Abhishek Kumar Singh

Erythrocytes are particularly vulnerable toward age-dependent oxidative stress-mediated damage. Caloric restriction mimetics (CRMs) may provide a novel strategy for the maintenance of redox balance as well as effective treatment of age-associated diseases. Herein, we have investigated the beneficial effect of cotreatment with CRM-candidate drugs, rapamycin (an immunosuppressant drug and inhibitor of mammalian target of rapamycin) and metformin (an antidiabetic biguanide and activator of adenosine monophosphate kinase), against aging-induced oxidative stress in erythrocytes and plasma of aging rats. Male Wistar rats of age 4 (young) and 24 months (old) were coexposed to rapamycin (0.5 mg/kg body weight [b.w.]) and metformin (300 mg/kg b.w.), and data were compared with the response of rats receiving an independent exposure to these chemicals at similar doses. The exposure of individual candidate drugs significantly reversed the age-dependent alterations in the endpoints associated with oxidative stress such as reactive oxygen species, ferric reducing ability of plasma, malondialdehyde, reduced glutathione, plasma membrane redox system, plasma protein carbonyl, and acetyl cholinesterase in erythrocytes and plasma of aging rats. However, the cotreatment with rapamycin and metformin showed a significant augmented effect compared with individual drug interventions on reversal of these age-dependent biomarkers of oxidative stress, suggesting a synergistic response. Thus, the findings open up further possibilities for the design of new combinatorial therapies to prevent oxidative stress- and age-associated health problems.

Metformin, a biguanide drug commonly used to treat type 2 diabetes, has been noted to function as a caloric restriction mimetic. Its antidiabetic effect notwithstanding, metformin is currently being considered an antiaging drug candidate, although the molecular mechanisms have not yet been unequivocally established. This study aims to examine whether short-term metformin treatment can provide protective effects against oxidative stress in young and old-age rats. Young (age 4 months) and old (age 24 months) male Wistar rats were treated with metformin (300 mg/kg b.w.) for 4 weeks. At the end of the treatment period, an array of biomarkers of oxidative stress were evaluated, including plasma antioxidant capacity measured in terms of ferric reducing ability of plasma (FRAP), reactive oxygen species (ROS), lipid peroxidation (MDA), reduced glutathione (GSH), total plasma thiol (SH), plasma membrane redox system (PMRS), protein carbonyl (PCO), advanced oxidation protein products (AOPPs), and advanced glycation end products (AGEs) in control and experimental groups. Metformin treatment resulted in an increase in FRAP, GSH, SH, and PMRS activities in both age groups compared to respective controls. On the other hand, treated groups exhibited significant reductions in ROS, MDA, PCO, AOPP, and AGE level. Save for FRAP and protein carbonyl, the effect of metformin on all other parameters was more pronounced in old-aged rats. Metformin caused a significant increase in the PMRS activity in young rats, however, the effect was less pronounced in old rats. These findings provide evidence with respect to restoration of antioxidant status in aged rats after short-term metformin treatment. The findings substantiate the putative antiaging role of metformin.

The developing brain is found highly vulnerable towards the exposure of different environmental chemicals/drugs, even at concentrations, those are generally considered safe in mature brain. The brain development is a very complex phenomenon which involves several processes running in parallel such as cell proliferation, migration, differentiation, maturation and synaptogenesis. If any step of these cellular processes hampered due to exposure of any xenobiotic/drug, there is almost no chance of recovery which could finally result in a life-long disability. Therefore, the developmental neurotoxicity (DNT) assessment of newly discovered drugs/molecules is a very serious concern among the neurologists. Animal-based DNT models have their own limitations such as ethical concerns and lower sensitivity with less predictive values in humans. Furthermore, non-availability of human foetal brain tissues/cells makes job more difficult to understand about mechanisms involve in DNT in human beings. Although, the use of cell culture have been proven as a powerful tool for DNT assessment, but many in vitro models are currently utilizing genetically unstable cell lines. The interpretation of data generated using such terminally differentiated cells is hard to extrapolate with in vivo situations. However, human umbilical cord blood stem cells (hUCBSCs) have been proposed as an excellent tool for alternative DNT testing because neuronal development from undifferentiated state could exactly mimic the original pattern of neuronal development in foetus when hUCBSCs differentiated into neuronal cells. Additionally, less ethical concern, easy availability and high plasticity make them an attractive source for establishing in vitro model of DNT assessment. In this review, we are focusing towards recent advancements on hUCBSCs-based in vitro model to understand DNTs.