RESUMO
Psychosis is a known risk factor for developing metabolic syndrome (MetS). The risk is even greater in patients who are taking second-generation antipsychotics (SGAs). SGAs exacerbate metabolic abnormalities and lead to a 3-fold increased risk of severe weight gain, type 2 diabetes, and cardiovascular disease in patients. Mitochondrial dysfunction is a hallmark of MetS. Mitochondria process glucose and fatty acids into ATP. If these processes are impaired, it can result in dyslipidaemia, hyperglycaemia and an imbalance between nutrient input and energy output. This leads to increased adiposity, insulin resistance and atherosclerosis. It is unclear how SGAs induce MetS and how mitochondria might be involved in this process. It has been found that SGAs impair cellular glucose uptake in liver, dysregulating glucose and fatty acid metabolism which leads to an accumulation of glucose and/or lipids and an increase reactive oxygen species (ROS) which target mitochondrial proteins. This affects complexes of the electron transport chain (ETC) to reduce mitochondrial respiration. While there is a suggestion that SGAs may interact with a variety of processes that disrupt mitochondrial function, some of the results are conflicting, and a clear picture of how SGAs interact with mitochondria in different cell types has not yet emerged. Here, we outline the current evidence showing how SGAs may trigger mitochondrial dysfunction and lead to the development of MetS.
RESUMO
Neural stem cell (NSC) transplantation is an emerging and promising approach to combat neurodegenerative diseases. While NSCs can differentiate into neural cell types, many therapeutic effects are mediated by paracrine, "drug-like" mechanisms. Neurodegenerative diseases are predominantly a burden of the elderly who commonly suffer from comorbidities and thus are subject to pharmacotherapies. There is substantial knowledge about drug-drug interactions but almost nothing is known about a potential impact of pharmacotherapy on NSCs. Such knowledge is decisive for designing tailored treatment programs for individual patients. Previous studies revealed preliminary evidence that the anti-depressants fluoxetine and imipramine may affect NSC viability and proliferation. Here, we derive a hypothesis on how commonly applied drugs, statins and antihypertensives, may affect NSC viability, proliferation, and differentiation. We conducted a systematic review and meta-analysis looking at potential effects of commonly prescribed antihypertensive and antihyperlipidemic medication on NSC function. PubMed and Web of Science databases were searched on according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. Publications were assessed against a priori established selection criteria for relevancy. A meta-analysis was then performed on data extracted from publications eligible for full text review to estimate drug effects on NSC functions. Our systematic review identified 1,017 potential studies, 55 of which were eligible for full text review. Out of those, 21 were included in the qualitative synthesis. The meta-analysis was performed on 13 publications; the remainder were excluded as they met exclusion criteria or lacked sufficient data to perform a meta-analysis. The meta-analysis revealed that alpha-2 adrenoceptor agonists, an anti-hypertensive drug class [p < 0.05, 95% confidence intervals (CI) = -1.54; -0.35], and various statins [p < 0.05, 95% CI = -3.17; -0.0694] had an inhibiting effect on NSC proliferation. Moreover, we present preliminary evidence that L-type calcium channel blockers and statins, particularly lovastatin, may reduce NSC viability. Although the data available in the literature is limited, there are clear indications for an impact of commonly applied drugs, in particular statins, on NSC function. Considering the modes of action of the respective drugs, we reveal plausible mechanisms by which this impact may be mediated, creating a testable hypothesis, and providing insights into how future confirmative research on this topic may be conducted.
