Effect of the Antioxidant Pharmacological Agent Mexidol on Locomotor Behavior in Rats Impaired by Silver Nanoparticles

Nanosilver (AgNPs) is widely used in various manufacturing sectors, including agriculture, food processing, and medicine. Many consumer products used in everyday life release silver either as ions or nanoparticles. Without proper regulation, consumption of Ag-containing materials will lead to significant risks for ecosystems and humans. Nonspecific oxidative stress is considered one of the most serious problems associated with nanoparticle toxicity. In this regard, research into the use of antioxidant drugs to prevent and protect against the negative consequences caused by exposure to Ag NPs on the body is promising. The purpose of this work was to evaluate the effect of the antioxidant drug Mexidol on the motor behaviour of rats that received daily Ag NPS with drinking water. For two weeks, rats in the 1 experimental group received an aqueous solution with 10-12 nm particles added to their drinking water. The daily dose of Ag NPs was 15.75 mg/kg. The second group of rats additionally received Mexidol, an antioxidant drug, intraperitoneally at a dose of 10 mg/kg as a 0.5% solution twice daily. All animals were tested in an Open Field (OF) on the first and 15th day of the experiment. During the final testing in the OF, urine samples were collected from the rats using dry chemistry test strips. Rats receiving Ag NPs in their drinking water for two weeks urine analysis revealed significant impairment of renal function. Chronic exposure to Ag NPs can negatively impact fundamental behavioural patterns in rats, particularly their stress responses and locomotor activity. In 1 group of rats defined a decrease in locomotor activity and an increase in anxiety-like behaviour compared to the first day of the experiment. In rats additionally receiving Mexidol injections, the drug improved exploratory behaviour and reduced emotional responses.

The applications of silver-containing materials are numerous and currently extremely important for industry and various human needs [1-3]. Silver nanoparticles (Ag NPs) are used in many industrial processes and are components of a wide variety of products and systems used in everyday life (food, consumer goods, etc.) [2,3]. Due to their unique physicochemical properties, Ag NPs are used in biomedicine as key components of antibacterial, antifungal, and antiviral drugs. The antiseptic activity of substances containing silver ions is due to the complexing, biochemical, and catalytic activity of silver, which interacts with bacterial and viral enzyme systems [3-5].

The widespread use of Ag NPs in various areas of life raises concerns due to their possible toxicity to biota, so recently the attention of researchers has been focused on determining the conditions for the beneficial and safe use of Ag NPs for humans and animals [3,6,7].

The main cause of metal NP toxicity for organisms at all levels of biological organization is considered to be oxidative stress, which initiates excessive production of free radicals: Reactive Oxygen Species (ROS) or reactive nitrogen species, which cause oxidative damage to cells [8,9]. At the same time, the body's Antioxidant Defence System (AOS) is launched to reduce and regulate radical activity [9,10]. Penetration of Ag NPs into the body occurs orally, by inhalation or dermal routes, after which they enter virtually all cells of the body via endocytosis and diffusion [10-12]. A significant amount of data obtained during experimental studies both in vitro and in vivo clearly confirms the fact of easy penetration of Ag NPs through the blood-brain barrier into the brain; due to their small size and large surface area, they enter the systemic circulation and then into the Central Nervous System (CNS), where they interact with cellular components, causing neurotoxic effects [12]. By reacting with cell membrane proteins, Ag NPs activate oxidative stress signalling pathways to generate ROS, which leads to damage to intracellular proteins and nucleic acids, and ultimately causes apoptosis and inhibition of cell proliferation [11-14]. Oxidative stress in cells, particularly in the nervous system, is of exceptional interest, as it is considered a key modulator in many neurodegenerative diseases.

Many natural and synthetic antioxidants can mitigate oxidative stress and restore redox balance. However, studies have shown that substances that act as antioxidants in vitro may not always be effective as pharmacological antioxidant agents in the body [15]. Pharmacological drug Mexidol (2-ethyl-6-methyl-3-oxypyridine succinate) is chemically a molecule of the antioxidant emoxypine with added succinic acid. Numerous studies have shown that the drug possesses antioxidant and membrane-protective properties, increasing the body's resistance to various damaging factors, including intoxication with metal-containing compounds [16]. Mexidol has an effect on various types of stressful situations, for example, stress due to a new environment, anxiety and fear caused by negative influences previously received in these conditions [16].

The open field test, a standard behavioural test for assessing fear, anxiety, and motor activity in laboratory rodents, is often used to assess cognitive function and behavioural activity in animals.

