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. 2024 Mar 4;13(2):tfae032. doi: 10.1093/toxres/tfae032

Tannic acid ameliorates the hazards effect of beryllium induced neuro-alterations and oxidative stress in adult male rats

Mohamed M Rezk 1,✉
PMCID: PMC10917228  PMID: 38455638

Abstract

Background

Tannic acid (TA) is one of the most consumed and famous polyphenols with a widespread attention in the medical field according to its unique structural, pharmaceutical, physicochemical, antioxidant and other biological features. A rare study was conducted on the hazard effect of beryllium (Be) on the central nervous system.

Aims

This study aims to show the ability of beryllium to cross the blood brain barrier. Demonstrate the effect of beryllium and tannic acid separately or with each other on brain ions (Na+, K+, Ca++) and on norepinephrine, dopamine, serotonin, finally on the glutathione and malondialdehyde.

Animals grouping

Seventy-two rats were divided into four groups as control, Be, TA, and Be+TA where Be was injected intraperitoneally as 1 mg/Kg b. wt, TA was orally administrated as 5% in aquas solution.

Results

The administration of beryllium showed its ability to cross the blood brain barrier and accumulated in cortex > cerebellum>hypothalamus also, a significant increase in Na+, Ca++ cooperated with a significant decrease in K+ ions content was observed. Norepinephrine, dopamine, and serotonin showed a general significant decrease in their content joined with a significant decrease in glutathione (GSH) and elevation in malondialdehydes (MDA) because of Be intoxication. On the other hands the daily oral administration of tannic acid showed a general significant decrease in Na+, Ca++ ions content parallel with a significant increase K+ also, a non-significant change in the three measured neurotransmitters was noticed.

Conclusion

Tannic acid showed a mitigation effect against Be intoxication which may regarded to the tannic acid antioxidant, chelating effect.

Keywords: tannic acid, beryllium, neurotransmitters, GSH, MDA, rat

Introduction

Tannic acid (TA) is one of the phenolic acid groups and considered as a natural tannin which is composed of glucose unit trapped by ten gallic acid molecules.1 Plants which are reach with polyphenol derivatives is considered as a reservoir for tannic acid as herbs, fruits, cereals and specially tea and red win and characterized by a colorless to solid pale yellow with an astringent taste.2 Tannic acids as a natural compound are one of the most abundant natural compounds as hemicellulose, cellulose and lignin which used as a row material as a tanning agent in coating, leather, adhesive, surgery, food industry and pharmacological applications.3

The unique chemical property of tannic acid comes from its polyphenols composition which is characterized by pyrogallol aromatic ring structures with catechol. One of the TA chemical properties is the good water solubility which reaching 300 gL−1 giving it the suitability for chemical modification in a green way, easy to store in the air for 30 days.4,5 Under certain conditions, TA is a hydrolysable and biodegradable moreover, it is cheap in price, widely available, biocompatible, and environmentally harmless.6

Many studies showed that tannic acid has some potent pharmacological effect as anti-inflammatory,7 anticarcinogenic,8 possesses-lipogenic9 antioxidant and scavenging activity.10 With a high hemostatic efficiency and instant coagulation, tannic acid could conjugate with various proteins in blood.11 Furthermore, Tannic acid has some clinical uses and applications as anti-viral, anti-inflammation agent, anti-bacterial, antioxidant.12 Moreover, it is considered as a precise therapy for many therapeutic applications as burn wounds, bone regeneration, skin adhesive for coagulation, skin adhesive for UV resistance, wound healing, and drug loading.13–15

There is a strong research trend for the use of natural products or materials in reducing or treating the harmful effects which result from the exposure to hazard elements.16,17 used the root extraction of Saussurea lappa to ameliorate the studied thorium hazards effect.18 showed the impact of alginate treatment on single/successive thorium neuro-comparative study and the physiological parameters of the Adult male albino rats.19 Cardamom extraction showed a promising amelioration effect on the uranium hazards on rodents.20–22

Beryllium (Be) is a chemical element with atomic number 4.23 Many characterizations of beryllium making it as an important strategically metal according to its extremely lightweight, high heat adsorption capacity, high melting point, nonmagnetic and corrosion resistant and has the lowest thermal neutron adsorption cross-section of any metal. Thermal neutron adsorption cross-section of any metal.24,25 Beryllium is used in many industries such as aerospace, defense, nuclear reactors, and electronics.

Beryllium is a toxic metal that can cause serious health effects when inhaled or ingested.26,27 The exposure to beryllium by inhalation of dust containing Be or ingestion or drinking Be contaminant food or water can cause health effects.28 Chronic Beryllium Disease (CBD), sometimes called berylliosis, is a chronic granulomatous lung disease caused by an immunological response from exposure to beryllium.26 CBD, if not treated and the exposure to beryllium is continued, can progress to a life-threatening disease which can lead to death. Inhaling airborne beryllium can cause a lung disease called chronic beryllium disease (CBD). Occupational exposure to beryllium has also been linked to lung cancer. Many studies showed the hazards effect of beryllium on the many liver functions with an exceedingly rare study on its effect on brain function.29

So, the aim of the present study is to show the ability of beryllium to cross the blood brain barrier, distribution, and accumulation on three different brain areas “cerebral cortex, cerebellum, and hippocampus”. Also, A neuro-study of beryllium and tannic acid separately or together on some brain ions content (Na+, K+ and Ca++) moreover, their effect on norepinephrine, dopamine, and serotonin. Study the oxidative stress of beryllium and antioxidant effect of tannic acid. Finally, express the antioxidant, chelation and antioxidant effect of tannic acid that ameliorate the Be hazards.

Material and methods

Chemicals

Beryllium standard was purchased from Sigma, Germany where tannic acid was Merck, USA. The study was conducted in conformity with the animal ethics committee of the National Research Center in Egypt.

Animals grouping

Rattus rattus rats (72 rat) purchased from the Holding Company for Biological Products and Vaccines, “VACSERA”, Helwan, Cairo, Egypt. The animals weighing about 110 ± 20gm were housed in a plastic cage, seven rats for each cage, and let for 1 week for acclimation at temperature approximately 22 °C with a 12 h light/dark cycle. Food and water were given ad libidum. Animals were grouped into four groups. Animals which are injected intraperitoneally with saline are considered as control group. Where intraperitoneal injected with Be 1 mg/Kg was the Be group, the dose of beryllium was selected according to the Be LD50 value of beryllium nitrate is 3.16 mg/kg.30,31

Tannic acid (TA) group is the group with animals which orally gavage with tannic acid (5%) finally, the Be+TA group, where the animals were intraperitoneal injected with Be and drinking TA.

