Exploring Zn(II)-Acetyl l-carnitine complex for simultaneous management of depression, chronic pain, and neuroprotection

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.