Rezk: A comparative neuro-study of solo or accompanied low and high boric acid doses with date molasses in adult male albino rats
Abstract
Boric acid (BA) is a weak acid and the simplest compound resulting from the dissolution of boron in water. There is great competition to determine whether boron is an essential or nonessential nutrient. Date molasses is a potent type of sweetener with valuable components, such as flavonoids and phenolics, and has significant health benefits. This study investigated the neuro-essentiality and neurotoxicity of boric acid boron in adult male albino rat cortex and cerebellum brain areas and the impact of date molasses treatment. Animals were grouped into the following groups: control, low and high boric acid doses, 10 and 500 mg/kg, respectively, with or without 250 mg/kg date molasses. The results revealed the ability of BAs to cross the blood–brain barrier and accumulate in the cerebellum and cortex, revealing the ability of date molasses to decrease BA accumulation at different time intervals. Additionally, the results varied between a nonsignificant increase or decrease in calcium ion content, monoamines (norepinephrine, dopamine, and serotonin), glucose, adenosine triphosphate, malondialdehyde and glutathione, depending on the BA dose. Moreover, date molasses mitigated any unwanted BA results. In conclusion, boric acid, which is within a permissible limit, could be essential and have a neuroprotective effect, whereas at a sublethal level, it could have a neurotoxic effect. Additionally, Date molasses can have neuroprotective effects and antagonize the neurotoxic effects of boric acid through its antioxidant and scavenging effects.
Keywords: Boric acid, neurotransmitters, molasses, MDA, GSH, rat
Introduction
Boron, with an atomic number of 5, is the 51st most common earth’s crust element, with an average concentration of 8 mg/kg. Borates are the main boron-bearing compounds, as boron combines with oxygen, such as boric acid, borax, sodium tetraborate and boron oxide [ 1]. Boron compounds constitute a countable percentage in many industries, with 2 % in fire retardants and agriculture, 4 % in soaps, bleaches, and detergents and 70 % in glass and ceramics. Additionally, other uses of boron include nuclear applications such as shielding, control, improving the safety of nuclear reactors by absorbing neutron radiation and controlling the rate of the reaction during nuclear fission even to slow or stop it [ 2]; metallurgy; ingredients such as cosmetics or medical preparations; and the production of approximately one hundred eighty-nine pesticides with boric acid or its salts [ 3]. Boron is found in food and drinking water [ 4] and in small amounts in living plants and has a strong effect on cell membrane function; however, there is great competition for the identification of boron as a nonessential human nutrient [ 5] or essential nutrient for humans [ 6, 7]. Humans can also be exposed to borates or boric acid through food or water ingestion, which are considered the most common methods of exposure, by inhibiting dust or powder containing boron or during the use of medical preparations, cosmetics or even pesticides [ 8]. The reported daily boron intake rates for adult humans (male or female) are 1.28 and 1.0 mg B/day, respectively [ 9]. Weir Jr and Fisher [ 10] reported that the LD50 value of boric acid for male rats is 2.16 g/kg. Murray [ 6] reported that boric acid administration resulted in the same pharmacokinetic behavior between humans and rodents. Boric acid that is orally administered can be rapidly absorbed through the gastrointestinal tract [ 11, 12] and then distributed in body fluid, resulting in a near-born level between soft tissue and plasma, with excess levels in bone, hair, and teeth at birth [ 13]. Boric acid is composed of B‒O bonds, which are difficult for the body to break down to metabolize. The excretion or elimination of boric acid is not related to the route of administration; the boron half-life is < 24 hours for humans and rodents, which means that approximately 94–97 % of the administered boron can be excreted via urine or feces in the first 24 hours of treatment [ 14]. Acute inhalation exposure to boron results in mild eye, nose and throat irritation associated with breathlessness and cough [ 15]. Chronic boron administration results in vomiting, diarrhea, and hiccups, followed by a decrease in the hemoglobin level, depletion of splenic hematopoiesis and hemorrhage in the lungs, liver inflammation and coagulative necrosis