The decapitation for rats was done after the 1st, 7th, and 14th day; six animals in each time. According to Glowinski and Iversen32 the brain of each rat was dissected and divided into two halves; cerebral cortex, cerebellum and hippocampus were separated. Then each area was weighed and stored at −30 °C till used.

The brain areas were chosen according to their functions where the cerebral cortex is responsible for motor function, sensory, and has a key role in memory, attention, and consciousness. The cerebellum plays a significant role in learning, memory, and sequences motor activities. Hippocampus which plays an important role in the consolidation of the information from short-term memory to long-term memory and spatial navigation.33

Determination of ions content in the different brain areas

Brain areas digestion

Each brain area of the 1st half was weighted and placed in a glass beaker with 7 mL of 90% nitric acid, 7 mL hydrogen peroxide and 2 mL 70% perchloric acid. At 130 C°, then heated the beakers with their contents till complete dryness, then added diluted 1:1 hydrochloric acid followed by boiling then let for cooling to diluted into 25 mL volumetric flask using de-ionized water.34,35

Beryllium (be) estimation

In a 25.0 mL measuring flask, 1 mL of sample was added to 0.2 mL of 5% EDTA, 5.0 mL of buffer solution (sodium acetate trihydrate—glacial acetic acid, pH 4.6) and 2.0 mL of 0.05% (w/v) of Chrome Azurol S dye (CAS), then all these contents was diluted up to the volume with double distilled water. Subsequently, the absorbance of the solution was measured at 568 nm against its blank solution that prepared in the same manner.36

Sodium (Na+), potassium (K+), and calcium (Ca++) determination

From 100 ppm pure stock solution of each element, a series of chemical standards were prepared for Na+, K+ and Ca++ ranging from 0.5 ppm to 40 ppm for estimate each element concentration in related to its specific chemical standard curve using Flame photometry instrument model PFP7/C according to Marczenko37 with accuracy better than ±2.2%.

Determination of brain reduced glutathione (GSH) and malondialdehyde (MDA) levels

Each brain area of the second half was separately homogenized in ice cold isotonic potassium chloride (1.2%), then centrifuged for 10 min at 3,000 r.p.m. Then, the clear supernatant was separated for the determination of both GSH and MDA where GSH was determined according to Ellman38 by shaking a mixture of 0.5 mL of trichloro acetic acid to 0.5 mL clear supernatant for 10–15 min. Then centrifugation at 2,000 rpm for 5 min. Accurately, in a separate test tubes, 0.2 mL of the resulted clear was mixed to 1.7 mL of the phosphate buffer and 0.1 mL of the Elman’s reagent (250 mL volumetric flask, 12.4 mg 5,5-dithiobis-2-nitrobenzoic acid (DTNB) was dissolved into 50 mL 0.1 M phosphate buffer at pH 7.6, 120 mL 96% ethanol and 80 mL distilled water) was added to each tube. After standing for 5 min, the density was measured at 412 nm against a reagent blank. Where the MDA level was determined depending on the way of Ohkawa et al.39 Briefly, preparation of stock solution by dissolving of 15% (W/V) trichloroacetic acid and 0.375% (W/V) Thio barbituric acid and 0.25 mol/L hydrochloric acid in 50 mL distilled water. Then, by adding 0.5 mL of the homogenized supernatant with 1 mL of the stock solution then heated for 30 min in a boiling water bath, after cooling, the mixture was centrifugation in 2,000 r.p.m. for 15 min, and then measuring the absorbance of the clear supernatant against blank at 535 nm.

Determination of brain monoamines concentrations by HPLC methods

Norepinephrine (NE), dopamine (DA), and serotonin (5-HT) in the 2nd portion of brain areas were measured by HPLC system; on an Agilent HP1100 series HPLC (USA) apparatus the samples were analyzed. Briefly, in (10% w/v) methanol, the samples were homogenized followed by centrifugation for 10 min. at 4,000 r.p.m. The supernatant was injected into an AQUA column 150 mm 5 μ C18, with mobile phase 20 mM potassium phosphate, pH 2.5, flow rate 1.5 mL/min, UV 190 nm. NE, DA, and 5-HT as μg per gram brain tissue were detected after 12 min in comparing to that of the standard obtained from Sigma-Aldrich and calculated according to the method of Pagel and Lutzoni.40

Statistical analysis

According to Tukey’s test and by using the one-way analysis of variance (ANOVA), the statistical analysis of data was conducted. The Statistical Package for the Social Science (SPSS) version 20. The data were expressed as mean ± SEM.

Results

The continuous administration of beryllium by intraperitoneal injection showed that beryllium has the capacity to penetrate the blood brain barrier and distribute in the three studied brain areas cerebellum, cerebral cortex and hippocampus’ and accumulate in them reaching its maximum concentration after the 14th day of Be administration with about 120 parts per billion (ppp) in the cerebral cortex. On the other hands, the chelation activity of tannic acid against beryllium was appeared as a significant decrease in Be ions contents in the three studied areas with a percent change as 25, 38.2 and 46.7% for cortex, hippocampus, and cerebellum respectively (Fig. 1).

Fig. 1.

Fig. 1

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Effect of oral administration of tannic acid (5%.) on beryllium ions content (ppp/kg tissue) in rats treated with beryllium chlorides (1 mg/kg b. wt) in cerebral cortex, cerebellum, and hippocampus at the end of the experiment. (data represented as mean ± SEM, n = 6, significant b with respect to Be group).

Beryllium daily administration showed a significant increase in sodium and calcium ions content of hippocampus brain area reached its maximum effect after fourteen days of administration (Table 1). Meanwhile, the beryllium effect on potassium ions content showed a significant decrease as compared to its corresponding control value. On the other hand, the daily administration of tannic acid showed a non-significant effect on the first day of administration of the hippocampus sodium ions content followed by a significant a significant decrease on the 7th and 14th day of tannic administration. Potassium ions content showed a significant increase after the 7th and 14th day of experiment because of tannic acid treatment. A non-significant change was observed on Ca++ ions after the tannic acid administration on the 1st and 7th day of administration as compared to control. The group of beryllium treatment in parallel with the tannic administration (Be+TA) showed a meaningful change effect in Na+, K+ and Ca++ ions content as compared it their corresponding value in the control group. In comparing the effect of administration between Be+TA group and Be group, Na ions content showed a significant decrease on the 14th day of Be+TA administration where in calcium ions content, the increment was observed significantly from the first day tell the end of the experiment.

