Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not

Akan, Pınar; Kızıldağ, Servet; Örmen, Murat; Genç, Şermin; Öktem, Mehmet Ali; Fadiloğlu, Meral

doi:10.1016/j.cbi.2008.09.016

Cited by 16 publications

(13 citation statements)

References 35 publications

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“…PREGS and DHEAS differentially regulate neuronal cell survival, in both in vitro and in vivo Aβ peptide-induced AD models. PREGS exacerbates the decrease in cell viability induced by Aβ 25-35 peptide in pheochromocytoma PC12 cell cultures (Akan et al 2009). However, it shows neuroprotective action in mice centrally injected with the peptide (Yang et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25–35 peptide-induced toxicity in vitro and in vivo in mice

et al. 2014

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Rationale PREGS and DHEAS are pro-mnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient brains, their low concentrations are correlated with high levels of Aβ and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. Objective The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Aβ25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. Methods B104 cells pretreated with the steroids before Aβ25-35 were analyzed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Aβ25-35 and the steroids, were analyzed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. Results ent-PREGS and PREGS significantly attenuated the Aβ25-35-induced decrease in cell viability. Both steroids prevented the Aβ25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Aβ25-35-induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Aβ25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Aβ25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Aβ25-35 in contrast to the natural steroids. Conclusion The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD.

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Section: Introductionmentioning

confidence: 99%

Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25–35 peptide-induced toxicity in vitro and in vivo in mice

et al. 2014

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“…Steroids may have different effects on neuronal survival and excitability depending on whether they are free or sulfa-conjugated [36,73]. In AD, there is a significant decline of sulfa-conjugated steroid levels (PS, DHEAS) in certain brain regions compared to those of age-matched, non-demented controls [74].…”

Section: Discussionmentioning

confidence: 98%

“…While P treatment at nanomolar concentrations has a protective effect against AB toxicity, it has a toxic effect in higher concentrations ([lM) in neuronal cells [36,37]. PS is a controversial neurosteroid which acts as a cognitive enhancer and a modulator of neurotransmission via the regulation of GABA, NMDA or sigma receptors [76][77][78] and also it can induce excitotoxicity at high nanomolar or micromolar concentrations [35,36,38,79]. The elevated P levels observed in our study may be part of a cellular defense mechanism against AB toxicity.…”

Section: Discussionmentioning

confidence: 99%

“…In recent years, it has been suggested that neurosteroids could play a key role in neuronal cell survival [1,34] and the induction of their synthesis could be used as a potential early event indicating neuronal excitotoxicity [35]. On the other hand, it was also reported that the exogenous application of P had protective effects against AB toxicity at relatively lower concentrations (nM) but also had toxic effects in higher concentrations ([lM) in neuronal cells [36,37]. Treatment with PS, which is a memory modulator, induced neuronal excitotoxicity in lM concentrations [38].…”

Section: Introduction and Aimmentioning

confidence: 98%

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Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

et al. 2016

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Increased amyloid beta (AB) peptide concentration is one of the initiating factors in the neurodegeneration process. It has been suggested that cholesterol induces the synthesis of AB peptide from amyloid precursor protein or facilitates the formation of amyloid plaque by lowering the aggregation threshold of the peptide. It is also shown that AB peptides may affect cholesterol metabolism and the synthesis of steroid hormones such as progesterone and estradiol. Pregnenolone (P) and pregnenolone sulfate (PS) are the major steroids produced from cholesterol in neural tissue. In toxicity conditions, the effect of AB peptides on P and PS levels has not yet been determined. Furthermore, it has not been clearly defined how changes in cellular P and PS levels affect neuronal cell survival. The aim of this study was to determine the effects of AB peptides on cellular changes in P and PS levels depending on the level of their main precursor, cholesterol. Cholesterol and toxic concentrations of AB fragments (AB 25-35, AB 1-40 and AB 1-42) were applied to PC-12 and SH-SY5Y cells. Changes in cellular cholesterol, P and PS levels were determined simultaneously in a dose-and time-dependent manner. The cell viability and cell death types were also evaluated. AB peptides affected both cell viability and P/PS levels. Steroid levels were altered depending on AB fragment type and the cholesterol content of the cells. Treatment with each of the AB fragments alone increased P levels by twofold. However, combined treatment with AB peptides and cholesterol increased P levels by approximately sixfold, while PS levels were increased only about 2.5 fold in both cell lines. P levels in the groups treated with AB 25-35 were higher than those in AB 1-40 and AB 1-42 groups. The cell viabilities were significantly low in the group treated by AB and cholesterol (9 mM). The effect of AB peptides on P levels might be a result of cellular self-defense. On the other hand, the rate of P increase might be playing a key role in the cell death mechanism of AB toxicity depending on cellular cholesterol levels.

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“…Pregnenolone could thus mitigate GABA dysregulation and/or NMDA receptor hypofunction in schizophrenia (Coyle 2006;Javitt 2004Javitt , 2007Millan 2005;Rujescu et al 2006) via metabolism to other neurosteroids, among other possible contributing mechanisms of action. For example, pregnenolone protects against glutamate and amyloid β-protein toxicity; decreases apoptosis (Akan et al 2009;Gursoy et al 2001;Leskiewicz et al 2008); enhances learning and memory (Flood et al 1992); regulates/increases myelination (Bloom et al 2002;Koenig et al 1995;Zhu and Glaser 2008); enhances neuritic outgrowth (Fontaine-Lenoir et al 2006); impacts synaptic plasticity (Bu and Zu 2013); and demonstrates multiple actions relevant to microtubule assembly, polymerization, growth, and migration (Fontaine-Lenoir et al 2006;Hsu et al 2006;Murakami et al 2000;Weng et al 2013). Also relevant to the pathophysiology and treatment of schizophrenia, pregnenolone rescues schizophrenia-like behaviors in dopamine transporter knockout mice (Wong et al 2012).…”

Section: Preclinical Overview: Pregnenolone and Pregnenolone Metabolimentioning

confidence: 99%

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

et al. 2014

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Pregnenolone protects the PC-12 cell line against amyloid beta peptide toxicity but its sulfate ester does not

Cited by 16 publications

References 35 publications

Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25–35 peptide-induced toxicity in vitro and in vivo in mice

Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Aβ25–35 peptide-induced toxicity in vitro and in vivo in mice

Amyloid Beta Peptides Affect Pregnenolone and Pregnenolone Sulfate Levels in PC-12 and SH-SY5Y Cells Depending on Cholesterol

Proof-of-concept randomized controlled trial of pregnenolone in schizophrenia

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