Erythropoietin Rescues Memory Impairment in a Rat Model of Chronic Cerebral Hypoperfusion via the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β Pathway

Abstract

Vascular dementia is the second most common cause of dementia in older people and is characterized by the sudden onset of impairments in thinking skills and behavior, which generally occur following a stroke. Unfortunately, effective therapy for vascular dementia remains inadequate. Erythropoietin (EPO) is a glycoprotein hormone that controls erythropoiesis, or red blood cell production. Recently, a prominent role for EPO has been defined in the nervous system, and there is growing interest in the potential therapeutic use of EPO for neuroprotection. However, whether it is protective from memory impairments and the underlying mechanisms of vascular dementia (VD) remains unknown. In the current study, we reported that supplements with exogenous erythropoietin (EPO) for 4 weeks could restore impaired memory in 2-vessel occlusion (2VO) rats, a well-established vascular dementia animal model. EPO also rescued impairments in dendritic spines and cholinergic dysfunctions in the hippocampus. Moreover, EPO suppressed the overactivation of GSK-3β in the hippocampus by stimulating the JAK2/STAT5/PI3K/Akt signal pathway. Furthermore, we found that genetic knockdown of the EPO receptor (EPO-R) by shRNA blocks the neuroprotection conferred by EPO on memory in VD. We hypothesized that EPO treatment is able to rescue the memory impairments in VD by stimulating the EPO-R/JAK2/STAT5/PI3K/Akt/GSK-3β pathway and suggest the potential usage of EPO in the therapy for VD.

A novel squaramide compound alleviates cognitive deficits through activation of Akt and Erk1/2 in a rat model of vascular dementia

“…The effect of bpV(pis) was tested for the first time in the vascular dementia rats induced by 2VO. Consistent with previous findings, animal spatial cognitive function and memory functions and morphological structure in hippocampus tissue were impaired in the VD model (Chen et al, 2018b;Hu et al, 2017;Li et al, 2017;Ma et al, 2018), whereas bpV(pis) treatment significantly alleviated cognitive impairment and the morphological changes induced by 2VO.…”

GSK3β: a plausible mechanism of cognitive and hippocampal changes induced by erythropoietin treatment in mood disorders?

“…The involvement of GSK3β in EPO-mediated neuroprotection via PI3K/AKT is well documented in the literature (e.g. see refs 45 , 114 – 116 ). In the context of primary hippocampal neurons, EPO treatment triggers pro-survival mechanisms by activation of PI3K/AKT 45 , which suppresses downstream target GSK3β (i.e., by increasing phosphorylation of Ser9 in GSK3β) 117 .…”

“…In contrast, PI3K/AKT pathway inactivation results in GSK3β pro-apoptotic functions. In a recent study, Ma and colleagues 116 administered exogenous EPO to rats for 4 weeks using an animal model of vascular dementia. Their results indicated improvements in memory impairment, promotion of hippocampal dendritic spine growth as well as deactivation of GSK3β via an EPO-R/JAK2/STAT5/PI3K/Akt/GSK3β pathway 116 (Fig.…”

Cognitive interventions for adults with chronic kidney disease: protocol for a scoping review

“…Methylphenidate is another central nervous system stimulant that has shown some benefit for cancer-related cognitive impairment in early-phase studies [26]. Erythropoietin is a hormonal treatment for anemia (used commonly in CKD patients) that has been reported to have neuroprotective effects in both animal [27,28] and human studies [29,30], while other approaches, such as antidepressant medications for stroke [31] and depression [32], have also been associated with positive cognitive outcomes.…”