Table 1.

Effect of oral administration of tannic acid (5%) on sodium, potassium, and calcium ions content (μg/g) in rats treated with beryllium chloride (1 mg/kg b. wt) in hippocampus brain area in different time intervals.

Hippocampus Control Be TA Be+TA
1st Day 546.32 ± 6.32 623.51 ± 12.07a 531.48 ± 10.29 614.31 ± 10.07a
Na+ ions content 7th Day 561.32 ± 4.53 664.97 ± 11.63a 511.92 ± 14.19a 655.77 ± 9.63a
14th Day 559.32 ± 10.53 713.08 ± 3.78a 478.85 ± 12.12a 611.21 ± 9.13ab
1st Day 480.55 ± 14.83 430.89 ± 9.63a 490.49 ± 12.77 450.89 ± 9.63a
K+ ions content 7th Day 499.27 ± 22.02 312.84 ± 7.89a 530.44 ± 6.34a 320.84 ± 7.89a
14th Day 470.00 ± 21.49 264.41 ± 6.77a 499.47 ± 6.29a 350.64 ± 13.17a
1st Day 17.46 ± 0.92 26.56 ± 0.65a 16.28 ± 0.26 24.56 ± 0.65ab
Ca++ ions content 7th Day 17.32 ± 0.28 38.14 ± 0.74a 16.06 ± 0.31 30.15 ± 0.99ab
14th Day 17.64 ± 0.33 44.82 ± 1.09a 15.42 ± 0.36a 33.22 ± 1.06ab
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Data represented as mean ± SEM, n = 6, significant awith respect to control group, bwith respect to Be group.

In cerebral cortex (Table 2), the administration of beryllium caused a significant increase in Na+ and Ca++ ions content accompanied by a significant decrease in the K+ ions content throughout the experiment period in related to control value. The first day of tannic acid administration showed a non-significant change in both Na+ and K+ ions content where Ca++ ions content showed a significant increase after the 1st, 7th, and 14th day of treatment in comparing to control group. In comparing to control group, sodium ions content in Be+TA group showed a significant increase allover the experimental period where, a significant decrease in K+ ions content was observed on the 1st and 14th day of treatment and the only significant increase in Ca++ ions content was observed on the 7th day of the experiment. A momentous change was observed in the cortical three ions content of Be+TA group as compared to their corresponding values in Be group.

Table 2.

Effect of oral administration of tannic acid (5%) on sodium, potassium, and calcium ions content (μg/g) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebral cortex brain area in different time intervals.

Cortex Control Be TA Be+TA
1st Day 110.38 ± 14.22 156.65 ± 6.64a 107.15 ± 2.76 140.42 ± 5.32ab
Na+ ions content 7th Day 111.77 ± 14.87 164.44 ± 8.32a 99.55 ± 4.91a 144.33 ± 6.15ab
14th Day 108.88 ± 16.36 187.25 ± 5.55a 96.66 ± 2.83a 165.48 ± 4.66ab
1st Day 162.99 ± 2.05 143.47 ± 5.05a 164.21 ± 9.83 153.55 ± 7.06ab
K+ ions content 7th Day 168.74 ± 9.58 126.97 ± 6.67a 160.33 ± 5.21a 161.21 ± 6.25b
14th Day 165.25 ± 5.69 115.88 ± 7.62a 156.55 ± 7.25a 135.78 ± 3.17ab
1st Day 6.47 ± 0.12 7.76 ± 0.11a 5.41 ± 0.13a 6.52 ± 0.11b
Ca++ ions content 7th Day 6.58 ± 0.09 8.24 ± 0.06a 5.11 ± 0.08a 7.21 ± 0.08ab
14th Day 6.99 ± 0.5 8.61 ± 0.16a 5.82 ± 0.08a 7.09 ± 0.07b
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Data represented as mean ± SEM, n = 6, significant awith respect to control group, bwith respect to Be group.

In Be group, the cerebellum Na+ ions content showed a non-significant change after one day of Be administration then, a significant increase was noticed after the 7th and 14th day as compared to control. in an opposite direction, K+ ions showed a significant decrease in its content allover the experiment. Where, Ca++ ions content was increased significantly throughout the treatment period versus control. In TA group, a general non-significant change was observed allover the treatment except on the 7th day of Na+ ions and for K+ and Ca++ at the 14th day as compared to control.

In Be+TA group, as compared to control, a significant increase in Na++ ions were noticed on the 7th an 14th day, a significant decrease in K+ ions content was observed on the 1st, 7th, and 14th day, finally, a significant increase in Ca++ ions content was determined allover the experimental period. In Comparing Be+TA group with Be group, a mitigation effect was observed because of TA treatment in Na+, K+, and Ca++ ions content (Table 3).

Table 3.

Effect of oral administration of tannic acid (5%) on sodium, potassium, and calcium ions content (μg/g) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebellum brain area in different time intervals.

Cerebellum Control Be TA Be+TA
1st Day 893.50 ± 12.64 945.61 ± 16.72 890.54 ± 11.35 909.32 ± 9.54b
Na+ ions content 7th Day 899.55 ± 11.53 928.83 ± 13.67a 883.44 ± 10.32a 915.96 ± 10.32a
14th Day 890.34 ± 10.58 1140.55 ± 19.66a 880.21 ± 9.32 1095.68 ± 15.21ab
1st Day 505.08 ± 23.44 409.77 ± 15.99a 518.50 ± 7.84 455.32 ± 5.36ab
K+ ions content 7th Day 500.56 ± 13.39 386.21 ± 0.98a 523.77 ± 9.31 401.33 ± 4.22ab
14th Day 496.56 ± 11.21 359.56 ± 0.96a 5.31.22 ± 8.21a 403.21 ± 5.36ab
1st Day 41.06 ± 0.93 56.84 ± 0.21a 39.84 ± 0.24 43.55 ± 0.26b
Ca++ ions content 7th Day 41.14 ± 1.02 63.49 ± 0.31a 39.11 ± 0.12 46.32 ± 0.36ab
14th Day 42.56 ± 0.95 70.23 ± 0.51a 38.21 ± 0.11a 50.34 ± 0.56ab
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Data represented as mean ± SEM, n = 6, significant awith respect to control group, bwith respect to Be group.

