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Publicly Available Published by De Gruyter September 24, 2016

Neuropharmacological evaluation of a novel 5-HT3 receptor antagonist (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone (6g) on lipopolysaccharide-induced anxiety models in mice

Shvetank Bhatt, Radhakrishnan Mahesh, Thangaraj Devadoss and Ankur Jindal

Abstract

Background:

5-HT3 receptor antagonists play a key role in the management of psychiatric disorders such as, depression and anxiety. They may act through modulation of serotonergic transmission. In the present study, a novel and potential 5-HT3 receptor antagonist, 6g (4-benzylpiperazin-1-yl)(3-methoxyquinoxalin-2-yl) methanone, which exhibited good log P (3.08) and pA2 (7.5) values was screened for its anxiolytic property in lipopolysaccharide (LPS) induced anxiety models.

Methods:

LPS, an endotoxin, present in the cell wall of Gram negative bacteria was injected 0.83 mg/kg, i.p. as a single dose to induce anxiety-like symptoms in mice. Compound 6g (1 and 2 mg/kg, p.o.) and standard fluoxetine (FLX) (20 mg/kg, p.o.) were injected to treatment groups for 7 days and evaluated in various behavioral paradigms such as elevated plus maze (EPM), light and dark (L/D) test, and open field test (OFT). Their effects on serotonin levels in mice brain were also examined.

Results:

The results showed that LPS induced anxiety-like symptoms in mice, as indicated by a significantly decreased percentage open arm entries and percentage time spent in open arms in EPM; decreased time spent in light area and number of transition between chambers in L/D test; decreased ambulation and rearing scores in OFT. Compound 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) reversed the LPS-induced behavioral changes and significantly affected all the behavioral parameters mentioned above. In addition 6g (1 and 2 mg/kg, p.o., 7 days) and FLX treatment (20 mg/kg, p.o., 7 days) increased the levels of serotonin in mice brain.

Conclusions:

Compound 6g produced anxiolytic-like effects in various anxiety paradigms in LPS-treated mice as well as restored the decreased serotonin levels in mice brain.

Introduction

Anxiety is a psychopharmacological disorder characterized by somatic, responsive, sensitive, cognitive, and behavioral components [1]. Anxiety is a condition of fear and apprehension that leads to insomnia. When anxiety becomes overpowering, it becomes a serious issue and may fall under the category of an anxiety disorder. Moreover, anxiety disorders are associated with marked debility which has a negative effect on daily life with an incidence of 18.1% and prevalence of 28.8% [2].

Some studies revealed that various inflammatory markers are involved in the pathophysiology of anxiety and depression [3], [4], [5]. In the present study lipopolysaccharide (LPS) is used to induce inflammation-mediated anxiety in mice. LPS is an endotoxin present in the cell wall of Gram negative bacteria. Peripheral administration of LPS stimulates indoleamine 2,3-dioxygenase (IDO) and alters serotoninergic and glutamatergic signaling pathways. IDO is an extrahepatic enzyme which is present in macrophages and other immunological cells where it dissociates the important amino acid tryptophan in kynurenine pathway. This enzyme is induced by various pro-inflammatory cytokines, such as interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α) [3], [4]. The increase in inflammatory markers leads to an increase in the oxidative stress parameters, which can result in anxiety and depression-like symptoms in animals.

5-HT3 receptor is the only serotonergic receptor belonging to the superfamily of ligand gated ion channels. Many 5-HT3 receptor antagonists are investigated and extensively used in clinical practice for cancer chemotherapy induced nausea and vomiting. The 5-HT3 receptors are well expressed in the central nervous system in regions involved in the emesis reflex, pain perception, reward system, memory, depression, and anxiety disorders. In the periphery they are located on a variety of neurons and immune cells [6], [7].

The involvement of 5-HT3 receptors in anxiety disorders are supported by studies using 5-HT3 knockout mice which show the regulation of 5-HT3 (3A subtype) in anxiety-related behaviors [8], [9]. Serotonergic signaling in prefrontal cortex demonstrates an important role in regulating sensation, emotion, and memory under normal and pathological conditions. Increased availability of 5-HT over 5-HT2 and 5-HT3 receptors increases anxiety, while blockade of 5-HT3 receptors produces anxiolytic-like effect [10], [11]. Several preclinical and clinical studies have suggested that 5-HT3 receptors may be a relevant target in the treatment of affective disorders such as anxiety and depression [11], [12], [13], [14].

