Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine–dihydropyridine hybrid molecule

Figueredo, Yanier Núñez; Rodríguez, Estael Ochoa; Reyes, Yamila Verdecia; Domínguez, Carmen Carrillo; Parra, Alicia Lagarto; Sánchez, Jeney Ramírez; Hernández, René Delgado; Verdecia, Marlene Porto; Pardo-Andreu, Gilberto L.

doi:10.1179/1743132813y.0000000216

Cited by 33 publications

(11 citation statements)

References 56 publications

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“…In fact, various studies have shown that zebrafish respond similar to mammals when treated with many pharmacological compounds [27][28][29]. For example, benzodiazepine medication causes sedative effects in mouse [30,31] and zebrafish [32]. For caffeine, it is not different: both rodents and zebrafish present anxiety-like behavior following caffeine exposure [33][34][35][36].…”

Section: Introductionmentioning

confidence: 99%

Caffeine Dose-Response Relationship and Behavioral Screening in Zebrafish

Santos¹,

Ruiz-Oliveira²,

Silva³

et al. 2017

The Question of Caffeine

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It has been centuries since humans consume coffee and get the benefits of this bean. Many researches worldwide continue to show healthful properties of coffee, while others suggest a number of side effects. In fact, anything consumed in excess may cause disturbance of the body functioning, whereas caffeine is a central nervous system stimulant that increases focus and improves performance, its high concentration can cause insomnia, dizziness, and vomiting. Thus, the question is: which coffee dose promotes benefits and prevents risks? To answer it, we used the zebrafish, a popular animal model that is at the vanguard of psychopharmacological research due to its unique combination of complexity and simplicity, translational relevance and applicability to high throughput behavioral drug screens. In the current study, we examine time-course and dose-dependent changes in zebrafish following exposure to caffeine. Our data show an inverted U-shaped path for the locomotor parameters and crescent path for the anxiety-like parameters. High doses are harmful to the individual, because the stimulating effect disappears and anxiogenic effects take place. We conclude that temporal analysis of zebrafish behavior is a sensitive method for the study of acute caffeine exposure-induced functional changes in the vertebrate brain.

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Section: Introductionmentioning

confidence: 99%

Caffeine Dose-Response Relationship and Behavioral Screening in Zebrafish

Santos¹,

Ruiz-Oliveira²,

Silva³

et al. 2017

The Question of Caffeine

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“…For example, if the response of animals to a compound is tested in both the LDB and the open field, an increase in LDB-light in the absence of a change in locomotor activity in the open field would suggest that the investigated compound has a specific anxiolytic effect, but no sedative effect, which is highly desirable in anxiolytics especially from a translational perspective (82)(83)(84). Upon literature review, we have found as many records in which the open field was performed as a test of locomotor activity (80,81,85,86), as we have found records in which it was performed as a test of anxiety (87)(88)(89)(90). Here, we identify an issue with the continuation of such tests as long-held standards that may not be appropriate, due to the researcher's degree of freedom in the interpretation of the test's meaning (91,92).…”

Section: Discussionmentioning

confidence: 96%

Reliability of Mouse Behavioural Tests of Anxiety: a Systematic Review and Meta-Analysis on the Effects of Anxiolytics

Rosso

Wirz

Loretan

et al. 2021

Preprint

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Animal research on anxiety and anxiety disorders relies on valid animal models of anxiety. However, the validity of widely used rodent behavioural tests of anxiety has repeatedly been questioned, as they often fail to produce consistent results across independent replicate studies using different study populations or different anxiolytic compounds. In this study, we assessed the sensitivity of behavioural tests of anxiety in mice to detect anxiolytic effects of drugs prescribed to treat anxiety in humans. To this end, we conducted a pre-registered systematic review of studies reporting tests of anxiolytic compounds against a control treatment using common behavioural tests of anxiety in mice. PubMed and EMBASE were searched on August 21 st 2019 for studies published in English and 814 papers were identified for inclusion. Risk of bias was assessed based on Syrcle’s risk of bias tool and the Camarades study quality checklist on a randomly selected subsample of 180 papers. Meta-analyses on effect sizes of treatments using standardized mean differences (Hedges’ g) showed that only two of 17 test measures reliably detected effects of anxiolytic compounds other than diazepam. Further, we report considerable variation in both direction and size of effects of most anxiolytics on most outcome variables, indicating poor replicability of test results. This was corroborated by high heterogeneity in most test measures. Finally, we found an overall high risk of bias. Our findings indicate a general lack of sensitivity of common behavioural tests of anxiety in mice to anxiolytic compounds and cast serious doubt on both construct and predictive validity of most of those tests. The use of animals to model human conditions can be justified only if the expected results are informative, reproducible, and translatable. In view of scientifically valid and ethically responsible research, we call for a revision of behavioural tests of anxiety in mice and the development of more predictive tests .

