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Link to original content: http://pubmed.ncbi.nlm.nih.gov/37259325/
Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice - PubMed Skip to main page content
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. 2023 Jan 24;16(2):175.
doi: 10.3390/ph16020175.

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

Elżbieta Żmudzka  1 , Klaudia Lustyk  2 , Monika Głuch-Lutwin  3 , Małgorzata Wolak  3 , Jolanta Jaśkowska  4 , Marcin Kołaczkowski  5 , Jacek Sapa  2 , Karolina Pytka  2
Affiliations

Novel Multimodal Salicylamide Derivative with Antidepressant-like, Anxiolytic-like, Antipsychotic-like, and Anti-Amnesic Activity in Mice

Elżbieta Żmudzka et al. Pharmaceuticals (Basel). .

Abstract

Depression, anxiety, and schizophrenia may coexist in psychiatric patients. Moreover, these disorders are very often associated with cognitive impairments. However, pharmacotherapy of these conditions remains challenging due to limited drug effectiveness or numerous side effects. Therefore, there is an urgent need to develop novel multimodal compounds that can be used to treat depression, anxiety, and schizophrenia, as well as memory deficits. Thus, this study aimed to evaluate the potential antidepressant-like, anxiolytic-like, antipsychotic-like effects, and anti-amnesic properties, of the novel arylpiperazine derivative of salicylamide, JJGW07, with an affinity towards serotonin 5-HT1A, 5-HT2A, and 5-HT7 and dopamine D2 receptors. Firstly, we investigated the compound's affinity for 5-HT6 receptors and its functional activity by using in vitro assays. JJGW07 did not bind to 5-HT6 receptors and showed antagonistic properties for 5-HT1A, 5-HT2A, 5-HT7, and D2 receptors. Based on the receptor profile, we performed behavioral studies in mice to evaluate the antidepressant-like, anxiolytic-like, and antipsychotic-like activity of the tested compound using forced swim and tail suspension tests; four-plate, marble-burying, and elevated plus maze tests; and MK-801- and amphetamine-induced hyperlocomotion tests, respectively. JJGW07 revealed antidepressant-like properties in the tail suspension test, anxiolytic-like effects in the four-plate and marble-burying tests, and antipsychotic-like activity in the MK-801-induced hyperlocomotion test. Importantly, the tested compound did not induce catalepsy and motor impairments or influence locomotor activity in rodents. Finally, to assess the potential procognitive and anti-amnesic properties of JJGW07, we used passive avoidance and object recognition tests in mice. JJGW07 demonstrated positive effects on long-term emotional memory and also ameliorated MK-801-induced emotional memory impairments in mice, but showed no procognitive properties in the case of recognition memory. Our results encourage the search for new compounds among salicylamide derivatives, which could be model structures with multitarget mechanisms of action that could be used in psychiatric disorder therapy.

