Demonstration of an anti‐oxidative stress mechanism of quetiapine

Abstract

Quetiapine is an atypical antipsychotic drug (APD) for the treatment of symptoms in patients with schizophrenia. This drug effectively alleviates positive and negative symptoms as well as cognitive impairment [1][2][3]. In addition, quetiapine is well tolerated and causes the lowest incidence of extra-pyramidal symptoms [1,4] We have shown that quetiapine, a new antipsychotic drug, protects cultured cells against oxidative stress-related cytotoxicities induced by amyloid b (Ab)25-35, and that quetiapine prevents memory impairment and decreases Ab plaques in the brains of amyloid precursor protein (APP) ⁄ presenilin-1 (PS-1) double-mutant mice. The aim of this study was to understand why quetiapine has these protective effects. Because the cytotoxicity of both Ab(25-35) and Ab(1-40) requires fibril formation, our first experiments determined the effect of quetiapine on Ab(25-35) aggregation. Quetiapine inhibited Ab(25-35) aggregation in cell-free aqueous solutions and blocked the fibrillar aggregation of Ab(25-35), as observed under an electron microscope. We then investigated why quetiapine inhibits Ab(25-35) aggregation. During the aggregation of Ab(25-35), a hydroxyl radical (OH • ) was released, which in turn amplified Ab(25-35) aggregation. Quetiapine blocked OH• -induced Ab(25-35) aggregation and scavenged the OH• produced in the Fenton system and in the Ab(25-35) solution, as analyzed using electron paramagnetic resonance spectroscopy. Furthermore, new compounds formed by quetiapine and OH• were observed in MS analysis. Finally, we applied Ab(25-35) to PC12 cells to observe the effect of quetiapine on living cells. Ab(25-35) increased levels of intracellular reactive oxygen species and calcium in PC12 cells and caused cell death, but these toxic effects were prevented by quetiapine. These results demonstrate an anti-oxidative stress mechanism of quetiapine, which contributes to its protective effects observed in our previous studies and explains the effectiveness of this drug for Alzheimer's disease patients with psychiatric and behavioral complications.

Quetiapine, Olanzapine and Haloperidol Affect Human Plasma Lipid Peroxidation in vitro

“…QUE at higher doses has a significant antioxidant effect. Similar data were demonstrated by Xu et al [37] . They showed that QUE protects cultured cells against oxidative stress-related cytotoxicities induced by amyloid-␤ by blocking hydroxyl radical generation induced by amyloid.…”

“…They showed that QUE protects cultured cells against oxidative stress-related cytotoxicities induced by amyloid-␤ by blocking hydroxyl radical generation induced by amyloid. QUE by eliminating hydroxyl radical attenuates oxidative stress thus protecting brain cells against oxidative-stress-related damage and improving cognitive function in patients with schizophrenia [37] . The antioxidant mechanism of QUE may contribute to the low incidence of EPS and movement disorders caused by this drug in patients with schizophrenia, and may be effective in treating TD caused by other antipsychotics [38] .…”

The Neuroprotective Effects of Decursin Isolated from Angelica gigas Nakai Against Amyloid β-Protein-Induced Apoptosis in PC 12 Cells via a Mitochondria-Related Caspase Pathway

“…Ab [25][26][27][28][29][30][31][32][33][34][35] , the most toxic peptide fragment derived from the amyloid precursor protein, was dissolved in deionized distilled water at a concentration of 1 mM, and was incubated in a 37°C for 72 h to induce maximal aggregation according to the previous report [39]. The solution was stored at -80°C to create stable conditions for the aged stock solution, and diluted in serum-free medium to desired concentrations immediately before use.…”

Synaptic Mitochondrial Pathology in Alzheimer's Disease

“…Previous studies have provided evidence for the protection of mitochondrial function in ameliorating synaptic changes and the consequent cognitive impairments in AD animal models. A representative example of the many mitochondria-protecting approaches is the application of antioxidants to human AD, AD animal and cell models, which demonstrates significant amelioration of mitochondrial/neuronal dysfunction against Ab toxicity (28,31,74,90). More recent studies suggested the striking efficacy of mitochondria-targeting antioxidants including MitoQ, SS peptides, and MitoE in strengthening mitochondria in their respiration, membrane potential, and calcium-handling capacity from toxic insults including the Ab (45,53,78).…”