in both mice and rats, and kidney failure in humans [ 16, 17]. Polyphenolics are found in many herbal extracts that are rich in flavonoids, which are strong reactive oxygen species (ROS) scavengers, antioxidants and neurons that protect against lethal damage [ 18]. Phoenix dactylifera L. (dates) is a unique variety of fruit grown in many countries, especially Egypt and Al-Madina Al-Munawwarah, Saudi Arabia. Date Palm (Phoenix dactylifera L.) Pits. Classification as kingdom: Plantae, division: Magnoliophyta, class: Liliopsida, order: Arecales, family: Arecaceae, genus: Phoenix, species: Phoenix dactylifera and the binomial name: Phoenix dactylifera Linn [ 19]. Date is considered a rich source of polyphenols, vitamins, proteins and minerals, such as iron, copper, zinc, calcium, potassium, cobalt, fluorine, sulphur, magnesium, manganese, phosphorus and selenium, whose most abundant bioactive compounds are polysaccharides [ 20]. This component is characterized by its impact in ameliorate the hazard of some metal toxicity as cardamum which mitigate the neuro and physiological uranium hazards [ 21- 23] also, Saussure Labba extract and alginate could ameliorate the thorium toxic effect [ 24, 25] .All these components give the date its medical properties [ 26, 27]. Its medical properties include hepatoprotective [ 28], cardioprotective [ 29], nephroprotective, antioxidant [ 30], antihyperlipidemic, anti-inflammatory [ 31], antibacterial and anticancer [ 32] properties. The present study aimed to investigate the neuro-essentiality and neurotoxicity of boric acid on the cortex and cerebellum brain areas of adult male albino rats through injection of boric acid at two different doses (low and high) for one and four weeks and to study the impact of date molasses treatment with boric acid administration.
Materials and Methods
Boric acid (H3BO3) was purchased from Sigma‒Aldrich (USA), and high-grade date palm (agwa) was purchased from the local market. All other chemicals or reagents were purchased from commercial sources and were of high analytical grade.
Boric acid was introduced in high and low dose, the high boric acid dose in the present study (500 mg/kg b.wt) was equal to nearly 1/5 or 1/10 of the literature acute lethal dose (LD50) which ranging from 2500 to almost 5000 mg/kg [ 10, 33, 34] on the other hand, the low boric acid dose (10 mg/kg b.wt) was selected according to [ 35, 36]. A high-grade dried date fruit was purchased from the market then washed with distilled water and then dried. The dried clean fruit pulverized with a small electric Blender, then the resulting powder was extracted in warm distilled water with constant shaking. The solution passed through filtrates paper and lyophilized. After vaporizing the water, solution with dose 250 mg/kg prepared and stored in the refrigerator at 2 ˚C – 8 ˚C tell used in treatment [ 37].
Animals
Male albino adult rats (100–120 g) were procured from the breeding unit of Holding Company for Biological Products and Vaccines (VACSERA, Cairo, Egypt) and held in a plastic cage (6/cage) for one week in ambient laboratory conditions with ad libitum access to food and water.
Experimental Design
Sixty rats were grouped into the following five groups: the control group, in which the rats were administered saline; the low-Boric acid (LBA) group, in which the rats were administered boric acid at a concentration of 10 mg/kg b.wt.; the high-Boric acid (HBA) group, in which the rats were administered boric acid at 500 mg/kg b.wt.; and the LBA+ molasses of date (Mo) group, in which the HBA+Mo group, in which the rats were administered Agwa (250 mg/kg.bwt) in addition to boric acid.
Tissue Sampling:
All the groups were decapitated after one or four weeks of treatment. After decapitation, the brain of each scarified head was immediately removed on filter paper to dry, and the cortex and cerebellum were separated according to the methods of [ 38]. Each of the brain areas was divided into two equal portions and then weighed to store at -80 °C for additional analysis.
First brain portion:
Digestion of brain area tissues
An acid mixture of nitric acid, hydrogen peroxide and perchloric acid at percentages of 90 %, 32 % and 70 %, respectively, was added to each brain area in a Teflon beaker and heated at 130 °C until fully dry. After cooling, 1:1 diluted HCl was added over the Teflon residual content, and the mixture was left on a hot plate until warming. Finally, the Teflon content was transferred to a volume of deionized water in a 25 ml volumetric flask.