The aim of our study was to evaluate the effect of the antioxidant drug Mexidol on locomotor behaviour in the open field test in rats that received Ag NPs daily in their drinking water.

The study was performed on 52 mature male rats Wistar weigh 300-350 g, maintained in a certified vivarium with artificial lighting day/night (12/12 hours) and free access to water and food. The animals were randomly divided into three experimental groups. Rats in Group 1 (n = 17) and Group 2 (n = 17) received an aqueous solution of Ag NPs (45 mg/L) added to their drinking water for 14 days, corresponding to a daily dose of 15.75 mg/kg. The aqueous solution of Ag NPs (AgBion-2, Nano industry Concern RUS) is a silver cluster dispersion produced by biochemical synthesis in reverse micelles. This allows us to obtain small and Nano sized Ag particles that are stable in micellar solutions for a long time, making it possible to study their properties in interaction with biological objects. For AgBion-2, we determined the wavelength of the maximum absorption in the visible region, which was 410 nm (SPECORD UV-VIS). According to the manufacturer's data, inductively coupled plasma mass spectrometry established that the total silver content in AgBion-2 is 0.045% (450 ppm), the average Ag particle size is 10-12 nm, the amount of water is 97.855%; the surfactant stabilizer (sodium dioctyl sulfosuccinate) is no more than 1%.

Additionally, animals in Group 2 were administered ethylmethylhydroxypyridine succinate (Mexidol, Pharmasoft, Russia) intraperitoneally twice daily (from days 1 to 14) at a dose of 10 mg/kg as a 0.5% solution at a volume of 0.5 ml per 100 g of animal weight. The control group (n = 18) received 1 ml of saline solution daily. Rats of Group 1 and the control Group (n = 18) were also injected intraperitoneally with saline solution twice a day at 1 ml.

All animals in the experimental groups were tested in the “open field” setup on days 1 and 15 of the experiment.

Open Field (OF) test

The OF setup was a round white arena with a diameter of 120 cm and side walls 35 cm high (Open Science Research and Production Corporation). The experiments were illuminated by artificial lighting (100 W) from a ceiling lamp located directly above the experimental setup. The open field was divided into sectors with burrow holes (2.5 cm in diameter): one central sector, 8 medial sectors, and 16 peripheral sectors. At the beginning of the experiment, the rat was placed in the central sector of the field, and the following parameters were recorded for 5 minutes: Horizontal Activity (HA)-the total number of sectors in the open field crossed by all four paws of the rat; Vertical Activity (VA)-the number of rearing with the forelimbs free or standing with support against the arena wall; the total number of burrow reactions resulting from Search Activity (SA), when the animal puts its head inside the holes or the number of sniffs of the edges of these holes; the number of times the rat entered the Central (C) sector of the "open field," the duration (sec) of grooming, and the number of defecations and urinations. Video recordings of animal behavioural reactions in the open field were analysed using Real Timer software (Open Science Research and Production Corporation, Russia).

Biochemical studies

To assess the physiological state of the animals, a portion of urine collected during voluntary urination during testing in the OF on the 15th day of the experiment was analysed using the dry chemistry method with DIRUI H 11 test strips (Dirui Industrial Co. Ltd, China). The test strip was dipped in urine droplets for 1-2 seconds, and after one minute, the colour of the test strip's reagent zone was compared with the colour chart. All test strip values (red blood cell count, bilirubin, urobilinogen, ketone bodies, protein, nitrites, glucose, ascorbic acid concentration, pH, and relative density) were recorded within 60 seconds, and the white blood cell count was recorded no earlier than after 2 minutes. The strips were evaluated in a high-speed urine analyser DIRUI H -500 (Dirui Industrial Co. Ltd, China).

Statistical processing of the obtained results was performed using the Statistica v 10.0 software package (StatSoft, USA), and a check for normality of distribution was performed. The significance of differences between groups was determined using the nonparametric Mann-Whitney test for two independent samples and the Wilcoxon- test for differences between dependent samples; the significance level was set at 5.0% (p < 0.05).

All animal manipulations were performed in compliance with the principles of the European Convention for the Protection of Vertebrate Animals used for Experimental and other Scientific Purposes (Strasbourg, 1986), in accordance with good laboratory practice, and with Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes.

