ВИВЧЕННЯ ГОСТРОЇ ТОКСИЧНОСТІ ПРЕПАРАТУ АРГОЦИД ПРИ ВНУТРІШНЬООЧЕРЕВИННОМУ ВВЕДЕННІ

The aim of the work. Study of acute toxicity of the veterinary drug Argocide –solution for intracisternal administration with intraperitoneal administration to sexually mature white rats.Materials and Methods. The object of the study was a series of a combined drug of Argocide containing silver citrate, D-panthenol and L-arginine for the treatment of subclinical mastitis in cattle. The acute toxicity study was carried out in experiments on white non-linear sexually mature rats of both sexes, according to the requirements for potential drugs. The tests were performed with intraperitoneal administration of the drug in various doses – from 2.0 to 6.3 ml / kg. Statistical processing of data was performed using the t-test of the Student. For the statistical processing of data, the MS Excel program was used.Results and Discussion. As a result of the study of acute toxicity of Argoсide, it was established that integral indices of animal life– weight and body temperature did not undergo significant individual changes during 14 days of observation after single intraperitoneal administration. In studies of doses ranging from 1.58 ml / kg body weight of the animal to 5.0 ml / kg, it is determined that no case of death of domestic animals has been recorded with intraperitoneal administration of the drug at any dose. When using the drug in doses of 2.5 ml / kg and above, the animals showed clinical signs of intoxication immediately after the administration of the drug, which may be due to irritation of the peritoneum. Three days after the intraperitoneal administration of Argocide, no clinical signs of intoxication were observed.Conclusions. The analysis of the obtained data allows to classify the Argocide drug, the solution for intracisternal injection according to the degree of safety to relatively harmless preparations (VI class), since the average lethal dose exceeds 3.0 ml / kg of body weight of the animal with intraperitoneal administration.Мета роботи. Вивчення гострої токсичності ветеринарного препарату Аргоцид, розчин для інтрацистернального введення, при внутрішньоочеревинному введенні статевозрілим білим щурам.Матеріали і методи. Об'єктом дослідження були серії препарату Аргоцид, який містить цитрат срібла, D- пантенол та L- аргінін, призначений для лікування субклінічного маститу великої рогатої худоби. Дослідження гострої токсичності тест-зразків препарату Аргоцид проводили у дослідах на білих нелінійних статевозрілих щурах обох статей, віповідно до вимог, що висувають до потенційних ліків. Випробування проведені при внутрішньочеревному введенні препарату в різних дозах – від 2,0 до 6,3 мл / кг. Статистична обробка даних була виконана з використанням t-критерію Стьюдента. Для статистичної обробки даних використано програму MS Excel.Результати й обговорення. У результаті дослідження гострої токсичності препарату Аргоцид встановлено, що інтегральні показники життєдіяльності тварин – маса та температура тіла не зазнавали суттєвих індивідуальних змін вподовж 14 діб спостереження після одноразового внутрішньоочеревинного введення. При досліджені дози препарату у діапазоні від 1,58 мл/кг маси тіла тварини до 5,0 мл/кг визначено, що жодного випадку загибелі тварин не зареєстровано за внутрішньоочеревинного введення препарату у будь-якій дозі. При застосуванні препарату у дозах 2,5 мл/кг та вище у тварин проявилися клінічні ознаки інтоксикації відразу після введення препарату, що може бути пов’язано з подразненням очеревини. Через 3 доби після внутрішньоочеревинного застосування Аргоциду жодних клінічних ознак інтоксикації не спостерігали.Висновки. Аналіз отриманих даних дозволяє віднести препарат Аргоцид, розчин для інтрацистернального введення за ступенем небезпеки до відносно нешкідливих препаратів (VI клас) оскільки середня летальна доза перевищує 3,0 мл/кг маси тіла тварини за внутрішньоочеревинного введення

Modulation of Behavioral and Neurochemical Responses of Adult Zebrafish by Fluoxetine, Eicosapentaenoic Acid and Lipopolysaccharide in the Prolonged Chronic Unpredictable Stress Model