Colorimetric determination of boric acid
In accordance with the methods of Parashar et al. [ 39] boron was determined by the formation of a reddish brown complex between boron and curcumin in the presence of an acidic mixture of sulfuric acid and glacial acetic acid, and the color intensity related to the percentage of boron at 545 nm was measured.
Calcium ion content determination
Using a Flam photometry (model PFP7) instrument, calcium ions were determined in relation to a series of calcium standards that were prepared from 0.5 to 40 ppm and according to Marczenko [ 40], with an accuracy percentage greater than ±2.2%.
Second brain portion:
Determination of the glucose level in the brain via HPLC
The determination of glucose levels was performed via HPLC with an HP1100 series HPLC apparatus (Agilent, USA). A μBondapak carbohydrate column with acetonitrile-water as the solvent system, a flow rate of 1.8 ml/min, and a refractive index detector was used [ 41].
Determination of brain monoamine concentrations via HPLC
The three monoamine contents in this study were determined via high-performance liquid chromatography (HPLC) with an HP1100 series HPLC apparatus (Agilent, USA). Twelve minutes after the injection of each sample in the AQUA column, 150 mm 5μ C18, purchased from Phenomenex, USA, was used to separate norepinephrine, dopamine, and serotonin, the monoamine content was determined as μg/g area tissue relative to its standard and calculated according to Farthing et al. [ 42].
Determination of GSH and MDA contents via HPLC
The MDA content in µ mol/g tissue was estimated in the HBLC conditions according to the methods of Karatas et al., and Gammoudi et al. [ 43, 44]. The thiol compounds of oxidized and reduced glutathione were detected by high-performance liquid chromatography (HPLC) via the method of Jayatilleke and Shaw [ 45].
Statistical analysis
The results are presented as the means ± standard errors of the means of 7 rats. These results were analyzed statistically with a probability level of 0.05 to determine the significant differences between individual treatment means. One-way analysis of variance was used with the Statistical Package for the Social Sciences (SPSS) version 20.
Results
Compared with the control, the daily oral administration of 10 mg/kg boric acid slightly increased the cortical and cerebral boron ion contents after one and four weeks, whereas the 500 mg/kg boric acid resulted in a sudden and highly significant increase in the boron ion content, which reached its maximum value at the end of the experiment. Compared with that in the control group, the boron brain area content significantly decreased in the boric acid-treated group (LBA and HBA) compared with the boric acid-treated group ( Fig. 1). Compared with the control, daily boric acid administration for one or four weeks significantly increased the calcium ion content of the cortex and cerebellum, and this significant increase was also observed in the HBA+Mo group. In the cerebellum, the calcium ion content significantly increased after four weeks of BA and/or Mo administration ( Fig. 2). The administration of boric acid at 10 mg/kg did not significantly affect NE, DA or 5HT in the cortex ( Table 1). In the cerebellum, the DA level significantly increased after 1 week of LBA treatment, whereas the 5HT level increased after 4 weeks compared with that of the control. On the other hand, boric acid at 500 mg/kg daily significantly increased the three measured monoamines in the two studied brain areas compared with the corresponding control values. Adenosine triphosphate, also known as ATP, is a molecule that carries energy within cells. It is the main energy currency of the cell, and it is the product of the processes of photophosphorylation (adding a phosphate group to a molecule using energy from light), cellular respiration, and fermentation. Compared with the control, boric acid treatment at 10 mg/kg significantly elevated the level of cortical ATP after four weeks, whereas the cerebellum ATP level increased from the first week and progressed to the end of the experimental period. On the other hand, the ATP level significantly decreased in both brain areas throughout the experimental period because of HBA treatment. Molasses treatment with BA improved the results of BA solo treatment ( Fig. 3). The glucose level did not significantly change after the administration of LBA, but the high-dose administration of boric acid increased the glucose level in the cerebellum and cortex brain areas of adult male albino rats after one and four weeks. Additionally, compared with the corresponding control, the HBA-treated date molasses significantly increased the glucose level ( Fig. 4). One week after boric acid alone, the cortical MDA content of the LBA-treated group did not significantly change, whereas the HBA content significantly increased compared with that of the control group. The cerebellum brain area showed a significant increase in the MDA level throughout boric acid administration. Compared with boric acid, molasses in combination with boric acid significantly decreased the cortical MDA level after the 1st and 4th weeks of administration, whereas in the cerebellum, the MDA level significantly increased at the end of the experiment ( Fig. 5). Despite the nonsignificant increase after four weeks, cortical GSH was significantly greater in the LBA group than in the control group in the 4th week. Cerebral GSH significantly increased throughout the period of LBA administration. HBA administration caused a significant decrease in GSH in both areas under investigation. Compared with the boric acid group, the date-treated group presented a mitigation effect on molasses ( Fig. 6).