We determined that urine pH in rats ranged from 6.8 to 7.4, with no statistically significant differences between groups (Table 1). The specific gravity of rat urine ranged from 1.015 to 1.040. In rats treated with Ag NPs in their drinking water for two weeks (Groups 1 and 2), renal function biomarkers significantly differed from controls. Signs of renal impairment were more pronounced in Group 1: significantly elevated bilirubin, urobilinogen, and total protein levels, as well as ketones and erythrocytes in the urine. The white blood cell count in Group 1 was tens of times higher than in Group 2 and the control (p < 0.05). Furthermore, ascorbic acid and glucose excretion were significantly increased in Group 1 (p < 0.05). Biochemical indicators of renal impairment in animals injected with Mexidol were significantly lower than in rats in Group 1, although the differences were not always statistically significant.

Open field testing

To assess the effect of Ag NPs and the effect of Mexidol on animal locomotion, GA indices and the number of rearings were monitored. On the first day of the experiment, no statistically significant differences in the searching behavior of animals in the three experimental groups were observed.

On day 15, the animals in the experimental groups differed significantly in the number of rearings and the number of square crossings. The GA and VA indices in Group 1 animals decreased sharply (p < 0.05) compared to the control group (Table 2), indicating suppression of locomotor activity in rats receiving NPs in their drinking water. Animals in this group stopped visiting the squares in the central zone, while rats injected with Mexidol visited the squares in the central zone of the OP, just as they had during testing on Day 1. Furthermore, Mexidol restored the number of rearings to the same level as in the control animals (p < 0.05).

On the first experimental day, autonomic responses (grooming directed at the paws and head, urination, and defecation) were comparable in animals of the three groups. After two weeks, grooming time in Group 1 rats significantly increased by 2 times compared to this indicator on the first experimental day (p < 0.05). Furthermore, on the 15th experimental day, rats in this group had a significantly higher number of defecations than on the first day, and this indicator significantly exceeded the number of boluses in Group 2 and control rats.

Most of the published research results concerning the mechanisms of toxic reactions caused by Ag NPs at the molecular and cellular levels were obtained from in vitro experiments [3,17,18]; despite a growing number of in vivo studies, data on the effects of Ag NPs on living organisms are contradictory and ambiguous [3,18-20].

In our study, rats received Ag NPs daily in their drinking water for two weeks. We added an aqueous solution of colloidal Nano silver (10-12 nm) AgBion-2 to their drinking bowls. AgBion-2 is widely used in everyday life to disinfect indoor surfaces, as well as in various medical facilities, pharmaceutical and immunobiological production facilities, food service and retail establishments, and elsewhere. Benn T, et al. [21] found that many households’ consumer products release silver when rinsed with water, in amounts of up to 45 mg Ag kg−1 of product and fractions smaller and larger than 100 nm [21]. The daily dose of Ag NPs received in drinking water in our study was 15.75 mg/kg.

Silver from orally administered Ag NPs is distributed to all organs, mainly accumulating in the "filter organs" of the body. It is known that metal Nano elements (< 100 nm) are capable of overcoming the Blood-Brain Barrier (BBB). With prolonged use of silver-containing drugs in animals, toxic effects and decreased cognitive functions are noted, presumably due to the accumulation of Ag NPS in the brain. The main targets Ag NPs are the intestines, liver, and kidneys [22,23]. Excretion occurs via bile and urine [6].

Urinalysis is a mandatory requirement for toxicity studies of various medicinal products. For rat studies to ensure compliance with GLP requirements, only one urine collection at the end of the study is recommended [24]. Dry chemistry urine testing using DIRUI H 11 test strips, which we used in our study, reliably detects renal toxicity.

Bilirubin is a marker of liver function and is the end product of haemoglobin breakdown. The kidneys can significantly contribute to bilirubin excretion through glomerular filtration of its conjugated derivatives under toxic loads of [25]. Our results indicate that silver nanoparticles have a toxic effect on the liver and kidneys of experimental rats, as evidenced by a significant increase (p < 0.05) in total bilirubin in the first experimental group. Furthermore, increased urinary albumin excretion was observed when Ag NPs were administered to rats via drinking water, while no protein was detected in the control group. An increase in urinary albumin excretion is considered a diagnostically significant marker of renal glomerular damage, which is accompanied by damage and dysfunction of the renal vascular endothelium, an increase in pressure in the glomerular capillary network (Glomerular hypertension), and disruption of the structural integrity of the glomerular basement membrane [25,26]. Membrane damage leads to disruption of oxidative processes in the kidneys, a low-energy shift in the adenylate system, and, as a consequence, disruption of filtration, reabsorption, and secretion processes. This may not be the only way in which Ag NPs can damage the kidneys. In addition, ketonuria was detected in analyses of Group 1 rats; this nonspecific condition may indicate a disruption of the water-salt balance during toxic damage to the body. Normally, ketones should be absent in urine or their quantity should be minimal [25-27]. Normal rodent urine contains very few red blood cells (0-3 cells per high-power field) [27]. In our study, rats in the experimental groups showed elevated red blood cell and white blood cell counts. An increase in red blood cell counts occurs with inflammation or damage to the urinary system, and common causes of white blood cells in urine (pyuria) include pyelonephritis, cystitis, interstitial nephritis, glomerulonephritis, and others.

