Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice: involvement of allopregnanolone biosynthesis

Oscar Sasso, Giovanna La Rana, Sergio Vitiello, Roberto Russo, Giuseppe D'Agostino, Anna Iacono, Emilio Russo, Rita Citraro, Salvatore Cuzzocrea, Pier Vincenzo Piazza, Giovanbattista De Sarro, Rosaria Meli, Antonio Calignano

Research output: Contribution to journalArticle

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Abstract

Palmitoylethanolamde (PEA) is an endogenous lipid neuromodulator that mediates a broad spectrum of pharmacological effects by activation of peroxisome proliferator-activated receptor alpha (PPAR-alpha). Detectable or high levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Here we report evidence that PEA, activating PPAR-alpha receptor and involving neurosteroids de novo synthesis, modulates pentobarbital-evoked hypnotic effect. A single i.c.v. administration of PEA (1-5microg) increases pentobarbital induced loss of righting reflex (LORR) duration in mice. This effect is mimicked by GW7647 (3microg), a synthetic PPAR-alpha agonist, and disappears in PPAR-alpha knockout mice. Antagonism experiments strongly support the engaging of neurosteroidogenic pathway in the increase of LORR duration induced by PEA. This effect disappeared using two inhibitors blocking the key steps of neurosteroids synthesis, aminogluthetimide and finasteride. Moreover, we demonstrated that in brainstem PEA increased the expression of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc), both involved in neurosteroidogenesis. Accordingly, allopregnanolone (ALLO) levels were in turn higher in brainstem of PEA and pentobarbital treated mice vs pentobarbital alone, as revealed by quantitative analysis using gas chromatography-mass spectrometry. A Our results demonstrate that exogenous administration of PEA, through a PPAR-alpha-dependent mechanism, modulates neurosteroids formation increasing ALLO levels and leading to a positive modulation of GABA(A) receptor. These data further strengthen our previous data on the role of PPAR-alpha in PEA's actions and could provide a new framework to understand its role in the CNS.
Original languageEnglish
Pages (from-to)195-206
Number of pages12
JournalEuropean Neuropsychopharmacology
Volume20
Issue number3
DOIs
Publication statusPublished - Mar 2010

Fingerprint

Pregnanolone
PPAR alpha
Pentobarbital
Hypnotics and Sedatives
Neurotransmitter Agents
Righting Reflex
Brain Stem
Finasteride
Lipids
GABA-A Receptors
Knockout Mice
Gas Chromatography-Mass Spectrometry
Cytochrome P-450 Enzyme System
palmidrol
Pharmacology

Keywords

  • animals
  • brain stem
  • drug synergism
  • endocannabinoids
  • ethanolamines
  • hypnotics and sedatives
  • male
  • mice
  • PPAR alpha
  • palmitic acids
  • pentobarbital
  • pregnanolone

Cite this

Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice : involvement of allopregnanolone biosynthesis. / Sasso, Oscar; La Rana, Giovanna; Vitiello, Sergio; Russo, Roberto; D'Agostino, Giuseppe; Iacono, Anna; Russo, Emilio; Citraro, Rita; Cuzzocrea, Salvatore; Piazza, Pier Vincenzo; De Sarro, Giovanbattista; Meli, Rosaria; Calignano, Antonio.

In: European Neuropsychopharmacology, Vol. 20, No. 3, 03.2010, p. 195-206.

Research output: Contribution to journalArticle

Sasso, O, La Rana, G, Vitiello, S, Russo, R, D'Agostino, G, Iacono, A, Russo, E, Citraro, R, Cuzzocrea, S, Piazza, PV, De Sarro, G, Meli, R & Calignano, A 2010, 'Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice: involvement of allopregnanolone biosynthesis', European Neuropsychopharmacology, vol. 20, no. 3, pp. 195-206. https://doi.org/10.1016/j.euroneuro.2009.09.003
Sasso, Oscar ; La Rana, Giovanna ; Vitiello, Sergio ; Russo, Roberto ; D'Agostino, Giuseppe ; Iacono, Anna ; Russo, Emilio ; Citraro, Rita ; Cuzzocrea, Salvatore ; Piazza, Pier Vincenzo ; De Sarro, Giovanbattista ; Meli, Rosaria ; Calignano, Antonio. / Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice : involvement of allopregnanolone biosynthesis. In: European Neuropsychopharmacology. 2010 ; Vol. 20, No. 3. pp. 195-206.
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AU - Sasso, Oscar

AU - La Rana, Giovanna

AU - Vitiello, Sergio

AU - Russo, Roberto

AU - D'Agostino, Giuseppe

AU - Iacono, Anna

AU - Russo, Emilio

AU - Citraro, Rita

AU - Cuzzocrea, Salvatore

AU - Piazza, Pier Vincenzo

AU - De Sarro, Giovanbattista

AU - Meli, Rosaria

AU - Calignano, Antonio

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N2 - Palmitoylethanolamde (PEA) is an endogenous lipid neuromodulator that mediates a broad spectrum of pharmacological effects by activation of peroxisome proliferator-activated receptor alpha (PPAR-alpha). Detectable or high levels of PEA in the CNS have been found, but the specific function of this lipid remains to be clarified. Here we report evidence that PEA, activating PPAR-alpha receptor and involving neurosteroids de novo synthesis, modulates pentobarbital-evoked hypnotic effect. A single i.c.v. administration of PEA (1-5microg) increases pentobarbital induced loss of righting reflex (LORR) duration in mice. This effect is mimicked by GW7647 (3microg), a synthetic PPAR-alpha agonist, and disappears in PPAR-alpha knockout mice. Antagonism experiments strongly support the engaging of neurosteroidogenic pathway in the increase of LORR duration induced by PEA. This effect disappeared using two inhibitors blocking the key steps of neurosteroids synthesis, aminogluthetimide and finasteride. Moreover, we demonstrated that in brainstem PEA increased the expression of steroidogenic acute regulatory protein (StAR) and cytochrome P450 side-chain cleavage (P450scc), both involved in neurosteroidogenesis. Accordingly, allopregnanolone (ALLO) levels were in turn higher in brainstem of PEA and pentobarbital treated mice vs pentobarbital alone, as revealed by quantitative analysis using gas chromatography-mass spectrometry. A Our results demonstrate that exogenous administration of PEA, through a PPAR-alpha-dependent mechanism, modulates neurosteroids formation increasing ALLO levels and leading to a positive modulation of GABA(A) receptor. These data further strengthen our previous data on the role of PPAR-alpha in PEA's actions and could provide a new framework to understand its role in the CNS.

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KW - pregnanolone

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