Discussion
Boron is considered as one of the essential elements for the body, and its deprivation can alter rat brain electrical activity [ 46]. On the other hand, Sevim and Kara [ 47] demonstrated that exposure to boron at high doses has various hazardous effects on the central nervous system, such as irritability, delirium, and seizures. The exposure to boric acid in the present study revealed that boron ions can cross the brain protective barrier, which is called the blood–brain barrier (BBB), are distributed, and accumulate in the cortex and cerebellum. This observation confirmed the findings of Almeida et al. [ 48] study, which showed that boron and its compounds could cross the brain barrier and impact rodent behavior [ 49, 50]. Elsewhere, the present results showed that the administration of molasses together with boric acid could decrease the boron accumulation content in the brain area, which may be related to the ability of date molasses to chelate boron [ 51] and the high capacity of date molasses carbon to scavenge reactive oxygen species [ 52]. The present results revealed significant changes in the calcium ion contents and the measured neurotransmitters (DA, NE, and 5HT) after boric acid administration and/or at the end of the experiment for both the low- and high-dose boric acid treatments, whereas molasses mitigated the effects of the high-dose boric acid. Calcium, together with sodium and potassium ions, is considered the key for neurotransmitter release [ 53]. These results are in agreement with those of Naeger and Leibman [ 54], who reported that central nervous system toxicity could result from high-dose boron compound exposure, which may increase indolacetatdehydes and/or dopamine in the brain [ 55]. Boron is involved in many vital activities, such as glycogen and calcium metabolism, in both animals and plants [ 56]. Additionally, boron has a role in the cell membrane, especially in tight junctions, where its level affects the membrane structure intensity in the shape and thickness of the plasma membrane [ 56, 57], which in turn regulates synaptic transmission [ 58]. Fukui et al. [ 59] reported that boron-bearing compounds, when administered at high levels, can attach to the sulfhydryl group of the Na/K ATPase and Ca-ATPase enzymes, which decreases the action pump activity and consequently causes a rapid influx of Na ions accompanied by a loss of K ions. Additionally, the high level of boron could disturb neurotransmitters by increasing their synthesis due to the high affinity of boron for s-adenosyl methionine, which has a role in neurotransmitter synthesis, and oxidized nicotinamide adenine dinucleotide (NAD+), which has a role in the Krebs cycle and the liberation of ATP [ 60]. On the other hand, boric acid administration at low or essential levels has neuroprotective effects by regulating neurotransmitter synthesis, increasing ATP lipidation and controlling cell membrane ion channels [ 49]. Abedi et al. [ 61] reported that data extraction acts as a dopamine regulator during the sexual intercourse of rats in addition to its positive electrophysiological marker and antagonist of NMDA, which regulates Na/K ATPase to control neurotransmitter release [ 62]. Monosaccharides and disaccharides, which are considered the major components of date molasses, can regulate 5HT and the level of corticotropin-releasing factor in rats [ 63, 64]. These findings could explain the effects of boric acid on the effects of boric acid on the cell membrane, its ability to affect Na/K or Ca ATPase enzymes, and its affinity for s-adenosyl methionine and oxidized nicotinamide adenine dinucleotide. On the other hand. The ability of date molasses to regulate dopamine, 5HT, NMDA and Na/K ATPase.