Long-term recurrent stress is a common cause of neuropsychiatric disorders. Animal models are widely used to study the pathogenesis of stress-related psychiatric disorders. The zebrafish (Danio rerio) is emerging as a powerful tool to study chronic stress and its mechanisms. Here, we developed a prolonged 11-week chronic unpredictable stress (PCUS) model in zebrafish to more fully mimic chronic stress in human populations. We also examined behavioral and neurochemical alterations in zebrafish, and attempted to modulate these states by 3-week treatment with an antidepressant fluoxetine, a neuroprotective omega-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA), a pro-inflammatory endotoxin lipopolysaccharide (LPS), and their combinations. Overall, PCUS induced severe anxiety and elevated norepinephrine levels, whereas fluoxetine (alone or combined with other agents) corrected most of these behavioral deficits. While EPA and LPS alone had little effects on the zebrafish PCUS-induced anxiety behavior, both fluoxetine (alone or in combination) and EPA restored norepinephrine levels, whereas LPS + EPA increased dopamine levels. As these data support the validity of PCUS as an effective tool to study stress-related pathologies in zebrafish, further research is needed into the ability of various conventional and novel treatments to modulate behavioral and neurochemical biomarkers of chronic stress in this model organism. © 2021, The Author(s).This research was supported solely by the Russian Science Foundation (RSF) grant 19‐15‐00053. K.A.D. is supported by the Special Rector’s Productivity Fellowship for SPSU PhD Students, and the lab is supported by St. Petersburg State University state budgetary funds (project ID 73026081). A.V.K. is the Chair of the International Zebrafish Neuroscience Research Consortium (ZNRC) and President of the International Stress and Behavior Society (ISBS, www.stress-and-behavior.com) that coordinated this collaborative multi-laboratory project. The consortium provided a collaborative idea exchange platform for this study, it is not considered as affiliation and did not fund the study. A.V.K. lab is supported by the Southwest University (SWU) Zebrafish Platform Construction Fund (Chongqing, China). The authors thank Professor Raul R. Gainetdinov (Institute of Translational Biomedicine, St. Petersburg State University, St. Petersburg, Russia) for his generous assistance with the HPLC studies in his laboratory. The funders had no role in the design, analyses, and interpretation of the submitted study, or decision to publish

Acute behavioral and Neurochemical Effects of Novel N-Benzyl-2-Phenylethylamine Derivatives in Adult Zebrafish

Hallucinogenic drugs potently affect brain and behavior and have also recently emerged as potentially promising agents in pharmacotherapy. Complementing laboratory rodents, the zebrafish (Danio rerio) is a powerful animal model organism for screening neuroactive drugs, including hallucinogens. Here, we test a battery of ten novel N-benzyl-2-phenylethylamine (NBPEA) derivatives with the 2,4- and 3,4-dimethoxy substitutions in the phenethylamine moiety and the -OCH3, -OCF3, -F, -Cl, and -Br substitutions in the ortho position of the phenyl ring of the N-benzyl moiety, assessing their acute behavioral and neurochemical effects in the adult zebrafish. Overall, substitutions in the Overall, substitutions in the N-benzyl moiety modulate locomotion, and substitutions in the phenethylamine moiety alter zebrafish anxiety-like behavior, also affecting the brain serotonin and/or dopamine turnover. The 24H-NBOMe(F) and 34H-NBOMe(F) treatment also reduced zebrafish despair-like behavior. Computational analyses of zebrafish behavioral data by artificial intelligence identified several distinct clusters for these agents, including anxiogenic/hypolocomotor (24H-NBF, 24H-NBOMe, and 34H-NBF), behaviorally inert (34H-NBBr, 34H-NBCl, and 34H-NBOMe), anxiogenic/hallucinogenic-like (24H-NBBr, 24H-NBCl, and 24H-NBOMe(F)), and anxiolytic/hallucinogenic-like (34H-NBOMe(F)) drugs. Our computational analyses also revealed phenotypic similarity of the behavioral activity of some NBPEAs to that of selected conventional serotonergic and antiglutamatergic hallucinogens. In silico functional molecular activity modeling further supported the overlap of the drug targets for NBPEAs tested here and the conventional serotonergic and antiglutamatergic hallucinogens. Overall, these findings suggest potent neuroactive properties of several novel synthetic NBPEAs, detected in a sensitive in vivo vertebrate model system, the zebrafish, raising the possibility of their potential clinical use and abuse