Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 195-206 |
| Number of pages | 12 |
| Journal | European Neuropsychopharmacology |
| Volume | 20 |
| Issue number | 3 |
| DOIs | |
| Publication status | Published - Mar 2010 |
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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 journal › Article
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TY - JOUR
T1 - Palmitoylethanolamide modulates pentobarbital-evoked hypnotic effect in mice
T2 - involvement of allopregnanolone biosynthesis
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
N1 - Copyright 2009 Elsevier B.V. All rights reserved.
PY - 2010/3
Y1 - 2010/3
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.
AB - 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.
KW - animals
KW - brain stem
KW - drug synergism
KW - endocannabinoids
KW - ethanolamines
KW - hypnotics and sedatives
KW - male
KW - mice
KW - PPAR alpha
KW - palmitic acids
KW - pentobarbital
KW - pregnanolone
U2 - 10.1016/j.euroneuro.2009.09.003
DO - 10.1016/j.euroneuro.2009.09.003
M3 - Article
C2 - 19864116
VL - 20
SP - 195
EP - 206
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
SN - 0924-977X
IS - 3
ER -