Ouabain-Induced Signaling and Cell Survival in SK-N-SH Neuroblastoma Cells Differentiated by Retinoic Acid

Author(s):

Evgeny E. Akkuratov, Jian Wu, David Sowa, Zahoor A. Shah and Lijun LiuPages 1343-1349 (7)

Abstract:

Ouabain stimulates activation of various signaling cascades such as protein kinase B (Akt) and Extracellular-signaling-regulated kinase 1/2 (ERK 1/2) in various cell lines. Retinoic acid (RA) is commonly used to induce neuroblastoma differentiation in cultures. Upon RA administration, human neuroblastoma cell line, SK-N-SH demonstrated neurite extensions, which is an indicator of neuronal cell differentiation. Here we report that ouabaininduced signaling is altered under the action of 1 μM RA in human neuroblastoma SK-N-SH cells. RA increased the expression of p110α subunit of phosphoinositide 3-kinase (PI3K), Akt and β1 subunit of Na+/K+-ATPase. Ouabain activated Akt and ERK 1/2 in differentiated SK-N-SH cells; this effect was not observed in non-differentiated SK-N-SH cells. Long-term incubation of non-differentiated SK-N-SH with 1 μM ouabain led to a decrease in the number of cells; this effect was reduced in differentiated SK-N-SH cells. Taken together, these results suggest that ouabain leads to cell death in neuroblastoma cells rather than neuronal cells due to the different response to ouabain manifested by activation of Akt and ERK 1/2.

Highlights

RA increases the expression of p110α subunit of PI3K, Akt and β1 subunit of Na+/K+-ATPase

Ouabain induces activation of Akt and ERK 1/2 in differentiated SK-N-SH cells but not in non-differentiated cells

1 µM ouabain leads to a decrease in the number of cells in non-differentiated SK-N-SH

Reduction of ouabain-induced cell death in differentiated SK-N-SH

Keywords:

Na+/K+-ATPase, neuroblastoma, ouabain, retinoic acid, phosphoinositide 3-kinase, signaling cascades.

Affiliation:

Department of Biochemistry and Cancer Biology, College of Medicine and Life Sciences, University of Toledo, Toledo, OH, USA.

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The Effects of Testosterone Supplementation on Cognitive Functioning in Older Men.

Author(s):

Eka J. Wahjoepramono, Prita R. Asih, Vilia Aniwiyanti, Kevin Taddei, Satvinder S. Dhaliwal, Stephanie J. Fuller, Jonathan Foster, Malcolm Carruthers, Giuseppe Verdile, Hamid R Sohrabi and Ralph N. MartinsPages 337-343 (7)

Abstract:

Reduction in testosterone levels in men during aging is associated with cognitive decline and risk of dementia. Animal studies have shown benefits for testosterone supplementation in improving cognition and reducing Alzheimer’s disease pathology. In a randomized, placebo-controlled, crossover study of men with subjective memory complaint and low testosterone levels, we investigated whether testosterone treatment significantly improved performance on various measures of cognitive functioning. Forty-four men were administered a battery of neuropsychological tests to establish the baseline prior to being randomly divided into two groups. The first group (Group A) received 24 weeks of testosterone treatment (T treatment) followed by 4 weeks washout, and then 24 weeks of placebo (P); the second group (Group B) received the same treatments, in reverse order (Placebo, washout, and then T treatment). In group A (TèP), compared to baseline, there was a modest (1 point) but significant improvement in general cognitive functioning as measured by the Mini Mental State Examination (MMSE) following testosterone treatment. This improvement from baseline was sustained following the washout period and crossover to placebo treatment. Similar Mini Mental State Examination (MMSE) scores were observed when comparing testosterone treatment with placebo. In group B (PèT) a significant increase was observed from baseline following testosterone treatment and a trend towards an increase when compared to placebo treatment. Improvements in baseline depression scores (assessed by Geriatric Depression Scale) were observed following testosterone/placebo treatment in both groups, and no difference was observed when comparing testosterone with placebo treatment. Our findings indicate a modest improvement on global cognition with testosterone treatment. Larger clinical trials with a longer follow- up and with the inclusion of blood and brain imaging markers are now needed to conclusively determine the significance of testosterone treatment.

Keywords:

Testosterone, Androgen, cognition, ageing, memory, dementia, depression, Apolipoprotein E, Alzheimer’s disease.

Affiliation:

Suite 22, Hollywood Medical Centre 85 Monash Avenue, Nedlands, WA 6009, Australia

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mTOR, a Potential Target to Treat Autism Spectrum Disorder

Author(s):

Atsushi SatoPages 533-543 (11)

Abstract:

Mammalian target of rapamycin (mTOR) is a key regulator in various cellular processes, including cell growth, gene expression, and synaptic functions. Autism spectrum disorder (ASD) is frequently accompanied by monogenic disorders, such as tuberous sclerosis complex, phosphatase and tensin homolog tumor hamartoma syndrome, neurofibromatosis 1, and fragile X syndrome, in which mTOR is hyperactive. Mutations in the genes involved in the mTOR-mediated signaling pathway have been identified in some cases of syndromic ASD. Evidences indicate a pathogenic role for hyperactive mTOR-mediated signaling in ASD associated with these monogenic disorders, and mTOR inhibitors are a potential pharmacotherapy for ASD. Abnormal synaptic transmission through metabotropic glutamate receptor 5 may underlie in a part of ASD associated with hyperactive mTOR-mediated signaling. In this review, the relationship between mTOR and ASD is discussed.

Keywords:

Autophagy, fragile X syndrome, mammalian target of rapamycin, metabotropic glutamate receptor 5, neurofibromatosis, phosphatase and tensin homolog, tuberous sclerosis complex

Affiliation:

Department of Pediatrics, The University of Tokyo Hospital, Addictive Substance Project, Tokyo Metropolitan Institute of Medical Science, Hongo 7-3-1, Bunkyo-ku, Tokyo, 113- 8655, Japan.

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The Potential of Nasal Oxytocin Administration for Remediation of Autism Spectrum Disorders

Author(s):

Yuko Okamoto, Makoto Ishitobi, Yuji Wada and Hirotaka KosakaPages 564-577 (14)

Abstract:

Administration of oxytocin has been proposed as a treatment for the core symptoms of autism spectrum disorder (ASD), including social-communicative deficit. Previous clinical trials have investigated the efficacy and safety of oxytocin intranasal single-dose and long-term administration for individuals with ASD. All studies suggest that singledose and long-term administration are well tolerated, and no severe adverse events have been reported. However, the efficacy of long-term oxytocin administration is controversial. Some studies have reported significant improvement of the core symptoms of ASD by long-term oxytocin administration, while other studies showed no such improvement. To elucidate the factors influencing the efficacy of oxytocin administration, it is necessary to examine the effects of administration schedules (e.g., dosage amount, frequency per day) and participant characteristics (e.g., age, sex, intellectual ability). In addition to doubts about the efficacy of particular methods of administration, questions remain about the mechanism of action of intranasal oxytocin on the central nervous system. Examination of changes in the neural underpinnings of social behavior and simultaneous oxytocin levels in blood or cerebrospinal fluid could prove important in elucidating the pharmacokinetics of intranasal oxytocin administration, which could be essential for establishing optimal oxytocin treatments for individuals with ASD.

Keywords:

Autism spectrum disorders, long-term administration, open-label trial, oxytocin, randomized controlled trials, single- dose, treatment.

Affiliation:

Research Center for Child Mental Development, University of Fukui, Eiheiji, Fukui 910-1193, Japan.

Graphical Abstract:

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