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“…Compounds and reagents JM-20 was synthesized, puri ed, and characterized as previously reported [22], in Analytic Chemistry Laboratory of CIDEM. All general chemicals used were purchased from Sigma-Aldrich (St. Louis, MO, USA).…”

Section: Methodsmentioning

confidence: 99%

“…starting on 15th day after the beginning of AlCl 3 treatment and until the end of the study. The dose range was selected based on previous experience [22]. To eliminate possible interactions, administration between these two compounds was staggered 30 minutes.…”

Section: Experimental Designmentioning

confidence: 99%

Multifunctional Molecule, JM-20, Reverses Aluminum Chloride-Induced Memory Impairment and Neuronal Damage in Rats

Wong-Guerra

Montano-Peguero

Ramírez-Sánchez

et al. 2021

Preprint

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Alzheimer's disease (AD) is a neurodegenerative disease that worsens with aging. Today, there is a worldwide effort to find new drugs that could delay the onset, slow the progression, or improve symptoms of AD. Oral administration of aluminum to rodents recapitulates some pathological alterations observed in AD, being considered a convenient tool for modeling and testing the efficacy of new therapeutics. Our previous studies have shown that JM-20, a dihydropyridine and benzodiazepine hybrid molecule protected memory in an environment with cholinergic dysfunction, high oxidative stress, hyperactivation of acetylcholinesterase (AChE) enzyme, and mitochondrial damage produced by scopolamine. In order to gain further insight into the effects on JM-20 on AD pathology, we evaluated the protective effects of JM-20 after chronic AlCl3 administration to rats, and assessed several types of episodic memory alterations and associated-pathological mechanisms, including mitochondrial dysfunction, AChE hyperactivity, inflammation, and apoptosis-related proteins. We used behavioral tasks to test spatial, working an emotional- associative memory, as well as molecular, enzymatic and histological assays to evaluate selected biochemical parameters. Our study showed that JM-20 prevented memory decline alongside with the inhibition of aluminum-induced alterations of oxidative parameters, and increase of AChE activity and of tumor necrosis factor alpha (TNF-α) levels. JM-20 also preserved anti-apoptotic proteins and protected against axonal and neuronal damaged in the hippocampus and prefrontal cortex. Altogether, our findings expanded our understanding of the ability of JM-20 to preserve essential types of memory in rats under neurotoxic conditions, and suggest its potential capacity to counteract etiological factors of AD by breaking the progression of key neurodegeneration-associated steps in a rat model of the disease.

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Characterization of the anxiolytic and sedative profile of JM-20: a novel benzodiazepine–dihydropyridine hybrid molecule

Abstract: These results indicate that JM-20 has an anxiolytic profile similar to DZP and its dihydropyridine moiety did not appear to interfere with the GABAergic activity associated with benzodiazepine. Furthermore, JM-20 did not show significant acute toxic effects in mice.

Cited by 33 publications

References 56 publications

Caffeine Dose-Response Relationship and Behavioral Screening in Zebrafish

Caffeine Dose-Response Relationship and Behavioral Screening in Zebrafish

Reliability of Mouse Behavioural Tests of Anxiety: a Systematic Review and Meta-Analysis on the Effects of Anxiolytics

Multifunctional Molecule, JM-20, Reverses Aluminum Chloride-Induced Memory Impairment and Neuronal Damage in Rats

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