In the different brain areas (Fig. 2), despite being non-significant on the 1st and 7th days of TA administration, norepinephrine level showed a significant increase on the 14th days of TA treatment as compared to control. On the other hand, the norepinephrine content showed a general significant decrease because of the treatment with Be alone or with TA after one, seven and fourteen days of administration as compared to control. In comparing Be+TA with Be, a general significant depletion in norepinephrine level was detected allover experimental time in the three studied brain areas.

Fig. 2.

Fig. 2

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Effect of oral administration of tannic acid (5%) on norepinephrine level (μg/g) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebral cortex, cerebellum and hippocampus in different time intervals. (data represented as mean ± SEM, n = 6, significant a with respect to control group, b with respect to Be group).

Compared to the control results, the daily intraperitoneal administration of tannic acid throughout the experiment showed a non-significant change in the dopamine cerebellum and hippocampus areas while, in the cortex area, it showed a significant increase allover the treatment period as compared to control (Fig. 3). As the administration of Be progresses, the decline action on dopamine content increases appearing from the first day of administration tell the end of the experiment. Also, the daily administration of Be+TA showed a significant decrease in dopamine content all over the experimental period in the studied brain areas versus control. While in comparing to Be group, dopamine showed a significant increase throughout the 14 days of the experiment.

Fig. 3.

Fig. 3

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Effect of oral administration of tannic acid (5%) on dopamine level (μg/g) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebral cortex, cerebellum and hippocampus in different time intervals. (data represented as mean ± SEM, n = 6, significant a with respect to control group, b with respect to Be group).

After one, seven and fourteen days of the Be daily IP routine in the studied brain areas, a decreasing in the serotonin content was significantly noticed, this notification was also seen in the daily Be+TA treatment routine but with a lowest action as comparing each value with its corresponding one in the control group (Fig. 4). In the opposite direction, serotonin showed a significant increase in its content after TA treatment all over the experimental period. A significant increase was noticed in the serotonin content after the 1st, 7th and 14th day in comparing Be+TA with Be group.

Fig. 4.

Fig. 4

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Effect of oral administration of tannic acid (5%) on serotonin level (μg/g) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebral cortex, cerebellum and hippocampus in different time intervals. (data represented as mean ± SEM, n = 6, significant a with respect to control group, b with respect to Be group).

A significant decrease in malondialdehyde level was observed after 14 days of tannic acid administration in the three studied brain areas. On the opposite direction, the administration of beryllium showed a significant increase in MDA throughout the treatment period as compared to control. As the tannic acid was administrated at the same time if beryllium administration, MDA level showed a significantly increase in its level after the 1st, 7th, and 14th day of treatment in cortex, cerebellum and hippocampus brain areas as compared to control where in comparing to Be group, cortical MDA level showed a non-significant change after one day of treatment (Fig. 5).

Fig. 5.

Fig. 5

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Effect of oral administration of tannic acid (5%) on malondialdehyde level (mmol/mg protein) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebral cortex, cerebellum, and hippocampus in different time intervals. (data represented as mean ± SEM, n = 6, significant a with respect to control group, b with respect to Be group).

Reduced glutathione level showed a significant increase as the treatment of tannic acid increase as compared to control (Fig. 6). On the other hands, the daily administration of beryllium alone or along with tannic acid showed a significant decrease in GSH level after one, seven and fourteen days of treatment in cortex, cerebellum, and hippocampus brain areas in corresponding to control value. In comparing Be+TA group with Be group, a significant increase in GSH level was noticed allover the experimental period.

Fig. 6.

Fig. 6

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Effect of oral administration of tannic acid (5%) on glutathione level (mmol/mg protein) in rats treated with beryllium chloride (1 mg/kg b. wt) in cerebral cortex, cerebellum, and hippocampus in different time intervals. (data is represented as mean ± SEM, n = 6, significant a with respect to control group, b with respect to Be group).

Discussion

In the present study, the daily intraperitonially administration of beryllium showed the ability of beryllium ions to access the brain and accumulate in the studied brain areas as cerebral cortex> cerebellum> hippocampus. This result comes in agreement with other studies which showed that beryllium could hardly access the rodent brain and accumulated in its area.41–43

The brain is surrounded by the blood brain barrier which is considered as the door that regulates the entrance of any molecules to the central nervous system based on the size, hydrophobicity, and charge of the molecules.44 Any disturbance could happen to the BBB, various harmful, immunological, ionic, and chemical factors may gain access to the CNS which may induce a cascade of biochemical, electrophysiological, and inflammatory responses that may lead to neurological disorders.45

The entrance of Be to the brain by crossing the BBB may increase the brain fluidity and the inflammatory response also, it could bind with many proteins and in doing so alerts their function without inhibiting their synthesis.46 Suman and Bhadauria47 showed that beside the reactive oxygen species production because of beryllium intoxication, the beryllium could attach to the active sited of various enzymes in the brain leading to its disturbance that led to neuronal death. A significant increase in brain lactate dehydrogenase was resulted after Be treatment which means an increase in brain tissue destruction.48 Beryllium is known that it could alert Adenosine tri-phosphatase (ATPase) which is responsible for the membrane transportation.49 In the present study, a significant elevation in Na + Ca++ ions content was observed with a depletion in K+ ions content because of Be intoxication which may regarded to the Na+/K+ ATPase function alteration, increase of brain tissue destruction or neuronal death.

Beryllium toxicity participates in inhibiting or alerting protein phosphorylation reactions.50–52 It is Known the phosphorylation process of protein is done by adding a phosphate group to an amino acid by the action of protein kinase where, protein phosphatases are enzymes that reverse the process by removing the phosphate group from the phosphorylated protein.53 Protein kinases and phosphatase worked together to control the signaling pathway, neurotransmitter biosynthesis, neurotransmitter release, postsynaptic potentials, ion channel conductance beside that, the brain contains multiple types of calcium-dependent protein kinases.54 Price and Joshi55 showed that beryllium could be combined to ferritin in a significant great amount.it is known that, ferritin is considered as the storage or reservoir of body iron (Fe) in the body which has a major role in the neurotransmitter’s synthesis, uptake, and degradation56 also, Fe considered as a major cofactor for many enzymes which are essential for many monoamines neurotransmitters synthesis.57

In the present study the daily administration of beryllium showed an elevation in the level of calcium ions content which may be regarded to the beryllium alteration effect in the calcium-dependent protein kinases which may lead to increment in the calcium level which have a leading role in the neurotransmitter release. Also, there are a depletion in the studied neurotransmitters (NE, DA, 5HT) in the different brain areas of the present study may be due to the increment in Ca level, alteration in protein phosphorylation process and the depletion in the level of Fe which all in turn affect the neurotransmitters synthesis, uptake, and degradation.

