The present findings showing the crucial role of EPOR in survival of astrocytes is in accordance with other reports demonstrating severe embryonic neurogenesis defects in animals null for either the EPO or EPOR gene, suggesting that EPOR is essential for EPO action during embryonic neurogenesis. The Amikacin hydrate impairment of glutamate uptake in EPOR-siRNA transfected APC hints to the possible decreased activity of glutamate 
transporters. The association between EPO-EPOR signalling pathway and GS is seen from slightly diminished expression of GS protein detected in EPOR-siRNA transfected APC by Western blotting and dramatically decreased the GS-activity both under NC and HC. Hypoxia and aging in culture conditions lead to increased expression of EPOR suggesting EPOR as a Gomisin-D marker of cell vulnerability. This assumption is further supported by our in vivo data showing a prominent increase in EPOR expression during aging in the brains of wild type and APP/PS1 mice. Here we also show decreased EPO expression in APP/PS1 in comparison with age-matched WT controls. This finding hints at the limited capacity of brain cells to up-regulate EPO as a mechanism of defence against hypoxic and Gluinduced cytotoxicity during Alzheimer’s-like pathologies. The scenario of EPOR upregulation as a self-defensive mechanism under Alzheimer’s-like neurodegeneration is supported by several studies showing a protective effects of EPO against Amyloid beta toxicity. EPO prevents early and late apoptotic neuronal injury during A�� toxicity involving the EPOR signalling and nuclear translocation of NF��B. An in vivo study of Arabpoor et al. has shown a proliferative effect of EPO on neurons in the dentate gyrus of rats with streptozotocininduced AD-like defects. The clinical relevance of our data showing a prominent increase in overall expression of EPOR in the brains of APP/PS1 mice is reflected by the studies showing increased EPOR in hippocampal and cortical astrocytes in patients with mild cognitive impairment and sporadic AD. Human study of Brettschneider et al. showed that EPO concentration in the cerebrospinal fluid of AD patients did not differ from their age-matched controls. This fact was explained by the existence of either a relative deficiency of EPO in the brain of AD patients and/or by the removal of free EPO molecules from brain intercellular fluid by increased numbers of EPOR. Our data support this assumption of Brettschneider et al. by demonstration of decreased EPO expression in the brains of transgenic APP/PS1 mice which correlates with increased EPOR expression when compared with their age-matched WT controls. In conclusion, the present study shows for the first time the direct correlation between the extent of culture-induced aging of astrocytes and the efficacy of EPO to improve the extracellular glutamate clearance and metabolism. Our results demonstrate the synchronizing effects of EPO on the individual chains of glutamate turnover and detoxification in young and aged astroglial cells. On one hand administration of EPO activates the glutamate transporters that reduces the extracellular concentrations of glutamate and on the other hand, increases the enzymatic activity of GS that contributes to catalysis of intracellular glutamate. The protective effects of EPO shown here depend on functionality of EPOR, without which astrocytes undergo overall apoptosis. These effects of EPO on glutamate turnover allow to consider EPO as a potent neuroprotective agent for anti-aging interventions both during normal aging and age-related degenerative diseases.