As various preclinical studies state that the compound 6g might possibly cause the modification in serotonergic transmission mainly through the involvement of limbic system [12], [13]. Despite preclinical screening of compound 6g for its antidepressant and anxiolytic potential in various rodent models, the effect of compound 6g in LPS-induced anxiety is yet to be explored to identify its potential usefulness in the treatment/prevention of anxiety disorder [14]. Therefore, the present study was designed to explore the anxiolytic-like effect of compound 6g in LPS-induced anxiety model in mice. The results of the present study states that 7 days treatment with compound 6g reversed the LPS-induced anxiety-like behavior in mice. Moreover, compound 6g attenuated the LPS-induced decrease in serotonin levels in mice brain.

Materials and methods

Experimental animals

The present research work was carried out using male Swiss abino mice (22–25 g), procured from Chaudhary Charan Singh Haryana Agricultural University, Hisar, India. The animals were maintained in standard laboratory conditions (temperature 22 °C±2 °C and room humidity, 60%±10%) with a 12:12 h light/dark cycle. The animals were fed with standard diet and filtered water ad libitum. The experimental procedures on animals were carried out in compliance with the Institutional Animal Ethics Committee of Birla Institute of Technology & Science, Pilani, India (Protocol No. IAEC/RES/14/04).

Drugs and treatment

Fluoxetine (FLX) was obtained as a gift sample from Cipla Pharmaceuticals Ltd., Mumbai, India. ELISA kits for serotonin neurotransmitter estimation were procured from DLD, Diagnostika, GMBH, Germany. The tested molecule 6g was synthesized in our medicinal chemistry laboratory, Department of Pharmacy, BITS, Pilani, Rajasthan, India and selected from a series of compounds based on Log P and pA2 values. Fluoxetine and compound 6g were freshly prepared in distilled water and administered per oral (p.o.) in a constant volume of 10 mL/kg.

LPS-induced anxiety procedure

The animals were divided into five groups of eight animals each as: normal control; LPS control; 6g (1 mg/kg, p.o.); 6g (2 mg/kg, p.o.); and FLX (20 mg/kg, p.o.). For the induction of anxiety, LPS (0.83 mg/kg, i.p.) was injected to mice in all the groups (except normal control) on Day-0. Compound 6g (1 and 2 mg/kg, p.o.) and FLX (20 mg/kg, p.o.) were administered for 7 days (started at Day-1).

Behavioral assessment

On Day-8 and Day-9 all the behavioral tests (elevated plus maze, EPM, L/D, open field test, OFT) were performed as shown in Table 1.

Table 1:

Study plan of LPS-induced anxiety model.

Days
0123456789
TreatmentLPS Injection
Strain/testsSwiss albino mouseBehavioral tests (EPM, L/D)Behavioral tests (OFT), brain samples were collected for biochemical analysis

Elevated plus maze

The EPM test was first evaluated for rats and later adapted for mice [15]. In brief, the apparatus consisted of a wooden maze with two enclosed arms (30 cm×5 cm×15 cm) and two open arms (30 cm ×5 cm×0.25 cm) that extended from a central platform (5 cm×5 cm) to form a plus sign. The plus maze apparatus was elevated to a height of 45 cm and placed inside a sound-attenuated room. The trial was started by placing a mouse on the central platform of the maze facing its head towards an open arm. The behavioral performances recorded during a 5-min test period were: percentage open arm entries (OAE) and percentage time spent in open arms (TSOA) [16]. Entry into an arm was considered valid only when all four paws of the mouse were inside that arm. The apparatus was thoroughly cleaned with 70% ethanol after each trial.

Light/dark aversion test

The light/dark (L/D) apparatus was composed of a box divided into two separate compartments, occupying two-thirds and one-third of the total size, respectively. The larger compartment (light compartment) was illuminated by a 60-Watt bulb, while the smaller one (dark compartment) was entirely black and enclosed under a dark cover. Both the compartments were separated by a partition with a tunnel to allow passage from one compartment to the other [17]. At the beginning of the test, mice were placed individually at the center of the light compartment facing towards the tunnel and were allowed to explore the entire apparatus for 5 min. The behavioral parameters namely, latency time (time required for the first crossing to the light compartment), total time spent in the light compartment, and the number of transitions between the L/D compartments were recorded. A compartment entry was considered valid when the animal's all four paws were inside that chamber. The apparatus was thoroughly cleaned with 70% ethanol after each trial [14].

Open field test

The apparatus consisted of a wooden box (60 cm×60 cm×30 cm) with the floor divided into 16 squares (15 cm×15 cm) by black parallel and intersecting lines. The apparatus was illuminated with a 60-Watt bulb suspended 100 cm above the base of the arena. At the beginning of the test, mice were placed individually at the center of the square arena. The ambulation scores (number of square crossed) and rearing number (standing upright on hind legs) were recorded for 5 min period. After each individual test session the floor was thoroughly cleaned with 70% ethanol [14], [18].

