, A. Pande, A. Thapliyal, Molecular docking of phyto-
based metal phenolic networks for bio-applications: a review, J. Mater. Chem. B 9 compounds against VP1 and VP2 proteins of IPNV (Infectious Pancreatic Necrosis
(2021) 4098–4110, https://doi.org/10.1039/d1tb00383f. Virus) for deriving possible therapeutic agents, in: Materials Today: Proceedings,
[25] X. Liang, K. Cao, W. Li, X. Li, D.J. McClements, K. Hu, TA-fortified zein-pectin 2022, https://doi.org/10.1016/j.matpr.2022.09.445.
nanoparticles: stability, properties, antioxidant activity, and in vitro digestion, [51] H. Badoni, P. Sharma, S.M. Waheed, S. Singh, Phytochemical analyses and
Food Res. Int. 145 (2021), 110425, https://doi.org/10.1016/j. evaluation of antioxidant, antibacterial and toxic properties of Emblica officinalis
foodres.2021.110425. and Terminalia bellirica fruit extracts, Asian J. Pharm. Clin. Res. 9 (6) (2016)
[26] A.Y. R, R. Kamel, A.E. N, P. Shao, A.F M, Recent advances in TA (Gallotannin) 96–102.
anticancer activities and drug delivery systems for efficacy improvement; a [52] Badoni H., Singh N., Sharma P., Pal M.K., & Kahera R. Neuroinflammation:
comprehensive review, Molecules 26 (2021), https://doi.org/10.3390/ network of brain cells, cytokines and their action. Interdisciplinary Research in the
molecules26051486. Current Era, 67. (Book Chapter).
[27] J. Yeo, J. Lee, S. Yoon, W.J. Kim, TA-based nanogel as an efficient anti- [53] Badoni H., Singh S., Sharma P. & Waheed S.M. (2016). In silico investigation of
inflammatory agent, Biomater. Sci. 8 (2020) 1148–1159, https://doi.org/10.1039/ phytoconstituents from various plants against neuroinflammatory markers as
c9bm01384a. potent therapeutic targets. Vol 8, Issue 3.
[28] M. Kumari, S. Jain, Screening of potential sources of tannin and its therapeutic [54] H. Badoni, P. Sharma, M.K. Pal, K. Pant, Sharma N Bhawna, N. Singh, S.
application, Int. J. Nutr. Food Sci. 4 (2015) 26–29. M. Waheed, B Agarwal, Anti-Parkinson’s activity of Emblica officinalis and
Terminalia bellirica, J. Crit. Rev. 7 (2020) 17.

10