Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes

involvement of peroxisome-proliferator activated receptor-α

G. Mattace Raso, E. Esposito, S. Vitiello, A. Iacono, A. Santoro, G. D'Agostino, O. Sasso, R. Russo, P. V. Piazza, A. Calignano, R. Meli

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

Palmitoylethanolamide (PEA) regulates many pathophysiological processes in the central nervous system, including pain perception, convulsions and neurotoxicity, and increasing evidence points to its neuroprotective action. In the present study, we report that PEA, acting as a ligand of peroxisome-proliferator activated receptor (PPAR)-α, might regulate neurosteroidogenesis in astrocytes, which, similar to other glial cells and neurones, have the enzymatic machinery for neurosteroid de novo synthesis. Accordingly, we used the C6 glioma cell line and primary murine astrocytes. In the mitochondrial fraction from cells stimulated with PEA, we demonstrated an increase in steroidogenic acute regulatory protein (StAR) and cytochrome P450 enzyme (P450scc) expression, both comprising proteins considered to be involved in crucial steps of neurosteroid formation. The effects of PEA were completely blunted by GW6471, a selective PPAR-α antagonist, or by PPAR-α silencing by RNA interference. Accordingly, allopregnanolone (ALLO) levels were increased in supernatant of PEA-treated astrocytes, as revealed by gas chromatography-mass spectrometry, and this effect was inhibited by GW6471. Moreover, PEA showed a protective effect, reducing malondialdehyde formation in cells treated with l-buthionine-(S,R)-sulfoximine, a glutathione depletor and, interestingly, the effect of PEA was partially inhibited by finasteride, a 5α-reductase inhibitor. A similar profile of activity was demonstrated by ALLO and the lack of an additive effect with PEA suggests that the reduction of oxidative stress by PEA is mediated through ALLO synthesis. The present study provides evidence indicating the involvement of the saturated acylethanolamide PEA in ALLO synthesis through PPAR-α in astrocytes and explores the antioxidative activity of this molecule, confirming its homeostatic and protective role both under physiological and pathological conditions.
Original languageEnglish
Pages (from-to)591-600
Number of pages10
JournalJournal of Neuroendocrinology
Volume23
Issue number7
Early online date16 Jun 2011
DOIs
Publication statusPublished - Jul 2011

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Pregnanolone
Peroxisome Proliferator-Activated Receptors
Astrocytes
Cytochrome P-450 Enzyme System
Neurotransmitter Agents
palmidrol
Finasteride
Pain Perception
RNA Interference
Malondialdehyde
Glioma
Neuroglia
Gas Chromatography-Mass Spectrometry
Glutathione
Oxidoreductases
Seizures
Oxidative Stress
Central Nervous System

Keywords

  • animals
  • animals, newborn
  • astrocytes
  • brain neoplasms
  • cell culture techniques
  • cell line, tumor
  • cells, cultured
  • drug evaluation, preclinical
  • endocannabinoids
  • ethanolamines
  • glioma
  • mice
  • mice, inbred BALB C
  • PPAR alpha
  • palmitic acids
  • pregnanolone
  • rats
  • up-regulation

Cite this

Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes : involvement of peroxisome-proliferator activated receptor-α. / Raso, G. Mattace; Esposito, E.; Vitiello, S.; Iacono, A.; Santoro, A.; D'Agostino, G.; Sasso, O.; Russo, R.; Piazza, P. V.; Calignano, A.; Meli, R.

In: Journal of Neuroendocrinology, Vol. 23, No. 7, 07.2011, p. 591-600.

Research output: Contribution to journalArticle

Raso, GM, Esposito, E, Vitiello, S, Iacono, A, Santoro, A, D'Agostino, G, Sasso, O, Russo, R, Piazza, PV, Calignano, A & Meli, R 2011, 'Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes: involvement of peroxisome-proliferator activated receptor-α', Journal of Neuroendocrinology, vol. 23, no. 7, pp. 591-600. https://doi.org/10.1111/j.1365-2826.2011.02152.x
Raso, G. Mattace ; Esposito, E. ; Vitiello, S. ; Iacono, A. ; Santoro, A. ; D'Agostino, G. ; Sasso, O. ; Russo, R. ; Piazza, P. V. ; Calignano, A. ; Meli, R. / Palmitoylethanolamide stimulation induces allopregnanolone synthesis in C6 Cells and primary astrocytes : involvement of peroxisome-proliferator activated receptor-α. In: Journal of Neuroendocrinology. 2011 ; Vol. 23, No. 7. pp. 591-600.
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AU - Esposito, E.

