Janetsi Y. Caro-Ramírez , Leandro O. Bazán , Oscar E. Piro , Gustavo A. Echeverría , Khalil Jori , Martín Mizrahi , Carlos A. Franca , María Luz Lambrisca , Joaquín A. Bustos , Carlos H. Laino , María Varcalcel , Clarisa Salado , Luciana G. Naso , Patricia A.M. Williams , Evelina G. Ferrer
{"title":"Exploring Zn(II)-Acetyl l-carnitine complex for simultaneous management of depression, chronic pain, and neuroprotection","authors":"Janetsi Y. Caro-Ramírez , Leandro O. Bazán , Oscar E. Piro , Gustavo A. Echeverría , Khalil Jori , Martín Mizrahi , Carlos A. Franca , María Luz Lambrisca , Joaquín A. Bustos , Carlos H. Laino , María Varcalcel , Clarisa Salado , Luciana G. Naso , Patricia A.M. Williams , Evelina G. Ferrer","doi":"10.1016/j.jinorgbio.2025.112857","DOIUrl":null,"url":null,"abstract":"<div><div>Acetyl-<span>l</span>-carnitine (ALC) is synthesized in the brain, liver, and kidneys and plays crucial roles in energy metabolism, acetylcholine production, protein synthesis, and neuronal protection, contributing to its antidepressant and neuroprotective properties. Zinc, a vital biometal, is essential for depression and neuroprotection, exhibiting antidepressive effects alone or combined with classical antidepressants. The pharmacological benefits of metal coordination complexes often result from synergistic or additive effects. In this study, we present a novel multifunctional zinc complex, Zn(<em>ALC</em>)Cl<sub>2</sub>(H<sub>2</sub>O), which crystallizes in the monoclinic chiral space group <em>P</em>2<sub>1</sub>, featuring a distorted tetrahedral Zn(II) environment. This new compound demonstrates significantly higher antidepressant activity, reducing immobility in the forced swimming test by 54 % compared to commercial ALC. Additionally, it exhibits <em>in vivo</em> antinociceptive properties, increases latency time, and proves effective in a diabetic neuropathy model by preventing the glucose-induced decrease in intracellular GSH levels. <em>In vitro</em> studies indicate that the complex can cross the blood-brain barrier and offer neuroprotection against glutamate-induced excitotoxicity and oxygen-glucose deprivation, with a drug classification of 10 <em>versus</em> 5 for ALC. Furthermore, under astrocytosis conditions, the Zn complex neutralizes the toxic effects of TGFβ-treated astrocytes. These findings highlight Zn(<em>ALC</em>)Cl<sub>2</sub>(H<sub>2</sub>O) as a promising candidate for treating depression and neurodegenerative diseases.</div></div>","PeriodicalId":364,"journal":{"name":"Journal of Inorganic Biochemistry","volume":"267 ","pages":"Article 112857"},"PeriodicalIF":3.8000,"publicationDate":"2025-02-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Inorganic Biochemistry","FirstCategoryId":"99","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0162013425000376","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Acetyl-l-carnitine (ALC) is synthesized in the brain, liver, and kidneys and plays crucial roles in energy metabolism, acetylcholine production, protein synthesis, and neuronal protection, contributing to its antidepressant and neuroprotective properties. Zinc, a vital biometal, is essential for depression and neuroprotection, exhibiting antidepressive effects alone or combined with classical antidepressants. The pharmacological benefits of metal coordination complexes often result from synergistic or additive effects. In this study, we present a novel multifunctional zinc complex, Zn(ALC)Cl2(H2O), which crystallizes in the monoclinic chiral space group P21, featuring a distorted tetrahedral Zn(II) environment. This new compound demonstrates significantly higher antidepressant activity, reducing immobility in the forced swimming test by 54 % compared to commercial ALC. Additionally, it exhibits in vivo antinociceptive properties, increases latency time, and proves effective in a diabetic neuropathy model by preventing the glucose-induced decrease in intracellular GSH levels. In vitro studies indicate that the complex can cross the blood-brain barrier and offer neuroprotection against glutamate-induced excitotoxicity and oxygen-glucose deprivation, with a drug classification of 10 versus 5 for ALC. Furthermore, under astrocytosis conditions, the Zn complex neutralizes the toxic effects of TGFβ-treated astrocytes. These findings highlight Zn(ALC)Cl2(H2O) as a promising candidate for treating depression and neurodegenerative diseases.
期刊介绍:
The Journal of Inorganic Biochemistry is an established international forum for research in all aspects of Biological Inorganic Chemistry. Original papers of a high scientific level are published in the form of Articles (full length papers), Short Communications, Focused Reviews and Bioinorganic Methods. Topics include: the chemistry, structure and function of metalloenzymes; the interaction of inorganic ions and molecules with proteins and nucleic acids; the synthesis and properties of coordination complexes of biological interest including both structural and functional model systems; the function of metal- containing systems in the regulation of gene expression; the role of metals in medicine; the application of spectroscopic methods to determine the structure of metallobiomolecules; the preparation and characterization of metal-based biomaterials; and related systems. The emphasis of the Journal is on the structure and mechanism of action of metallobiomolecules.