Journal of Korean Neurosurgical Society

The Korean Neurosurgical Society (대한신경외과학회)
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Sildenafil Ameliorates Advanced Glycation End Products-Induced Mitochondrial Dysfunction in HT-22 Hippocampal Neuronal Cells

  • Sung, Soon Ki (Department of Neurosurgery, Pusan National University School of Medicine) ;
  • Woo, Jae Suk (Department of Physiology, Pusan National University School of Medicine) ;
  • Kim, Young Ha (Department of Neurosurgery, Pusan National University School of Medicine) ;
  • Son, Dong Wuk (Department of Neurosurgery, Pusan National University School of Medicine) ;
  • Lee, Sang Weon (Department of Neurosurgery, Pusan National University School of Medicine) ;
  • Song, Geun Sung (Department of Neurosurgery, Pusan National University School of Medicine)
  • Received : 2015.11.30
  • Accepted : 2016.01.30
  • Published : 2016.05.01
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Abstract

Objective : Accumulation of advanced glycation end-products (AGE) and mitochondrial glycation is importantly implicated in the pathological changes of the brain associated with diabetic complications, Alzheimer disease, and aging. The present study was undertaken to determine whether sildenafil, a type 5 phosphodiesterase type (PDE-5) inhibitor, has beneficial effect on neuronal cells challenged with AGE-induced oxidative stress to preserve their mitochondrial functional integrity. Methods : HT-22 hippocampal neuronal cells were exposed to AGE and changes in the mitochondrial functional parameters were determined. Pretreatment of cells with sildenafil effectively ameliorated these AGE-induced deterioration of mitochondrial functional integrity. Results : AGE-treated cells lost their mitochondrial functional integrity which was estimated by their MTT reduction ability and intracellular ATP concentration. These cells exhibited stimulated generation of reactive oxygen species (ROS), disruption of mitochondrial membrane potential, induction of mitochondrial permeability transition, and release of the cytochrome C, activation of the caspase-3 accompanied by apoptosis. Western blot analyses and qRT-PCR demonstrated that sildenafil increased the expression level of the heme oxygenase-1 (HO-1). CoPP and bilirubin, an inducer of HO-1 and a metabolic product of HO-1, respectively, provided a similar protective effects. On the contrary, the HO-1 inhibitor ZnPP IX blocked the effect of sildenafil. Transfection with HO-1 siRNA significantly reduced the protective effect of sildenafil on the loss of MTT reduction ability and MPT induction in AGE-treated cells. Conclusion : Taken together, our results suggested that sildenafil provides beneficial effect to protect the HT-22 hippocampal neuronal cells against AGE-induced deterioration of mitochondrial integrity, and upregulation of HO-1 is involved in the underlying mechanism.

Keywords

References

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