Abdullah Al Shamsh Prottay, Emamuzzaman, Tawfik Rakaiyat Ripu, Md Nazim Sarwar, Towfiqur Rahman, Md Shakil Ahmmed, Mehedi Hasan Bappi, Md Emon, Siddique Akber Ansari, Henrique D M Coutinho, Muhammad Torequl Islam
{"title":"Anxiogenic-like effects of coumarin, possibly through the GABAkine interaction pathway: Animal studies with in silico approaches.","authors":"Abdullah Al Shamsh Prottay, Emamuzzaman, Tawfik Rakaiyat Ripu, Md Nazim Sarwar, Towfiqur Rahman, Md Shakil Ahmmed, Mehedi Hasan Bappi, Md Emon, Siddique Akber Ansari, Henrique D M Coutinho, Muhammad Torequl Islam","doi":"10.1016/j.bbr.2024.115392","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Anxiety disorder is the most common mental illness and a major contributor to impairment. Thus, there is an urgent need to find novel lead compounds to mitigate anxiety. It is widely recognized that the neurobiology of anxiety-related behavior involves GABAergic systems.</p><p><strong>Objectives: </strong>This research aimed to examine the anxiogenic action of coumarin (CMN), a natural benzopyrone derived from plants, and determine its underlying mechanism through in vivo and in silico investigations.</p><p><strong>Methods: </strong>This was accomplished by using a variety of behavioral procedures, including open field, swing, hole cross, and light-dark tests, on male and female Swiss albino mice that had been orally administered three experimental doses of CMN (1, 2, and 4 mg/kg). The CMN group was also examined with the GABA<sub>A</sub> receptor agonist diazepam (DZP, 2 mg/kg) and flumazenil antagonist (FLU, 0.1 mg/kg). Furthermore, CMN and standards were subjected to a molecular docking analysis to determine their binding affinities for the GABA<sub>A</sub> receptor subunits (α1, α4, β2, γ2, and δ). Several software programs were used to visualize the ligand-receptor interaction and analyze the pharmacokinetic profile.</p><p><strong>Results: </strong>Compared to typical treatments, our results show that CMN (1 mg/kg) significantly (p < 0.05) increases the locomotor activity of animals. Furthermore, CMN exerted the highest binding affinity (-6.5 kcal/mol) with the GABA-α1 receptor compared to conventional DZP. Along with FLU, CMN displayed several hydrophobic and hydrogen bonds with GABA<sub>A</sub> receptor subunits. The pharmacokinetic and drug-like properties of CMN are also remarkable. In animal studies, CMN worked synergistically with FLU to provide anxiogenic-like effects.</p><p><strong>Conclusion: </strong>We conclude that, based on in vivo and in silico data, CMN, alone or in combination with FLU, may be employed in future neurological clinical studies. However, further research is needed to confirm this behavioral activity and elucidate the possible mechanism of action.</p>","PeriodicalId":8823,"journal":{"name":"Behavioural Brain Research","volume":" ","pages":"115392"},"PeriodicalIF":2.6000,"publicationDate":"2024-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Behavioural Brain Research","FirstCategoryId":"102","ListUrlMain":"https://doi.org/10.1016/j.bbr.2024.115392","RegionNum":3,"RegionCategory":"心理学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BEHAVIORAL SCIENCES","Score":null,"Total":0}
Anxiogenic-like effects of coumarin, possibly through the GABAkine interaction pathway: Animal studies with in silico approaches.
Background: Anxiety disorder is the most common mental illness and a major contributor to impairment. Thus, there is an urgent need to find novel lead compounds to mitigate anxiety. It is widely recognized that the neurobiology of anxiety-related behavior involves GABAergic systems.
Objectives: This research aimed to examine the anxiogenic action of coumarin (CMN), a natural benzopyrone derived from plants, and determine its underlying mechanism through in vivo and in silico investigations.
Methods: This was accomplished by using a variety of behavioral procedures, including open field, swing, hole cross, and light-dark tests, on male and female Swiss albino mice that had been orally administered three experimental doses of CMN (1, 2, and 4 mg/kg). The CMN group was also examined with the GABAA receptor agonist diazepam (DZP, 2 mg/kg) and flumazenil antagonist (FLU, 0.1 mg/kg). Furthermore, CMN and standards were subjected to a molecular docking analysis to determine their binding affinities for the GABAA receptor subunits (α1, α4, β2, γ2, and δ). Several software programs were used to visualize the ligand-receptor interaction and analyze the pharmacokinetic profile.
Results: Compared to typical treatments, our results show that CMN (1 mg/kg) significantly (p < 0.05) increases the locomotor activity of animals. Furthermore, CMN exerted the highest binding affinity (-6.5 kcal/mol) with the GABA-α1 receptor compared to conventional DZP. Along with FLU, CMN displayed several hydrophobic and hydrogen bonds with GABAA receptor subunits. The pharmacokinetic and drug-like properties of CMN are also remarkable. In animal studies, CMN worked synergistically with FLU to provide anxiogenic-like effects.
Conclusion: We conclude that, based on in vivo and in silico data, CMN, alone or in combination with FLU, may be employed in future neurological clinical studies. However, further research is needed to confirm this behavioral activity and elucidate the possible mechanism of action.
期刊介绍：
Behavioural Brain Research is an international, interdisciplinary journal dedicated to the publication of articles in the field of behavioural neuroscience, broadly defined. Contributions from the entire range of disciplines that comprise the neurosciences, behavioural sciences or cognitive sciences are appropriate, as long as the goal is to delineate the neural mechanisms underlying behaviour. Thus, studies may range from neurophysiological, neuroanatomical, neurochemical or neuropharmacological analysis of brain-behaviour relations, including the use of molecular genetic or behavioural genetic approaches, to studies that involve the use of brain imaging techniques, to neuroethological studies. Reports of original research, of major methodological advances, or of novel conceptual approaches are all encouraged. The journal will also consider critical reviews on selected topics.
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