First evaluation of the anxiolytic-like effects of a bromazepam‑palladium complex in mice

A significant fraction of patients are affected by persistent fear and anxiety. Currently, there are several anxiolytic drug options, however their clinical outcomes do not fully manage the symptoms. Here, we evaluated the effects of a bromazepam‑palladium derivative [2-{(7-bromo-2-oxo-1,3-dihydro-2...

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Published in:	Journal of inorganic biochemistry Vol. 237; p. 112012
Main Authors:	Vieira, Mirella P.S., Silva, Ozileudiane B.S., Souza, Gabriela F., Cavalcante, Gabriela T.S., Souza, Fernanda M.A., Gitaí, Daniel L.G., Castro, Olagide W., Nicácio, Dannyele C.S.P., Cofré, Axel H.R., Amorós, Mariana A., Silva, Artur V., Neto, Geraldo José da Silva, Silva, Allysson H.Q., Correia, Walleska B.Z.G.B., Junkes, Janaína A., Duarte, Filipe S., Guedes, Jéssica S., Nogueira, Fábio C.S., Meneghetti, Mario R., Duzzioni, Marcelo
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-12-2022
Subjects:	Acute toxicity Animals Anti-Anxiety Agents - pharmacology Anti-Anxiety Agents - therapeutic use Anxiety Behavior, Animal Benzodiazepine-metal complexes Bromazepam Bromazepam - pharmacology Female Flumazenil - pharmacology gamma-Aminobutyric Acid Maze Learning Mice Palladium Palladium - pharmacology dd CRO DMSO NS GABAA NRU GHS PTX IC50 PTZ BZDs ICCVAM Anxiety AGC R2 Bromazepam ECA OECD 129 SDS d DMSO‑d6 (BMZ)PdCl2 ESI-HRMS pSAP IR Palladium Benzodiazepine-metal complexes i.p d.t m BMZ REA LD50 uHD NMR SEM Acute toxicity
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Summary:	A significant fraction of patients are affected by persistent fear and anxiety. Currently, there are several anxiolytic drug options, however their clinical outcomes do not fully manage the symptoms. Here, we evaluated the effects of a bromazepam‑palladium derivative [2-{(7-bromo-2-oxo-1,3-dihydro-2H-1,4-benzodiazepin-5-il)pyridinyl-κ2-N,N}chloropalladium(II)], [(BMZ)PdCl2], on fear/anxiety and memory-related behavior in mice. For this, female Swiss mice were treated intraperitoneally (i.p.) with saline (NaCl 0.9%) or [(BMZ)PdCl2] (0.5, 5.0, or 50 μg/kg). After 30 min, different tests were performed to evaluate anxiety, locomotion, and memory. We also evaluated the acute toxicity of [(BMZ)PdCl2] using a cell viability assay (neutral red uptake assay), and whether the drugs mechanism of action involves the γ-aminobutyric acid type A (GABAA) receptor complex by pre-treating animals with flumazenil (1.0 mg/kg, i.p., a competitive antagonist of GABAA-binding site). Our results demonstrate that [(BMZ)PdCl2] induces an anxiolytic-like phenotype in the elevated plus-maze test and that this effect can be blocked by flumazenil. Furthermore, there were no behavioral alterations induced by [(BMZ)PdCl2], as evaluated in the light-dark box, open field, and step-down passive avoidance tests. In the acute toxicity assay, [(BMZ)PdCl2] presented IC50 and LD50 values of 218 ± 60 μg/mL and 780 ± 80 mg/kg, respectively, and GSH category 4. Taken together, our results show that the anxiolytic-like effect of acute treatment with [(BMZ)PdCl2] occurs through the modulation of the benzodiazepine site in the GABAA receptor complex. Moreover, we show indications that [(BMZ)PdCl2] does not promote sedation and amnesia and presents the same toxicity as the bromazepam prototype. We evaluated the effects of a bromazepam-palladium complex on fear, anxiety and memory-related behaviors in mice. The results showed that the anxiolytic-like occurs through modulation of the benzodiazepine site in the GABAA receptor complex. There are indications that the complex does not promote sedation, amnesia and toxicity higher than bromazepam. [Display omitted] •Palladium-bromazepam complex, [(BMZ)PdCl2].•[(BMZ)PdCl2] showed an anxiolytic-like effect.•[(BMZ)PdCl2] did not affect locomotor activity and memory.•[(BMZ)PdCl2] showed similar acute toxicity to bromazepam.
ISSN:	0162-0134 1873-3344
DOI:	10.1016/j.jinorgbio.2022.112012