Bakken and Hunt [ 65] showed that a rat’s dietary bone decreases the concentration of serum insulin without changing the glucose serum level to protect against insulin resistance. Additionally, boron can inhibit the 6-phoshogluconate dehydrogenase enzyme, which has a role in the glucose metabolism process [ 66]. In the present study, the glucose level significantly increased in the two studied brain areas, the “cortex and cerebellum”, after one and four weeks of high boric acid dose administration, which may be related to the decrease in and inhibition of insulin and the 6-phoshogluconate dehydrogenase enzyme 6-phoshogluconate dehydrogenase enzyme, respectively, resulting in increased glucose levels. On the other hand, in the LBA group, the glucose level was within the control range because of the ability of boric acid to stabilize the insulin level. Date molasses administration could be a strong strategy to manage noninsulin-dependent diabetes mellitus by inhibiting α-amylase and α-glucosidase, which are regarded as the key enzymes involved in carbohydrate breakdown and intestinal absorption, respectively [ 67, 68]. Özdemir et al. [ 69] demonstrated the neuroprotective effect of boric acid by observing an increase in the level of total antioxidants and a decrease in the total oxidative stress value after boric acid administration in an Alzheimer’s disease rat model. Owing to its small atomic number, boron (5) has a high affinity for reacting with oxygen and reducing the number of nucleophilic electrons as a hydroxyl group [ 70]. Boric acid seems to interact with lipids, preventing their peroxidation and protecting the tissue [ 71]. In addition to antioxidant support mechanisms and increasing GSH levels, boric acid reduces oxidative stress by decreasing lipid peroxidation and the level of MDA [ 72]. On the other hand, exposure to high doses of boric acid can induce oxidative stress in rat tissues [ 73]. Date fruit extract or molasses treatment has a strong effect on the rat brain by increasing glutathione and reducing glutathione at the brain antioxidant level, which protects the brain from oxidative stress [ 74, 75]. Date extraction has a neuroprotective effect on a cerebral ischemia rat model by markedly reducing the level of MDA and depleting chain lipid peroxidation reactions to inhibit neuronal injury [ 75]. The cerebral cortex, which is also referred to as gray matter, plays a major role in various complex cognitive processes, such as memory, reasoning, thinking, language, sensory perception, emotion, and motor control. The cerebellum, which may be called the small brain, coordinates movement, eye movement control, and motor learning and maintains balance [ 76]. Boric acid at a harmful level, either low or high, can alter memory and learning ability, whereas boric acid at an essential level has a positive effect on memory and learning [ 69, 77]. Date can improve the learning and memory behavior of rats intoxicated by lead acetate [ 78].
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Figure 1.
Effects of date molasses administration (250 mg/kg b.wt.) on boron ion (ppm) accumulation in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt.) at different time intervals. (n = 6, significant change at P < 0.05, where a represents the control, b represents the boric acid group). 
Figure 2.
Effect of date molasses administration (250 mg/kg b.wt.) on the calcium ion content (ppm) in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt.) at different time intervals. (n = 6, significant change at P< 0.05, where a- with respect to the control, b- with respect to the boric group). 
Figure 3.
Effect of date molasses (250 mg/kg b.wt.) ATP (μg/g) in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt.) at different time intervals. (n = 6, significant change at P < 0.05, where a- with respect to the control, b- with respect to the boric group). 
Figure 4.
Effect of date molasses (250 mg/kg b.wt.) on glucose levels (μg/g) in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt) at different time intervals. (n = 6, significant change at P < 0.05, where a- with respect to the control, b- with respect to the boric group). 
Figure 5.
Effect of date molasses (250 mg/kg b.wt.) on the amount of MDA (μg/g) in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt.) at different time intervals. (n = 6, significant change at P < 0.05, where a- with respect to the control, b- with respect to the boric group). 
Figure 6.
Effect of date molasses (250 mg/kg b.wt.) on GSH (μg/g) in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt.) at different time intervals. (n = 6, significant change at P < 0.05, where a- with respect to the control, b- with respect to the boric group).. 
Table 1.
