Alzheimer's disease (AD) is a slowly progressive form of dementia, characterized by memory impairment and cognitive dysfunction. AD is mainly characterized by the deposition of amyloid β (Aβ) plaques and intracellular neurofibrillary tangles in the brain, along with neuronal degeneration and high levels of oxidative stress. Cilostazol (CSZ) was recently found to suppress the progression of cognitive decline in patients with stable AD receiving acetylcholinesterase inhibitors. This present study aimed to clarify the mechanism by which CSZ protects neurons from degeneration associated with Aβ(1-42). We used Aβ(1-42) to induce neurotoxicity in human neuroblastoma SH-SY5Y cells. Cells were pretreated with CSZ before co-treatment with Aβ. To evaluate the effect of CSZ on oxidative stress, we examined levels of reactive oxygen species (ROS), nicotinamide adenine dinucleotide phosphate oxidase (Nox) activity, mRNA expression of NOX4, and Cu/Zn-Superoxide Dismutase (SOD), as well as apoptosis biomarkers [MTT, (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide), caspase-3 and -9 activities and staining of annexin V]. We also assayed the activity of mitogen-activated protein kinases (MAPK): p38 MAPK and extracellular signal-regulated kinase1/2 (ERK1/2), and biomarkers of mitochondrial function (Bcl-2 and Bax), and cyclic adenosine monophosphate response element-binding protein (CREB). Aβ-induced oxidative stress (ROS, NOX4 activity, and expression of NOX mRNA), caspase activation (caspase-3 and -9), and p38 MAPK phosphorylation were suppressed by co-treatment with CSZ, but not by ERK1/2 activation. In addition, pretreatment with CSZ suppressed Aβ-induced apoptosis and increased cell viability via suppression of Bax (a proapoptotic protein), upregulation of Bcl-2 (an antiapoptotic protein) and Cu/Zn-SOD (a superoxide scavenging enzyme), and phosphorylation of CREB.Abbreviations: Aβ, amyloid β; AD, Alzheimer's disease; AMPK, AMP-activated protein kinase; APP, β-amyloid precursor protein; ASK, apoptosis signal-regulating kinase; ATRA, all-trans-retinoic acid; CREB, cyclic adenosine monophosphate response element-binding protein; CSZ, cilostazol; DTT, dithiothreitol; EDTA, ethylenediaminetetraacetic acid; ERK, extracellular signal-regulated kinase; FBS, Fetal bovine serum; HRP, Horseradish Peroxidase; JNK, c-jun N-terminal kinase; MAPK, mitogen-activated protein kinases; MCI, mild cognitive impairment; MEK, MAPK/ERK kinase; MKK, mitogen activated kinase kinase; MTT, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NADPH, nicotinamide adenine dinucleotide phosphate; NOX, nicotinamide adenine dinucleotide phosphate oxidase; PBS, phosphate-buffered saline; PCR, polymerase chain reaction; PDE, phosphodiesterase; RLU, relative light units; ROS, reactive oxygen species; SOD, Superoxide dismutase; TMB, 3,3 ,5,5 -tetramethylbenzidine. These findings suggested that CSZ could counteract neurotoxicity through multiple mechanisms, one mechanism involving the attenuation of oxidative stress by suppressing NOX activ...

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: Propofol is a short-acting intravenous anesthetic agent. Dexmedetomidine, a highly selective 2 -adrenergic receptor agonist, has a well-known sedative effect. Both agents exhibit cytoprotective effects in the nervous system under ischemic conditions. Recently, the combination of propofol plus dexmedetomidine was used for the sedation of mechanically ventilated patients in an intensive care unit, but there are few experimental reports of the protective effects of the propofol plus dexmedetomidine combination in cells. Meanwhile, intraoperative brain ischemia-reperfusion induces endoplasmic reticulum ER stress-mediated apoptosis. The aim of the present study was to clarify molecular details underlying the neuroprotection afforded by the combination of propofol plus dexmedetomidine against thapsigargin TG -induced ER stress in human neuroblastoma SH-SY5Y cells, and whether the combination provided more ef cient neuroprotection. TG was used to generate ER stress in SH-SY5Y cells. Cells were pretreated with propofol or dexmedetomidine, individually or in combination, for 1 h before cotreatment with TG for 20 h. There was a signi cant increase in Ca 2 i , caspase activation, and the expression of ER stress biomarkers in TG-induced apoptotic cells. The increase in Ca 2 i and the induction of ER stress by TG were suppressed by pretreatment with propofol, dexmedetomidine, and their combination. The dexmedetomidineinduced reduction in caspase activity and ER stress biomarkers was inhibited by pretreatment with an 2 -adrenergic receptor antagonist, but was enhanced by pretreatment with a cAMP inhibitor. Treatment with the propofol plus dexmedetomidine combination exhibited the strongest protection against TG-induced apoptosis. These results demonstrate that the combination of propofol plus dexmedetomidine at clinically relevant concentrations suppresses ER stress-induced apoptosis in neuroblastoma SH-SY5Y cells. The ndings suggest that the combination of propofol plus dexmedetomidine within a clinically relevant concentration range may be used safely in patients.