Serotonin estimation

Estimation of mice brain serotonin:

Serotonin estimation was done within 6 h of brain collection after completion of all behavioral studies on Day-9.

Harvest:

The mice were decapitated and their brains were harvested quickly as per procedure mentioned elsewhere [19], [20] and placed in a petridish on an ice bath.

Dissection and extraction:

The mice brain was carefully removed, blotted, and chilled. Dissections were performed on an ice-cooled glass plate. All the brain samples were collected and stored in deep freezer at −70 °C. Serotonin was extracted as per the procedure mentioned on the kit.

Estimation of serotonin: standard curve:

The standard curve for the serotonin assay was prepared by using the instruction on kit.

Statistical analysis

All the results are expressed as mean±Standard error of mean (SEM). The data obtained from studies were analyzed using one-way ANOVA followed by Dunnet’s test.

Results

Behavioral observations

Effect of 6g on %OAE and %TSOA using EPM in mice

In EPM, compound 6g (1 and 2 mg/kg, p.o.) and FLX (20 mg/kg, p.o.) significantly increased the percentage of both OAE [F (4, 35) =7.518, p<0.05] and TSOA [F (4, 35)=12.81, p<0.05] as compared to LPS control group (Table 2).

Table 2:

Effect of 6g on % TSOA and % OAE in EPM test.

Treatment% TSOA% OAE
Normal control80.00±3.5451.50±3.57
LPS control55.16±3.97a28.16±2.92a
LPS + 6g (1)71.16±3.06b42.00±3.19b
LPS + 6g (2)72.00±3.96b43.33±2.53b
LPS + FLX (20)89.00±2.79b44.16±3.17b

Tabulated results are expressed as mean percentage TSOA and OAE. Error bars represent mean SEM. ap<0.05 vs. normal control, bp<0.05 when compared with LPS control group, n=8/group. FLX, fluoxetine.

Effect of 6g on time spent in lit area, number. of transitions, and latency period in L/D test

6g (1 and 2 mg/kg, p.o.) and FLX (20 mg/kg, p.o.) treatment significanly [F (4, 35)=21.25, p<0.05] increased the number of entries from one compartment to other as well as decreased the latency time markedly [F (4, 35)=15.25, p<0.05] to leave compartment. Moreover 6g (2 mg/kg, p.o.) and FLX (20 mg/kg, p.o.) treatment significantly [F (4, 35)=19.55, p<0.05] increased the time spent in light chamber, while lower dose of 6g (1 mg/kg, p.o.) did not produce significant change in the time spent in light chamber (Table 3).

Table 3:

Effect of 6g on time spent in lit area, no. of transitions and latency period in L/D test.

TreatmentTime spent in lit area, sNo. of transitionsLatency, s
Normal control132.16±8.9016.50±1.4711.16±1.60
LPS control53.00±9.33a6.66±0.76a56.80±3.05a
LPS + 6g (1)68.00±9.8815.16±1.30b36.16±2.18b
LPS + 6g (2)86.60±6.00b15.00±1.80b26.00±2.86b
LPS + FLX (20)73.00±5.30b21.16±3.37b31.16±2.91b

Tabulated results are expressed as mean time spent in lit area, no. of transitions and latency period. Error bars represent mean±SEM. ap<0.05 vs. normal control, bp<0.05 vs. LPS control group; n=8/group. FLX, fluoxetine.

Effect of 6g on ambulation and rearing scores in mice using OFT

Compound 6g (1 and 2 mg/kg, p.o.) and FLX (20 mg/kg, p.o.) treatment significantly increased the number of squares crossed [F (4, 35)=34.21, p<0.05] as compared to LPS control group. None of the tested doses of FLX and 6g affected the rearing score as compared to LPS control (Table 4).

Table 4:

Effect of 6g on ambulation and rearing scores in OFT.

TreatmentLocomotor scoresRearing
Normal control145.67±4.089.40±0.64
LPS control71.45±3.33a8.85±0.76
LPS+6g (1)105.23±3.88b9.22±1.35
LPS+6g (2)120.23±6.22b8.66±1.80
LPS+FLX (20)123.22±5.34b10.20±3.31

Tabulated results are expressed as mean ambulation and rearing score. Error bars represent mean±SEM. ap<0.05 vs. normal control, bp<0.05 vs. LPS control group; n=8/group. FLX, fluoxetine.