In the present results, MDA level significantly increased because of Be intoxication, i.e. beryllium could induce an oxidative stress, this may regard to the elevation in hydrogen peroxide and superoxide free radicals’ production.58 It is a fact that as the production of ROS increases the level of GSH decreases which leads to damage in the cell membrane of many vital organs,59 also, ROS increase the lipids peroxidation of cell membrane leading to a plethora of alterations in the function and structure of cellular membranes.48 Beryllium induced oxidative stress and combined decreased the level of GSH and initiated the mRNA expression of antioxidant genes.42 So, the observed demonstration in the present study showed that there is a resulting failure in the antioxidant defense mechanisms resulting from beryllium injection.

Previous studies indicated the tannic acid antioxidant and neuroprotective capacity according to the polyphenol composition of TA.60–62 Tannic acid is known to activate some enzymes and ion channels in the brain and other tissue.63–65 In the present study, the administration of tannic acid at the same time of beryllium intraperitoneal injection showed a significant decrease in Na + and Ca++ with an increase in K+ ion contents as compared to Be group which is considered as an amelioration effect on Be hazards effect. These results come in agreement with Luduvico, Spohr65 which showed that tannic acid could reduce the impairment in Na+/K+ ATPase and Ca++ATPase activity in the mouse brain with a major depression disorder. This enzymes remediation showed a regulation effect in sodium, potassium and calcium ions content which is important in different neuronal function.

It is known that acid-sensing ion channels (ASICs) are found in the nervous system which have a role in the movement of sodium and calcium in and outside the cells and involved in various functions such as pain, taste, learning and memory.54 Hawashin et al.64 showed that tannic acid could modulate the activity of ASICs by alerting the properties of the plasma membrane and reduced neural cell death.66

Mono amines oxidase (MAO) is an enzyme which involved in the synthesis of dopamine, norepinephrine, and serotonin.67 Ashafaq et al.63 showed that tannic acid treatment could significantly protected the activity of MAO in rats treated with lead acetate. The present improvement in dopamine, norepinephrine and serotonin may be due to the ability of tannic acid to remediate enzyme, modulate the ASICs and protection of MAO activity.

Studies showed the effect of tannic acid on brain and animals’ behavior. Antidepressant effect of tannic acid is appeared in a depressive-like behavior animal model.62 Gerzson et al.61 showed that tannic acid could prevent the resulted impairment in in a model of streptozotocin-induced sporadic Alzheimer’s disease. Sehati et al.66 showed that there is an improvement in the locomotion and memory function in a chronic cerebral hypoperfusion rats model treated with tannic acid.

Ma et al.68 demonstrated that tannic acid could decrease LDH and inflammatory factor (TLR4, p38, p-p38, NF-kB (p65), p-NFkB (p-p65), caspase-3, Bax, and Bcl-2) in different organs of rodents exposed to isoproterenol or with postischemic brain.69 A reorganization is known that tannic acid could conjugate the metals ions (for instance, Fe3+) to prevent Fenton reaction which in turn stop the generation of hydroxyl radical making cell membrane safe from any damage.70 Tannic acid chemically composed of reactive hydroxyl groups with a degree of polymerization which present in its phenolic rings,71 these hydroxyl groups function as a chelator which chelate the beryllium and decrease its hazards. In another way, Tannic acid could hydrolysis to tannins and gallic acid which can cross the BBB to prevent the brain.72

Conclusion

From the present study and the previous one it could conclude that beryllium is a neurotoxic metal that can cross the blood brain barrier and accumulate in cerebral cortex, cerebellum, and hippocampus brain areas. The entrance of beryllium to brain causes a defect in brain Na+, K+ and Ca++ ion content and dopamine, norepinephrine, serotonin which may be regarded to its ability to disturb the ATPase, protein phosphorylation process and level of Fe which all in turn affect the neurotransmitters synthesis, uptake, and degradation. Additionally, A failure in the antioxidant defense mechanisms resulting from beryllium injection with an increase in oxidative stress. On the other hands, Tannic acid reduces the impairment in Na+/K+ATPase and Ca++ATPas activity and could modulated the level of sodium, potassium and, calcium ion contents in the brain. Also, tannic acid could remediate MAO enzyme and improve the dopamine, norepinephrine, and serotonin in brain which may be due in part to the ability of tannic acid to hydrolysis to tannins and gallic acid which can cross the BBB for preventing the brain also to the hydroxyl groups in tannic acid function as a chelator to beryllium ions and decrease its hazards.

Author contributions

MMR conceived and designed research, conducted experiment and analytical tools, analyzed data, wrote the manuscript, and has read and approved the manuscript.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Conflict of interest statement: The author declares that he has no known competing fiscal interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical approval

The ethics of animal use and care were followed in this study.