Keywords: anti-amnesic effect; antidepressant-like activity; antipsychotic-like properties; anxiolytic-like action; memory-enhancing; serotonin receptor antagonist.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The influence of JJGW07 on the immobility, swimming, and climbing times in the forced swim test (panel (A)) and the immobility time in the tail suspension test (panel (B)) in mice. In the forced swim test, mice were placed in water tanks and the immobility time, the swimming time, and the climbing time were measured for 4 min (after a 2 min adaptation period), whereas in the tail suspension test, mice were suspended by the tail 50 cm above a flat surface with an adhesive tape and the immobility time was measured for 6 min. JJGW07 was administered intraperitoneally (ip) 30 min before the test. The control group received an injection of 0.9% NaCl (ip). Values are expressed as means ± SD or medians with interquartile range; n = 8–10 mice per group. Statistical analysis: one-way ANOVA (Newman–Keuls post hoc) and Kruskal–Wallis test (Dunn post hoc); * p < 0.05 vs. control group.
Figure 2
Figure 2
The influence of JJGW07 on the number of punished crossings (Panel (A)), the number of buried marbles (Panel (B)), and time spent in the open arms (Panel (C)), as well as the number of entries into open arms (Panel (D)). (A) Mice were placed in the four-plate apparatus, and after a 15 s adaptation period, each crossing from one plate to another was punished by an electric shock. The number of punished crossings was measured for 60 s. (B) Mice were placed individually in cages with a 5 cm bedding layer, where 20 glass balls were placed. The number of buried marbles after 30 min of the test was counted. (C,D) In the elevated plus maze test, mice were placed individually in the center area of the maze and observed for 5 min. The number of entries into the open arms, as well as the time spent in the open arms, was measured. JJGW07 was administered intraperitoneally (ip) 30 min before the test. The control group received an injection of 0.9% NaCl (ip). Values are expressed as means ± SD; n = 8 mice per group. Statistical analysis: one-way ANOVA (Newman–Keuls post hoc), * p < 0.05, ** p < 0.01 vs. control group, FPT—the four-plate test, MBT—the marble-burying test, and EPM—the elevated plus maze test.
Figure 3
Figure 3
The effect of JJGW07 on the MK-801-induced (Panel (A)) and amphetamine-induced (Panel (B)) hyperlocomotion in mice. Locomotor activity was recorded in actometers separately for each mouse. After 30 min of adaptation, the number of crossings of photobeams was measured during 60 min. JJGW07 was administered intraperitoneally (ip) 30 min before the test. MK-801 (0.2 mg/kg, ip) was administered 15 min before the experiment, while amphetamine (2.5 mg/kg) was administered subcutaneously (sc) 30 min before the experiment. The control groups received either two injections of 0.9% NaCl (ip or sc), or 0.9% NaCl (ip) and MK-801 (ip), or 0.9% NaCl (ip) and amphetamine (sc). Values are expressed as means ± SD; n = 8–10 mice per group. Statistical analysis: one-way ANOVA (Newman–Keuls post hoc); ** p < 0.01, *** p < 0.001, **** p < 0.0001.
Figure 4
Figure 4
The influence of JJGW07 (Panel (A)) and aripiprazole (panel (B)) on the latency in the step-through passive avoidance task in mice. The experiment consisted of two sessions. In the acquisition trial, mice were placed individually in the light chamber of the apparatus, with the door opening after 30 s. When the animal crossed to the dark chamber, the door closed and the animal was punished with an electric shock (0.8 mA, 2 s). JJGW07 and aripiprazole were administered intraperitoneally (ip) 30 min before the start of the experiment. The control group received an ip 0.9% NaCl solution or 1% Tween. On the second day of the test, the mice were placed again in a bright chamber and the latency was measured for a maximum of 300 s (without the electrical impulse). Values are expressed as means ± SD; n = 8 mice per group. Statistical analysis: two-way ANOVA with repeated measures (Bonferroni post hoc); * p < 0.05, ** p < 0.01, *** p < 0.001 vs. acquisition trial.
Figure 5
Figure 5
The influence of JJGW07 (Panel (A)) and aripiprazole (Panel (B)) on the latency after the MK-801 administration in the step-through passive avoidance task in mice. The experiment consisted of two sessions. In the acquisition trial, mice were placed individually in the light chamber of the apparatus, with the door opening after 30 s. When the animal crossed to the dark chamber, the door closed and the animal was punished with an electric shock (0.8 mA, 2 s). JJGW07 and aripiprazole were administered intraperitoneally (ip) 30 min before the test, while MK-801 (0.125 mg/kg) was administered ip 15 min before the start of the experiment to induce the memory impairments. The control group received an ip 0.9% NaCl/1% Tween solution in two injections or 0.9% NaCl/1% Tween solution and MK-801 (0.125 mg/kg; ip). On the second day of the test, the mice were placed again in a bright chamber and the latency was measured for a maximum of 300 s (without the electrical impulse). Values are expressed as means ± SD; n = 8 mice per group. Statistical analysis: two-way ANOVA with repeated measures (Bonferroni post hoc); *** p < 0.001, **** p < 0.0001 vs. acquisition trial.
Figure 6
Figure 6
The influence of JJGW07 (Panel (A)) and aripiprazole (Panel (B)) on the novel object exploration time in mice as well as the influence of aripiprazole (Panel (C)) on the novel object exploration time after the MK-801 administration in mice. The experiment consisted of two sessions. On the first day, mice were placed and left in cages until they reached a total exploration time of 20 s for both identical subjects, but for no longer than 10 min. JJGW07 and aripiprazole were administered intraperitoneally (ip) 30 min before the start of the experiment, while MK-801 (0.125 mg/kg) was administered ip 15 min before the start of the experiment to induce the memory impairments. The control group received an ip 0.9% NaCl solution (A) or 1% Tween (B) as well as two injections of 1% Tween or 1% Tween (ip) and MK-801 (0.125 mg/kg; ip) (C). On the second day, mice were placed again in cages, where one subject was changed to a new one. The mice remained in the cage until they reached a total exploration time of 20 s for both objects, but for no longer than 10 min. Values are expressed as means ± SD; n = 8–10 mice per group. Statistical analysis: one-sample t-test; * p < 0.05, ** p < 0.01, **** p < 0.0001 vs. chance level = 10 s.
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