AU - Vitiello, S.

AU - Iacono, A.

AU - Santoro, A.

AU - D'Agostino, G.

AU - Sasso, O.

AU - Russo, R.

AU - Piazza, P. V.

AU - Calignano, A.

AU - Meli, R.

N1 - © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

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N2 - Palmitoylethanolamide (PEA) regulates many pathophysiological processes in the central nervous system, including pain perception, convulsions and neurotoxicity, and increasing evidence points to its neuroprotective action. In the present study, we report that PEA, acting as a ligand of peroxisome-proliferator activated receptor (PPAR)-α, might regulate neurosteroidogenesis in astrocytes, which, similar to other glial cells and neurones, have the enzymatic machinery for neurosteroid de novo synthesis. Accordingly, we used the C6 glioma cell line and primary murine astrocytes. In the mitochondrial fraction from cells stimulated with PEA, we demonstrated an increase in steroidogenic acute regulatory protein (StAR) and cytochrome P450 enzyme (P450scc) expression, both comprising proteins considered to be involved in crucial steps of neurosteroid formation. The effects of PEA were completely blunted by GW6471, a selective PPAR-α antagonist, or by PPAR-α silencing by RNA interference. Accordingly, allopregnanolone (ALLO) levels were increased in supernatant of PEA-treated astrocytes, as revealed by gas chromatography-mass spectrometry, and this effect was inhibited by GW6471. Moreover, PEA showed a protective effect, reducing malondialdehyde formation in cells treated with l-buthionine-(S,R)-sulfoximine, a glutathione depletor and, interestingly, the effect of PEA was partially inhibited by finasteride, a 5α-reductase inhibitor. A similar profile of activity was demonstrated by ALLO and the lack of an additive effect with PEA suggests that the reduction of oxidative stress by PEA is mediated through ALLO synthesis. The present study provides evidence indicating the involvement of the saturated acylethanolamide PEA in ALLO synthesis through PPAR-α in astrocytes and explores the antioxidative activity of this molecule, confirming its homeostatic and protective role both under physiological and pathological conditions.

AB - Palmitoylethanolamide (PEA) regulates many pathophysiological processes in the central nervous system, including pain perception, convulsions and neurotoxicity, and increasing evidence points to its neuroprotective action. In the present study, we report that PEA, acting as a ligand of peroxisome-proliferator activated receptor (PPAR)-α, might regulate neurosteroidogenesis in astrocytes, which, similar to other glial cells and neurones, have the enzymatic machinery for neurosteroid de novo synthesis. Accordingly, we used the C6 glioma cell line and primary murine astrocytes. In the mitochondrial fraction from cells stimulated with PEA, we demonstrated an increase in steroidogenic acute regulatory protein (StAR) and cytochrome P450 enzyme (P450scc) expression, both comprising proteins considered to be involved in crucial steps of neurosteroid formation. The effects of PEA were completely blunted by GW6471, a selective PPAR-α antagonist, or by PPAR-α silencing by RNA interference. Accordingly, allopregnanolone (ALLO) levels were increased in supernatant of PEA-treated astrocytes, as revealed by gas chromatography-mass spectrometry, and this effect was inhibited by GW6471. Moreover, PEA showed a protective effect, reducing malondialdehyde formation in cells treated with l-buthionine-(S,R)-sulfoximine, a glutathione depletor and, interestingly, the effect of PEA was partially inhibited by finasteride, a 5α-reductase inhibitor. A similar profile of activity was demonstrated by ALLO and the lack of an additive effect with PEA suggests that the reduction of oxidative stress by PEA is mediated through ALLO synthesis. The present study provides evidence indicating the involvement of the saturated acylethanolamide PEA in ALLO synthesis through PPAR-α in astrocytes and explores the antioxidative activity of this molecule, confirming its homeostatic and protective role both under physiological and pathological conditions.

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KW - ethanolamines

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KW - rats

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