References

  • 1. Aelenei N, Popa MI, Novac O, Lisa G, Balaita L. Tannic acid incorporation in chitosan-based microparticles and in vitro controlled release. J Mater Sci Mater Med. 2009:20(5):1095–1102. [DOI] [PubMed] [Google Scholar]
  • 2. Thiansilakul Y, Benjakul S, Grunwald EW, Richards MP. Retardation of myoglobin and haemoglobin-mediated lipid oxidation in washed bighead carp by phenolic compounds. Food Chem. 2012:134(2):789–796. [DOI] [PubMed] [Google Scholar]
  • 3. Chen C, Yang H, Yang X, Ma Q. Tannic acid: a crosslinker leading to versatile functional polymeric networks: a review. RSC Adv. 2022:12(13):7689–7711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4. Zhu C, Chalmers E, Chen L, Wang Y, Xu BB, Li Y, Liu X. A nature-inspired, flexible substrate strategy for future wearable electronics. Small. 2019:15(35):1902440. [DOI] [PubMed] [Google Scholar]
  • 5. Moghaddam SZ, Sabury S, Sharif F. Dispersion of rGO in polymeric matrices by thermodynamically favorable self-assembly of GO at oil–water interfaces. RSC Adv. 2014:4(17):8711–8719. [Google Scholar]
  • 6. Wang Z, Zhao S, Song R, Zhang W, Zhang S, Li J. The synergy between natural polyphenol-inspired catechol moieties and plant protein-derived bio-adhesive enhances the wet bonding strength. Sci Rep. 2017:7(1):9664. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7. Chu X, Wang H, Jiang Y-m, Zhang Y-y, Bao Y-F, Zhang X, Zhang JP, Guo H, Yang F, Luan YC, et al.  Ameliorative effects of tannic acid on carbon tetrachloride-induced liver fibrosis in vivo and in vitro. J Pharmacol Sci. 2016:130(1):15–23. [DOI] [PubMed] [Google Scholar]
  • 8. Gali HU, Perchellet EM, Klish DS, Johnson JM, Perchellet JP. Hydrolyzable tannins: potent inhibitors of hydroperoxide production and tumor promotion in mouse skin treated with 12-O-tetradecanoylphorbol-13-acetate in vivo. Int J Cancer. 1992:51(3):425–432. [DOI] [PubMed] [Google Scholar]
  • 9. Hu X, Wang H, Lv X, Chu L, Liu Z, Wei X, Chen Q, Zhu L, Cui W. Cardioprotective effects of tannic acid on isoproterenol-induced myocardial injury in rats: further insight into ‘French paradox’. Phytother Res. 2015:29(9):1295–1303. [DOI] [PubMed] [Google Scholar]
  • 10. Zhang Y, Xu J, Long Z, Wang C, Wang L, Sun P, Li P, Wang T. Hydrogen (H2) inhibits isoproterenol-induced cardiac hypertrophy via antioxidative pathways. Front Pharmacol. 2016:7:392. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Kozlovskaya V, Zavgorodnya O, Chen Y, Ellis K, Tse HM, Cui W, Thompson JA, Kharlampieva E. Ultrathin polymeric coatings based on hydrogen-bonded polyphenol for protection of pancreatic islet cells. Adv Funct Mater. 2012:22(16):3389–3398. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Andrade RG  Jr, Dalvi LT, SilvaJMC  Jr, Lopes GK, Alonso A, Hermes-Lima M. The antioxidant effect of tannic acid on the in vitro copper-mediated formation of free radicals. Arch Biochem Biophys. 2005:437(1):1–9. [DOI] [PubMed] [Google Scholar]
  • 13. Fan X, Wang S, Fang Y, Li P, Zhou W, Wang Z, Chen M, Liu H. Tough polyacrylamide-tannic acid-kaolin adhesive hydrogels for quick hemostatic application. Mater Sci Eng C Mater Biol Appl. 2020:109:110649. [DOI] [PubMed] [Google Scholar]
  • 14. Zheng X, Gao Y, Ren X, Gao G. Polysaccharide-tackified composite hydrogel for skin-attached sensors. J Mater Chem C. 2021:9(9):3343–3351. [Google Scholar]
  • 15. Wang Z, Wu X, Dong J, Yang X, He F, Peng S, Li Y. Porifera-inspired cost-effective and scalable “porous hydrogel sponge” for durable and highly efficient solar-driven desalination. Chem Eng J. 2022:427:130905. [Google Scholar]
  • 16. Abdel-Rahman M, Rezk MM, Abdel Moneim AE, Ahmed-Farid OA, Essam S. Thorium exerts hazardous effects on some neurotransmitters and thyroid hormones in adult male rats. Naunyn Schmiedeberg's Arch Pharmacol. 2020:393(2):167–176. [DOI] [PubMed] [Google Scholar]
  • 17. Abdel-Rahman M, Rezk MM, Ahmed-Farid OA, Essam S, Abdel Moneim AE. Saussurea lappa root extract ameliorates the hazards effect of thorium induced oxidative stress and neuroendocrine alterations in adult male rats. Environ Sci Pollut Res. 2020:27(12):13237–13246. [DOI] [PubMed] [Google Scholar]
  • 18. Rezk MM. A neuro-comparative study between single/successive thorium dose intoxication and alginate treatment. Biol Trace Elem Res. 2018:185(2):414–423. [DOI] [PubMed] [Google Scholar]
  • 19. Rezk MM, Mohamed AA, Ammar AA. Thorium harmful impacts on the physiological parameters of the adult male albino rats and their mitigation using the alginate. Toxicol Environ Heal Sci. 2018:10(5):253–260. [Google Scholar]
  • 20. Abdel-Rahman M, Bauomi A, Abdel-Kader S, Mohammaden T, Rezk MM. Effect of cardamom (Elletaria cardamomum) on brain ions and acetylcholine esterase enzyme of albino rats ingested uranium. Int J Basic Life Sci. 2015:3(3):122–138. [Google Scholar]
  • 21. Abdel-Rahman M, Rezk MM, Kader SA. The role of cardamom on the hazardous effects of depleted uranium in cerebellum and midbrain of albino rats. Toxicol Environ Heal Sci. 2017:9(1):64–73. [Google Scholar]
  • 22. Kader SMA, Bauomi AA, Abdel-Rahman M, Mohammaden TF, Rezk MM. Antioxidant potentials of (Elletaria cardamomum) cardamom against uranium hazards. Int J Basic Life Sci. 2015:3(4):164–181. [Google Scholar]
  • 23. Islam MR, Sanderson P, Johansen MP, Payne TE, Naidu R. Environmental chemistry response of beryllium to diverse soil-solution conditions at a waste disposal site. Environ Sci: Processes Impacts. 2023:25(1):94–109. [DOI] [PubMed] [Google Scholar]
  • 24. Bodrenko I, Satta A, Caddeo C, Cozzolino G, Milenkovic S, Ceccarelli M, Mattoni A. Promising perspectives on the use of fullerenes as efficient Containers for Beryllium Atoms. Adv Funct Mater. 2023:33(42):2303786. [Google Scholar]
