ABSTRACT
Alzheimer's disease is one of the most common ageassociated diseases that frequently leads to memory disorders, cognitive decline and dementia. Evidence suggests that nicergoline serves an important role in the apoptosis of hippocampal cells, memory recovery, cognitive function and neuronal survival. However, the signaling pathway affected by nicergoline treatment remains to be elucidated. The purpose of the present study was to investigate the role of nicergoline in the cognitive competence of a mouse model of Alzheimer's disease. The apoptosis rates of hippocampal cells were studied in mice with Alzheimer's disease treated with nicergoline compared with the negative control. Apoptosisassociated gene expression levels in hippocampal cells, and hippocampus area, were analyzed in the experimental mice. Visual attention and inhibitory control were assessed and neural counting was performed in brain regions of interest. The phosphatidylinositol 3kinase (PI3K)/RACα serine/threonineprotein kinase (AKT) signaling pathway was additionally analyzed in hippocampal cells following treatment with nicergoline. The results of the present study demonstrated that nicergoline ameliorated apoptosis in hippocampal cells and hippocampus tissue in 3xTgAD mice with Alzheimer's disease. The data indicated that apoptosisassociated genes, including caspase3, BCL2 associated X, BH3 interacting domain death agonist and caspase9, were downregulated in hippocampal cells isolated from nicergoline-treated experimental mice. In addition, the expression levels of inflammatory factors, in addition to oxidative stress, were decreased in hippocampal cells treated with nicergoline. Additionally, amyloid precursor protein accumulation was cleared in the hippocampal area in nicergolinetreated mice. Nicergoline inhibited neuronal loss and prevented cognitive impairment through the restoration of learning/memory ability. It was additionally demonstrated in the present study that nicergoline improved motor attention impairment and cognitive competence in hippocampal cells by acting on the PI3K/AKT signaling pathway. Therefore, memory recovery, cognitive function and neuronal survival were repaired by nicergoline via inhibition of the PI3K/AKT signaling pathway, suggesting that nicergoline may be an efficient drug for the clinical treatment of patients with Alzheimer's disease.
Subject(s)
Alzheimer Disease/drug therapy , Cognition/drug effects , Neuroprotective Agents/therapeutic use , Nicergoline/therapeutic use , Nootropic Agents/therapeutic use , Phosphatidylinositol 3-Kinase/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Animals , Disease Models, Animal , Hippocampus/drug effects , Hippocampus/metabolism , Hippocampus/physiopathology , Male , Mice , Neurogenesis/drug effects , Neuroprotective Agents/pharmacology , Nicergoline/pharmacology , Nootropic Agents/pharmacology , Signal Transduction/drug effectsABSTRACT
BACKGROUND: Ischemia-reperfusion (I/R) injury is the major cause of delayed renal graft function in kidney transplantation. To date, there are no effective therapeutic approaches for preventing I/R injury. We previously reported that treatment of animals with small interference RNA (siRNA) would prevent warm I/R injury in nontransplant models and cold I/R injury in heart transplantation. In the present study, we further explore the feasibility of protecting grafts from extended cold I/R injury as applied to kidney transplantation by downregulating I/R-associated genes using siRNA. METHODS: Donor kidneys were intra-arterially perfused with siRNA containing solution during donor excision and preserved in siRNA containing solution. The siRNA-treated donor organs were then implanted into syngeneic recipient mice, and the 2 original kidneys were removed from the recipient. The effect of siRNA solution on extended cold I/R injury was determined by assessing renal function, histopathological change, cell apoptosis, and inflammation. RESULTS: The perfused siRNA solution knocked down the expression of complement 3, RelB, and Fas in the kidney at the mRNA and protein levels. Administration of siRNA solution reduced the levels of blood urea nitrogen and serum creatinine as compared with control groups. The siRNA cocktail decreased cell apoptosis and histopathological changes in the kidney and prolonged graft survival. The siRNA cocktail also reduced the expression of proinflammatory cytokines, IL-6, and TNFα. CONCLUSIONS: In conclusion, this is the first demonstration that perfusing donor organs with an siRNA cocktail solution can induce gene silencing in the kidney and prevent kidneys from extended cold I/R injury in kidney transplantation, highlighting the promise of the clinical application of siRNA-based therapies in the preservation of donor organs.
Subject(s)
Cold Ischemia , Kidney Transplantation/methods , Kidney/surgery , Organ Preservation/methods , Perfusion/methods , RNA, Small Interfering/administration & dosage , RNAi Therapeutics/methods , Reperfusion Injury/prevention & control , Animals , Apoptosis , Cold Ischemia/adverse effects , Complement C3/genetics , Complement C3/metabolism , Gene Expression Regulation , Inflammation Mediators/metabolism , Interleukin-6/genetics , Interleukin-6/metabolism , Kidney/metabolism , Kidney/pathology , Kidney/physiopathology , Kidney Transplantation/adverse effects , Male , Mice, Inbred C57BL , RNA, Small Interfering/metabolism , Recovery of Function , Reperfusion Injury/genetics , Reperfusion Injury/metabolism , Reperfusion Injury/pathology , Signal Transduction , Time Factors , Transcription Factor RelB/genetics , Transcription Factor RelB/metabolism , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/metabolism , fas Receptor/genetics , fas Receptor/metabolismABSTRACT
Ischemia reperfusion (I/R) injury is an unavoidable event occurring during heart transplantation, leading to graft failures and lower long-term survival rate of the recipient. Several studies have demonstrated that microRNAs (miRNAs) are vital regulators of signalling pathways involved in I/R injury. The present study aims to quantify the altered expression levels of miRNA and mRNA upon I/R injury in a mouse heart transplantation model, and to investigate whether these miRNA can regulate genes involved in I/R injury. We performed heterotopic heart transplantation on mouse models to generate heart tissue samples with I/R and non-I/R (control). The expression levels of miRNAs as well as genes were measured in heart grafts by microarray and real time RT-PCR. miRNA alteration in cardiomyocytes exposed to hypoxia was also detected by qRT-PCR. We observed significant alterations in miRNA and gene expression profile after I/R injury. There were 39 miRNAs significantly downregulated and 20 upregulated up to 1.5 fold in heart grafts with I/R injury compared with the grafts without I/R. 48 genes were observed with 3 fold change and p<0.05 and 18 signalling pathways were enriched using Keggs pathway library. Additionally, hypoxia/reperfusion induced primary cardiomyocyte apoptosis and altered miRNA expression profiles. In conclusion, this is the first report on miRNA expression profile for heart transplantation associated with I/R injury. These findings provide us with an insight into the role of miRNA in I/R injury in heart transplantation.