Serotonin estimation

Effect of 6g on the levels of serotonin in LPS-treated mice

The LPS treatment significantly (p<0.05) reduced the serotonin levels (ng/g wet brain tissue) in mice brain as compared to the normal vehicle-treated animals. 6g (1 and 2 mg/kg) and FLX (20 mg/kg) predominantly [F (4, 35)=12.14, p<0.05 enhanced the 5-HT levels as compared to LPS control mice (Table 5).

Table 5:

Effect of 6g on the level of 5-HT in LPS-treated rats.

Treatment groups, mg/kg5-HT, ng/g
Normal control506.99±15.12
LPS control371.22±17.22a
LPS+6g (1)421.00±15.78b
LPS+6g (2)445.23±10.32b
LPS+FLX (20)457.00±11.75b

Tabulated data represent the mean number of neurotransmitter level [5-HT (ng/g]. Results are expressed as mean±SEM. ap<0.05 vs. normal control, bp<0.05 vs. LPS control rats; n=8/group. FLX, fluoxetine.

Discussion

The present research work showed the neuropharmacological effects of a 5-HT3 receptor antagonist, compound 6g, in LPS-induced anxiety models in mice, namely EPM, L/D, and OFT. The effect of 6g on LPS-induced alteration in serotonin levels was also evaluated. The results of the present study showed that 7 days treatment with compound 6g reversed the LPS-induced anxiety-like behavior in mice. In addition, compound 6g also increased the serotonin levels in mice brain.

Previous studies have shown that peripheral administration of LPS induced many inflammatory cytokines such as, TNF-α, IL-1β, IL-1 α, IL-6 etc. [3], [4]. This finally leads to sickness and anxiety-like symptoms [5], [21], [22]. In addition, inflammation also increases various oxidative stress parameters that further lead to pronounced effect on anxiety-like symptoms (unpublished data).

The probable hypothetical mechanism of compound 6g is based on the consumption of tryptophan amino acid, a precursor for serotonin synthesis. Oxidation of tryptophan is generally initiated by tryptophan dioxygenase enzyme, and negligibly by IDO enzyme. However, IDO is greatly increased by pro-inflammatory mediators such as cytokines, including TNF-α and IFN-γ [5], [23], [24]. Kynurenine pathway has important neuropsychiatric implications for the degradation of tryptophan [4]. This pathway predominates during the inflammation and serotonin levels in the synapse are decreased. The compound 6g might possibly cause the modification in serotonergic signaling mainly in the limbic sytem [12]. Hence the compound 6g was evaluated for its anxiolytic potential as well as its effect on the serotonin levels in mice brain in LPS-induced anxiety. The results of the present study showed that chronic treatment with compound 6g reversed LPS-induced anxiety-like behavior in mice. Moreover, compound 6g enhanced the serotonin levels in mice brain.

Administration of LPS produced a decrease in the percentage of both OAE and TSOA in mice during EPM, while treatment with 6g increased both the parameters. In L/D model, LPS administration decreased the time spent in light area as well as the number of transitions from one compartment to other and also increased the latency time, while treatment with compound 6g reversed all the parameters significantly [5], [25], [26]. In OFT, LPS administration decreased the ambulation scores, while there was no significant effect observed on rearing. Treatment with compound 6g increased the ambulation scores but there was no significant effect observed on rearing scores. The results are in accordance with previous studies [27], [28], [29]. In addition to change in various behavioral parameters, the compound 6g also increased the levels of serotonin in LPS-treated mice brain. These results strengthen the proposed mechanism for compound 6g such that it may influence the serotonergic transmission by inhibiting the increased levels of inflammatory mediators responsible for degradation of tryptophan by highly activated IDO enzyme at the periphery [3], [12], [13].

Conclusions

Treatment with compound 6g showed anxiolytic-like effect in LPS-induced anxiety models in mice. The LPS-injected mice showed a significant alteration in the anxiety-like behavior. The single dose administration of LPS significantly increased anxiety (EPM and L/D and OFT model) symptoms. The chronic treatment with compound 6g significantly decreased LPS injection induced anxiety-like behavioral anomalies in mice. This study also strengthens our initial hypothesis that compound 6g may affect the brain serotonergic signaling. The improvement of LPS-induced reduction in brain serotonin levels by compound 6g also revealed that the compound possibly acts through enhancing the serotonergic transmission. Based on the aforementioned findings it can be concluded that LPS injection induced anxiety-like behavior in mice.

  1. Author contributions:All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership:None declared.

  4. Honorarium: None declared.

  5. Competing interests:The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Received: 2016-5-30
Accepted: 2016-7-22
Published Online: 2016-9-24
Published in Print: 2017-3-1

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