  • 25. Hou M-D, Zhou X-W, Liu M, Liu B. Molecular dynamics simulation of high temperature mechanical properties of nano-polycrystalline beryllium oxide and relevant experimental verification. Energies. 2023:16(13):4927. [Google Scholar]
  • 26. Kim K-W, Kim D, Won YL, Kang S-K. Effects of beryllium on human serum immunoglobulin and lymphocyte subpopulation. Toxicol Res. 2013:29(2):115–120. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27. Mudireddy SR, Abdul ARM, Gorjala P, Gary RK. Beryllium is an inhibitor of cellular GSK-3β that is 1,000-fold more potent than lithium. Biometals. 2014:27(6):1203–1216. [DOI] [PubMed] [Google Scholar]
  • 28. Hulo S, Radauceanu A, Chérot-Kornobis N, Howsam M, Vacchina V, de Broucker V, Rousset D, Grzebyk M, Dziurla M, Sobaszek A, et al.  Beryllium in exhaled breath condensate as a biomarker of occupational exposure in a primary aluminum production plant. Int J Hyg Environ Health. 2016:219(1):40–47. [DOI] [PubMed] [Google Scholar]
  • 29. Ivanenko N, Ivanenko A, Solovyev N, Zeimal AE, Navolotskii D, Drobyshev E. Biomonitoring of 20 trace elements in blood and urine of occupationally exposed workers by sector field inductively coupled plasma mass spectrometry. Talanta. 2013:116:764–769. [DOI] [PubMed] [Google Scholar]
  • 30. Mathur S, Flora SJ, Mathur R, das Gupta S. Mobilization and distribution of beryllium over the course of chelation therapy with some polyaminocarboxylic acids in the rat. Hum Exp Toxicol. 1993:12(1):19–24. [DOI] [PubMed] [Google Scholar]
  • 31. Mathur R, Asthana K, Sharma S, Prakash A. Measurement of lethal dose of some beryllium compounds. IRCS Medical Science Cell and Molecular Biology. 1985:13(2):163. [Google Scholar]
  • 32. Glowinski J, Iversen LL. Regional studies of catecholamines in the rat brain-I: the disposition of [3H] norepinephrine, [3H] dopamine and [3H] dopa in various regions of the brain. J Neurochem. 1966:13(8):655–669. [DOI] [PubMed] [Google Scholar]
  • 33. Ackerman S. Discovering the Brain. Washington (DC): National Academies Press (US); 1992. 2, Major Structures and Functions of the Brain. Available from: https://www.ncbi.nlm.nih.gov/books/NBK. [PubMed] [Google Scholar]
  • 34. Cicik B, Engin K. The effects of cadmium on levels of glucose in serum and glycogen reserves in the liver and muscle tissues of Cyprinus carpio (L., 1758). Turk J Vet Anim Sci. 2005:29(1):113–117. [Google Scholar]
  • 35. FAO . Fisheries of Africa. Report of the third session of the Working Party on Pollution and Fisheries. Accra, Ghana, 1992, 25–29. [Google Scholar]
  • 36. Fouad HK, Atrees MS, Badawy WI. Development of spectrophotometric determination of beryllium in beryl minerals using chrome Azurol S. Arab J Chem. 2016:9:S235–S239. [Google Scholar]
  • 37. Marczenko Z. Separation and spectrophotometric determination of elements; United state, 1986. Web.
  • 38. Ellman GL. Reprint of: tissue sulfhydryl groups. Arch Biochem Biophys. 2022:726:109245. [DOI] [PubMed] [Google Scholar]
  • 39. Ohkawa H, Ohishi N, Yagi K. Assay for lipid peroxides in animal tissues by thiobarbituric acid reaction. Anal Biochem. 1979:95(2):351–358. [DOI] [PubMed] [Google Scholar]
  • 40. Pagel M, Lutzoni F. Accounting for phylogenetic uncertainty in comparative studies of evolution and adaptation. In: Lässig M, Valleriani A, editors. Biological evolution and statistical physics. Berlin, Heidelberg: Springer Berlin Heidelberg; 2002. pp. 148–161 [Google Scholar]
  • 41. Drobyshev E, Kybarskaya L, Dagaev S, Solovyev N. New insight in beryllium toxicity excluding exposure to beryllium-containing dust: accumulation patterns, target organs, and elimination. Arch Toxicol. 2019:93(4):859–869. [DOI] [PubMed] [Google Scholar]
  • 42. el-Beshbishy HA, Hassan MH, Aly HA, Doghish AS, Alghaithy AA. Crocin “saffron” protects against beryllium chloride toxicity in rats through diminution of oxidative stress and enhancing gene expression of antioxidant enzymes. Ecotoxicol Environ Saf. 2012:83:47–54. [DOI] [PubMed] [Google Scholar]
  • 43. Faraci WS, Zorn S, Bakker AV, Jackson E, Pratt K. Beryllium competitively inhibits brain myo-inositol monophosphatase, but unlike lithium does not enhance agonist-induced inositol phosphate accumulation. Biochem J. 1993:291(2):369–374. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44. Bernardo-Castro S, Sousa JA, Martins E, Donato H, Nunes C, d’Almeida OC, Castelo-Branco M, Abrunhosa A, Ferreira L, Sargento-Freitas J. The evolution of blood-brain barrier permeability changes after stroke and its implications on clinical outcome: a systematic review and meta-analysis. Int J Stroke. 2023:18(7):783–794. [DOI] [PubMed] [Google Scholar]
  • 45. Coccolini F, Catena F. Textbook of emergency general surgery: traumatic and non-traumatic surgical emergencies; Cham: Springer, 2023.
  • 46. Strupp C. Beryllium metal II. A review of the available toxicity data. Ann Occup Hyg. 2011:55(1):43–56. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47. Suman KS, Bhadauria M. Beryllium induced toxic manifestations in rat brain: dose and duration dependent study. Indian J. Exp. Biol. 2019;57:610–618. [Google Scholar]
  • 48. Nirala SK, Bhadauria M, Upadhyay AK, Mathur R, Mathur A. Reversal of effects of intra peritoneally administered beryllium nitrate by tiron and CaNa 3 DTPA alone or in combination with-tocopherol. Indian J. Exp. Biol. 2009;47(12):955–963. [PubMed] [Google Scholar]
  • 49. Danko S, Yamasaki K, Daiho T, Suzuki H. Distinct natures of beryllium fluoride-bound, aluminum fluoride-bound, and magnesium fluoride-bound stable analogues of an ADP-insensitive phosphoenzyme intermediate of sarcoplasmic reticulum Ca2+-ATPase: changes in catalytic and transport sites during phosphoenzyme hydrolysis. J Biol Chem. 2004:279(15):14991–14998. [DOI] [PubMed] [Google Scholar]