Effect of date molasses administration (250 mg/kg b.wt.) on monoamines (μg/g) in the cortex and cerebellum brain areas of adult male albino rats treated with boric acid (10 or 500 mg/kg b.wt.) at different time intervals. (n = 6, significant change at P < 0.05, where a- with respect to the control, b- with respect to the boric group).
|
Cortex
|
Cerebellum
|
|
Weeks |
Groups |
NE |
DA |
5HT |
NE |
DA |
5HT |
|
1 Week |
Control |
1.38 ± 0.06 |
2.30 ± 0.10 |
1.25 ± 0.08 |
0.50 ± 0.01 |
1.22 ± 0.01 |
0.41 ± 0.02 |
|
LBA |
1.41 ± 0.07 |
2.45 ± 0.10 |
1.34 ± 0.05 |
0.51 ± 0.01 |
1.25 ± 0.01 |
0.43 ± 0.01 |
|
% change |
2.05 % |
6.52 % |
6.91 % |
2.19 % |
2.47 % |
4.85 % |
|
LBA+Mo |
1.26 ± 0.08b
|
2.18 ± 0.06b
|
1.13 ± 0.10b
|
0.54 ± 0.02 |
1.37 ± 0.01a
|
0.46 ± 0.01 |
|
% change control |
-8.78 % |
-5.30 % |
-9.88 % |
7.93 % |
-12.35 % |
-12.29 % |
|
% change LBA |
-10.61 % |
-11.10 % |
-15.70 % |
5.62 % |
9.64 % |
7.09 % |
|
HBA |
1.54 ± 0.05 |
2.54 ± 0.04a
|
1.62 ± 0.06a
|
0.59 ± 0.01a
|
1.33 ± 0.01a
|
0.62 ± 0.01a
|
|
% change |
11.46 % |
10.43 % |
36.41 % |
17.49 % |
9.05 % |
50.36 % |
|
HBA+Mo |
1.84 ± 0.14ab
|
2.76 ± 0.12a
|
1.71 ± 0.10a
|
0.61 ± 0.03a
|
1.39 ± 0.01a
|
0.63 ± 0.01a
|
|
% change control |
33.20 % |
19.91 % |
36.40 % |
21.47 % |
14.40 % |
52.79 % |
|
% change HBA |
19.50% |
8.58% |
5.52% |
3.39% |
4.91% |
1.61% |
|
4 Week |
Control |
1.38 ± 0.06 |
2.30 ± 0.10 |
1.25 ± 0.08 |
0.50 ± 0.01 |
1.22 ± 0.01 |
0.41 ± 0.02 |
|
LBA |
1.42 ± 0.10 |
2.21 ± 0.15 |
1.01 ± 0.01a
|
0.48 ± 0.02 |
1.23 ± 0.01 |
0.34 ± 0.01a
|
|
% change |
2.77 % |
-3.91 % |
-19.41 % |
-3.98 % |
1.23 % |
-17.07 % |
|
LBA+Mo |
1.49 ± 0.06b
|
2.41 ± 0.09b
|
1.36 ± 0.09b
|
0.55 ± 0.02 |
1.35 ± 0.02a
|
0.39 ± 0.02a
|
|
% change control |
8.01 % |
4.78 % |
8.63 % |
9.53 % |
11.11 % |
-5.42 % |
|
% change LBA |
5.09 % |
9.05 % |
34.80 % |
14.06 % |
9.76 % |
14.71 % |
|
HBA |
2.60 ± 0.05a
|
3.52 ± 0.12a
|
2.47 ± 0.14a
|
0.76 ± 0.02a
|
1.65 ± 0.02a
|
0.65 ± 0.02a
|
|
% change |
88.35 % |
53.04 % |
97.19 % |
50.55 % |
36.05 % |
56.43 % |
|
HBA+Mo |
2.07 ± 0.05ab
|
2.99 ± 0.15ab
|
1.94 ± 0.14ab
|
0.69 ± 0.02a
|
1.74 ± 0.02a
|
0.66 ± 0.02a
|
|
% change control |
49.99 % |
30.00 % |
54.91 % |
36.41 % |
43.21 % |
60.06 % |
|
% change HBA |
-20.37 % |
-15.06 % |
-21.44 % |
-9.39 % |
5.26 % |
2.33 % |
|
|
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