Thus, in our experiment, almost all significant markers of kidney function in rats in Group 1 receiving drinking water containing Ag NPs indicated serious functional impairment. In addition, two weeks of the toxic effect of Nano silver on the rats of this group caused violations of their locomotor behaviour.

The factors and mechanisms underlying the association of cognitive behavioural disorders with kidney pathology remain poorly understood. Ryabova YV, et al. [28] demonstrated that the development of oxidative stress in the kidneys is the primary mechanism of nephrotoxicity caused by the administration of inorganic nanoparticles, due to damage to cellular functions by reactive oxygen species due to an imbalance in the oxygen reduction ratio [28]. Oxidative processes aimed at repairing damage can serve as a source of additional free radicals, leading to further damage to cells located distal to the site of primary injury [29]. Uremic intoxication induces oxidative stress through super activation of NDMA receptors and activation of nitric oxide synthesis, which can provoke pronounced metabolic and structural changes in the brain//cause cognitive impairment [30-32].

The Open field test is one of the main methods for assessing behavioural indicators and cognitive abilities in rodents: exploration of a new environment, general locomotor activity, and the animals' emotional level. The fear response (or anxiety) of an animal exposed to a new and, therefore, potentially dangerous environment is accompanied by both frequent defecation and minimal horizontal activity, especially in the central zone. In our study, animals exposed to Ag NPs stopped entering the central squares and rearing on their hind legs, and grooming time significantly increased (p < 0.05), suggesting a stress response in this experimental group of rats. Furthermore, rats receiving Ag NPs in their drinking water defecate more frequently than controls. We believe that the higher defecation frequency is caused by activation of the sympathetic nervous system after exposure to stressful stimuli provided by the new environment. This may also be associated with functional impairment of certain brain structures, such as the basolateral amygdala and the hippocampus [33]. In recent years, toxicological studies using cellular and animal models have shown that AgNPs can disrupt signalling between neurons, interfere with the release and reuptake of neurotransmitters, and lead to neurotransmission disturbances. These disturbances can subsequently cause behavioural disturbances, cognitive impairments, and other neurological disorders in animals [34,35].

In our study, on the 15th day of the experiments, despite the unsatisfactory urine analysis data in animals treated with Mexidol, changes in their locomotor behaviour in the open field were minimal. The mechanism of action of this drug is due to its antioxidant and membrane-protective effects [16]. The number of intersections of the squares in the Mexidol-treated group of animals was statistically significantly higher (p < 0.05) than in the first experimental group. Mexidol reduced anxiety and fear, and the rats demonstrated more pronounced exploratory activity (number of stands) and a significantly greater number of approaches to the centre of the arena. This suggests that the drug Mexidol exerted an anti-stress effect in rats exposed to the toxic effects of Ag NPs, normalized locomotor behaviour, levelling somatovegetative disorders.

Given the rapid and extensive research currently underway in the development of new nanomaterials, it is necessary to address their potential toxicity to the central nervous system and search for effective neuroprotectors. For this purpose, studies of the effects of AgNPs on the body as a whole and on individual organs are important. Physiological biomarkers can be good indicators of the potentially toxic effects of nanomaterials. Recent studies have shown that uremic toxins directly or indirectly damage the central nervous system. Our experiments demonstrated that AgNPs cause severe renal failure. Furthermore, introducing AgNPs into drinking water induced stress in rats and a deficit in exploratory behaviour during open-field testing. The antioxidant and stress-protective drug Mexidol increased the rats' resistance to the effects of AgNPs.

The study was carried out within the framework of a scientific project of the state assignment of Lomonosov Moscow State University (Subjects “Neurobiological foundations of animal behavior” No. 121032500080-8).

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