  • 50. OSHA, Safety O, Administration H . Occupational safety and health standards, subpart Z—toxic and hazardous substances. Bloodborne Pathogens Title. 2003;29168–29190. [Google Scholar]
  • 51. Merian E. Metals and their compounds in the environment: occurrence, analysis, and biological relevance; 1991, pp. 779–785.
  • 52. Teixeira CF, Yasaka WJ, Silva LF, Oshiro TT, Oga S. Inhibitory effects of beryllium chloride on rat liver microsomal enzymes. Toxicology. 1990:61(3):293–301. [DOI] [PubMed] [Google Scholar]
  • 53. Hall JE, Hall ME. Guyton and Hall textbook of medical physiology e-book. United state, New York: Elsevier Health Sciences; 2020. [Google Scholar]
  • 54. Khonsary SA. Goodman and Gilman’sThe pharmacological basis of therapeutics. Surg Neurol Int. 2023:14:91. [Google Scholar]
  • 55. Price DJ, Joshi JG. Ferritin: protection of enzymatic activity against the inhibition by divalent metal ions in vitro. Toxicology. 1984:31(2):151–163. [DOI] [PubMed] [Google Scholar]
  • 56. Yoo J, Han J, Lim MH. Transition metal ions and neurotransmitters: coordination chemistry and implications for neurodegeneration. RSC Chem Biol. 2023:4(8):548–563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 57. Youdim MB, Green A. Iron deficiency and neurotransmitter synthesis and function. Proc Nutr Soc. 1978:37(2):173–179. [DOI] [PubMed] [Google Scholar]
  • 58. Sawyer RT, Dobis DR, Goldstein M, Velsor L, Maier LA, Fontenot AP, Silveira L, Newman LS, Day BJ. Beryllium-stimulated reactive oxygen species and macrophage apoptosis. Free Radic Biol Med. 2005:38(7):928–937. [DOI] [PubMed] [Google Scholar]
  • 59. Agrawal ND, Nirala SK, Shukla S, Mathur R. Co-administration of adjuvants along with Moringa oleifera attenuates beryllium-induced oxidative stress and histopathological alterations in rats. Pharm Biol. 2015:53(10):1465–1473. [DOI] [PubMed] [Google Scholar]
  • 60. Bona NP, Pedra NS, Azambuja JH, Soares MS, Spohr L, Gelsleichter NE, de M. Meine B, Sekine FG, Mendonça LT, de Oliveira FH, et al.  Tannic acid elicits selective antitumoral activity in vitro and inhibits cancer cell growth in a preclinical model of glioblastoma multiforme. Metab Brain Dis. 2020:35(2):283–293. [DOI] [PubMed] [Google Scholar]
  • 61. Gerzson MF, Bona NP, Soares MS, Teixeira FC, Rahmeier FL, Carvalho FB, da Cruz Fernandes M, Onzi G, Lenz G, Gonçales RA, et al.  Tannic acid ameliorates STZ-induced Alzheimer’s disease-like impairment of memory, neuroinflammation, neuronal death and modulates Akt expression. Neurotox Res. 2020:37(4):1009–1017. [DOI] [PubMed] [Google Scholar]
  • 62. Luduvico KP, Spohr L, Soares MSP, Teixeira FC, de  FariasAS, Bona NP, Pedra NS, de Oliveira Campello Felix A, Spanevello RM, Stefanello FM. Antidepressant effect and modulation of the redox system mediated by tannic acid on lipopolysaccharide-induced depressive and inflammatory changes in mice. Neurochem Res. 2020:45(9):2032–2043. [DOI] [PubMed] [Google Scholar]
  • 63. Ashafaq M, Tabassum H, Vishnoi S, Salman M, Raisuddin S, Parvez S. Tannic acid alleviates lead acetate-induced neurochemical perturbations in rat brain. Neurosci Lett. 2016:617:94–100. [DOI] [PubMed] [Google Scholar]
  • 64. Hawashin A, Brakmann IC, Tian Y, Gründer S, Ortega-Ramírez AM. Modulation of acid-sensing ion channels by tannic acid and Green tea via a membrane-mediated mechanism. ACS Chem Neurosci. 2023:14(14):2487–2498. [DOI] [PubMed] [Google Scholar]
  • 65. Luduvico KP, Spohr L, de  AguiarMSS, Teixeira FC, Bona NP, de  MelloJE, Spanevello RM, Stefanello FM. LPS-induced impairment of Na+/K+-ATPase activity: ameliorative effect of tannic acid in mice. Metab Brain Dis. 2022:37(6):2133–2140. [DOI] [PubMed] [Google Scholar]
  • 66. Sehati F, Ahmadi I, Farivar N, Ranjbaran M, Sadat-Shirazi M-s, Nabavizadeh F, Mahla Shavakandi S, Ashabi G. Tannic acid protects aged brain against cerebral hypoperfusion via modulation of Nrf2 and inflammatory pathways. Neurosci Lett. 2021:765:136263. [DOI] [PubMed] [Google Scholar]
  • 67. Bhattacharya P, Chatterjee S, Roy D. Impact of exercise on brain neurochemicals: a comprehensive review. Sport sciences for. Health. 2023:19(2):405–452. [Google Scholar]
  • 68. Ma D, Zheng B, du H, Han X, Zhang X, Zhang J, Gao Y, Sun S, Chu L. The mechanism underlying the protective effects of tannic acid against isoproterenol-induced myocardial fibrosis in mice. Front Pharmacol. 2020:11:716. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69. Kim SW, Kim DB, Kim HS. Neuroprotective effects of tannic acid in the postischemic brain via direct chelation of Zn2+. Anim Cells Syst. 2022:26(4):183–191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70. Basu T, Panja S, Shendge AK, Das A, Mandal N. A natural antioxidant, tannic acid mitigates iron-overload induced hepatotoxicity in Swiss albino mice through ROS regulation. Environ Toxicol. 2018:33(5):603–618. [DOI] [PubMed] [Google Scholar]
  • 71. de  MeloLFM, Aquino-Martins VGQ, da  SilvaAP, de  Oliveira RochaHA, Scortecci KC. Biological and pharmacological aspects of tannins and potential biotechnological applications. Food Chem. 2023:414:135645. [DOI] [PubMed] [Google Scholar]
  • 72. Mori T, Rezai-Zadeh K, Koyama N, Arendash GW, Yamaguchi H, Kakuda N, Horikoshi-Sakuraba Y, Tan J, Town T. Tannic acid is a natural β-secretase inhibitor that prevents cognitive impairment and mitigates Alzheimer-like pathology in transgenic mice. J Biol Chem. 2012:287(9):6912–6927. [DOI] [PMC free article] [PubMed] [Google Scholar]

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