Psychiatric Disorders and Oxidative Injury: Antioxidant Effects of Zolpidem Therapy disclosed In Silico

Abstract

Zolpidem ( N , N -Dimethyl-2-[6-methyl-2-(4-methylphenyl)imidazo[1,2- a ]pyridin-3-yl]acetamide) is a well-known drug for the treatment of sleeping disorders. Recent literature reports on positive effects of zolpidem therapy on improving renal damage after cisplatin and on reducing akinesia without sleep induction. This has been ascribed to the antioxidant and neuroprotective capacity of this molecule, and tentatively explained according to a generic structural similarity between zolpidem and melatonin. In this work, we investigate in silico the antioxidant potential of zolpidem as scavenger of five ROSs, acting via hydrogen atom transfer (HAT) mechanism; computational methodologies based on density functional theory are employed. For completeness, the analysis is extended to six metabolites. Thermodynamic and kinetic results disclose that indeed zolpidem is an efficient radical scavenger, similarly to melatonin and Trolox, supporting the biomedical evidence that the antioxidant potential of zolpidem therapy may have a beneficial effect against oxidative injury, which is emerging as an important etiopathogenesis in numerous severe diseases, including psychiatric disorders.

Major Depressive Disorder and Oxidative Stress: In Silico Investigation of Fluoxetine Activity against ROS

“…The most reactive sites are the hydroxyl group and the amine groups. Rather large negative ∆G • HAT values are also computed from the C atoms of the hydrocarbon chain, which is in agreement with the reactivity described for melatonin and zolpidem [38]. In order to verify whether there are more efficient scavenging channels for fluoxetine, we have also investigated the RAF mechanism involving the aromatic C sites.…”

“…Sci. 2019, 9, 3631 5 of 15 molecules displaying antioxidant properties, including Trolox [50], melatonin [51], and capsaicin [52], but also psychotropic drugs such as zolpidem [38]. These mechanisms are summarized in Figure 2.…”

“…Computational methodologies are nowadays largely employed to rationalize chemical and biochemical phenomena. Particularly, accurate mechanistic studies on the control of oxidative stress by endogenous defenses, including enzymes such as glutathione peroxidase [30][31][32], and molecular drugs that act as mimics of these enzymes [33][34][35][36][37] or as radical scavengers [38] have been reported by some of us. In this work, we investigate in silico the antioxidant activity of fluoxetine via HAT (hydrogen atom transfer) and RAF (radical adduct formation) mechanisms.…”

“…Also, for CH 3 O • , increasing the solvent polarity results in thermodynamically more favored reactions. The reactivity of C sites 14 and 15 of fluoxetine recalls the reactivity of the topologically similar C site 4 in melatonin [46] and zolpidem [38]. By comparing the transfer of the methylene hydrogens to HO • in these compounds, which were computed at the same level of theory, [38] The transition states and thus the activation energies were computed only for the exergonic reactions; they are reported in Table 1.…”

Emulated Clinical Trials from Longitudinal Real-World Data Efficiently Identify Candidates for Neurological Disease Modification: Examples from Parkinson’s Disease

“…Garcia-Santos et al 43 demonstrated that zolpidem prevented induced lipid peroxidation in rat liver and brain homogenates, showing antioxidant properties similar to melatonin. Bortoli et al 42 investigated in silico the antioxidant potential of zolpidem and identified it as an efficient radical scavenger similar to melatonin and Trolox. Although the mechanisms involved in the pathogenesis and progression of PD are not fully understood, there is overwhelming evidence that oxidative stress plays an important role in dopaminergic neuronal degeneration.…”