Does treatment with autophagy-enhancers and/or ROS-scavengers alleviate behavioral and neurochemical consequences of low-dose rotenone-induced mild mitochondrial dysfunction in mice?

Abstract

Bipolar-disorder’s pathophysiology and the mechanism by which medications exert their beneficial effect is yet unknown, but others’ and our data implicate patients’ brain mitochondrial-dysfunction and its amendment by mood-stabilizers. We recently designed a novel mouse bipolar-disorder-like model using chronic administration of a low-dose of the oxidative-phosphorylation complex I inhibitor, rotenone. Four and eight weeks rotenone treatment induced manic- and depressive-like behavior, respectively, accompanied by mood-related neurochemical changes. Here we aimed to investigate whether each of the autophagy-enhancers lithium (a mood-stabilizer), trehalose and resveratrol and/or each of the reactive oxygen species (ROS)-scavengers, resveratrol and N-acetylcystein and/or the combinations lithium+resveratrol or trehalose+N-acetylcystein, can ameliorate behavioral and neurochemical consequences of neuronal mild mitochondrial-dysfunction. We observed that lithium, trehalose and N-acetylcystein reversed rotenone-induced manic-like behavior as well as deviations in protein levels of mitochondrial complexes and the autophagy marker LC3-II. This raises the possibility that mild mitochondrial-dysfunction accompanied by impaired autophagy and a very mild increase in ROS levels are related to predisposition to manic-like behavior. On the other hand, although, as expected, most of the drugs tested eliminated the eight weeks rotenone-induced increase in protein levels of all hippocampal mitochondrial complexes, only lithium ubiquitously ameliorated the depressive-like behaviors. We cautiously deduce that aberrant autophagy and/or elevated ROS levels are not involved in predisposition to the depressive phase of bipolar-like behavior. Rather, that amending the depressive–like characteristics requires different mitochondria-related interventions. The latter might be antagonizing N-methyl-D-aspartate receptors (NMDARs), thus protecting from disruption of mitochondrial calcium homeostasis and its detrimental consequences. In conclusion, our findings suggest that by-and-large, among the autophagy-enhancers and ROS-scavengers tested, lithium is the most effective in counteracting rotenone-induced changes. Trehalose and N-acetylcystein may also be effective in attenuating manic-like behavior.

Non-canonical pathways in the pathophysiology and therapeutics of bipolar disorder

“…The putative link between BD and mitochondrial dysfunction rests on the notion that mitochondrial dysfunction is a critical pathological factor that can be intimately linked to a wide range of processes associated with treatment outcomes and disease progression or severity ( Scaini et al, 2016 , 2021 ). A recent preclinical study of low-dose rotenone-induced manic- and depressive-like behaviors corroborated the concept that BD involves a gradual decrease in mitochondrial function, with symptoms beginning only when a threshold is reached or when an event occurs that requires fully functional cells, making the individual more vulnerable to environmental factors that target mitochondrial function ( Damri et al, 2023 ). Mitochondria also critically regulate energy production and control the production of reactive oxygen species (ROS), which are also involved in mood disorders ( Barnham et al, 2004 ).…”

Mitochondria in depression: The dysfunction of mitochondrial energy metabolism and quality control systems

“…Moreover, mitochondrial dysfunction not only impairs energy production but can also be linked with metabolic and neuropsychiatric disorders such as depression 4 . The concept that mitochondrial dysfunction is one of the causes of depression, is supported by a wide range of studies on cell cultures, animal models, and clinical researches 5,7–9 . The review will focus on the findings that implicate abnormalities in mitochondrial morphology and function, as well as the resultant quality control systems as important etiological factors in the context of depressive disorders.…”

Reversal of rotenone-induced mild mitochondrial dysfunction and manic- and depressive-like behavior

“…Eight weeks of rotenone increased LC3II and p62 in hippocampus and only LC3II in frontal cortex. Drug treatment effects were mixed (Damri and others 2023). The most meaningful findings are that on the forced swim test, at four weeks, rotenone produced manic-like behavior and at eight weeks depressive-like behavior, and at eight weeks, rotenone increased frontal cortex protein levels of all five mitochondrial respiration complexes, and these effects were reversed by the autophagy enhancers and reactive oxygen species scavengers.…”