Possible Anandamide and Palmitoylethanolamide involvement in human stroke.
BACKGROUND
Endocannabinoids (eCBs) are ubiquitous lipid mediators that act on specific (CB1, CB2) and non-specific (TRPV1, PPAR) receptors. Despite many experimental animal studies proved eCB involvement in the pathogenesis of stroke, such evidence is still lacking in human patients. Our aim was to determine eCB peripheral levels in acute stroke patients and evaluate their relationship with clinical disability and stroke volume.


METHODS
A cohort of ten patients with a first acute (within six hours since symptoms onset) ischemic stroke and a group of eight age- and sex-matched normal subjects were included. Groups were also matched for metabolic profile. All subjects underwent a blood sample collection for anandamide (AEA), 2-arachidonoylglycerol (2-AG) and palmitoylethanolamide (PEA) measurement; blood sampling was repeated in patients on admission (T0), at 6 (T1) and 18 hours (T2) thereafter. Patients neurological impairment was assessed using NIHSS and Fugl-Meyer Scale arm subitem (FMSa); stroke volume was determined on 48 h follow-up brain CT scans. Blood samples were analyzed by liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry.


RESULTS
1)T0 AEA levels were significantly higher in stroke patients compared to controls. 2)A significant inverse correlation between T0 AEA levels and FMSa score was found. Moreover a positive correlation between T0 AEA levels and stroke volume were found in stroke patients. T0 PEA levels in stroke patients were not significantly different from the control group, but showed a significant correlation with the NIHSS scores. T0 2-AG levels were lower in stroke patients compared to controls, but such difference did not reach the significance threshold.


CONCLUSIONS
This is the first demonstration of elevated peripheral AEA levels in acute stroke patients. In agreement with previous murine studies, we found a significant relationship between AEA or PEA levels and neurological involvement, such that the greater the neurological impairment, the higher were these levels.
Naccarato
Marcello
M
Department of Medical, Technological and Translational Sciences, Neurology Unit, University of Trieste, Strada di Fiume 447, 34100 Trieste (TS), Italy. marcello.naccarato@katamail.com
Pizzuti
Daniela
D
Petrosino
Stefania
S
Simonetto
Marco
M
Ferigo
Laura
L
Grandi
Fabio Chiodo
FC
Pizzolato
Gilberto
G
Di Marzo
Vincenzo
V
D000368:Aged; D000369:Aged, 80 and over; D000577:Amides; D001095:Arachidonic Acids / Q000097:blood*; D063385:Cannabinoid Receptor Modulators / Q000097:blood; D002853:Chromatography, Liquid; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides / Q000097:blood; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D055432:Metabolomics; D008875:Middle Aged; D009422:Nervous System Diseases / Q000175:diagnosis; D010169:Palmitic Acids / Q000097:blood*; D053284:Polyunsaturated Alkamides / Q000097:blood*; D020521:Stroke / Q000209:etiology*
D000577:Amides; D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D004983:Ethanolamines; D005989:Glycerides; D010169:Palmitic Acids; D053284:Polyunsaturated Alkamides; C005958:palmidrol; C094503:glyceryl 2-arachidonate; C078814:anandamide
Neurosci Lett. 2007 Jan 29;412(2):114-7
17123706
Stroke. 2002 Aug;33(8):2112-4
12154273
J Neurosci. 2002 Nov 15;22(22):9771-5
12427832
J Cereb Blood Flow Metab. 2007 Jul;27(7):1387-96
17245417
Brain Res. 2008 Nov 13;1240:213-20
18823959
Brain. 2007 Oct;130(Pt 10):2543-53
17626034
Lipids Health Dis. 2003 Aug 19;2:5
12969514
J Neurochem. 2004 Mar;88(5):1159-67
15009671
Ann Neurol. 2000 Aug;48(2):257-61
10939579
Mol Pharmacol. 2006 Mar;69(3):691-6
16299067
Stroke. 2007 Oct;38(10):2733-7
17717318
Nat Rev Drug Discov. 2008 May;7(5):438-55
18446159
Mol Pharmacol. 2005 Jan;67(1):15-9
15465922
J Neurosci. 1999 Apr 15;19(8):2987-95
10191316
Br J Pharmacol. 2005 Mar;144(5):727-35
15678080
Neurobiol Dis. 2007 Jul;27(1):108-16
17553686
Nat Neurosci. 2008 Feb;11(2):152-9
18204441
J Pharmacol Exp Ther. 2007 Feb;320(2):599-606
17068202
FEBS J. 2007 Sep;274(17):4464-775
17666109
Cephalalgia. 2006 Mar;26(3):277-81
16472333
Proc Natl Acad Sci U S A. 1996 Apr 30;93(9):3984-9
8633002
Neuroscience. 2004;129(3):743-50
15541895
Diabetes. 2006 Nov;55(11):3053-60
17065342
FEBS J. 2009 Jan;276(1):2-12
19087195
Vet J. 2007 Jan;173(1):21-30
16324856
Curr Pharm Des. 2008;14(23):2370-42
18781987
Pain. 2008 Oct 31;139(3):541-550
18602217
Proc Natl Acad Sci U S A. 1995 Apr 11;92(8):3376-80
7724569
Pharmacopsychiatry. 2008 Mar;41(2):48-53
18311684
Stroke. 1989 Jul;20(7):864-70
2749846
Eur J Clin Pharmacol. 2008 Jan;64(1):1-8
18004553
Mol Neurobiol. 2007 Aug;36(1):68-74
17952651
Neuroscience. 2008 Mar 27;152(3):753-60
18304750
J Intern Med. 1994 Aug;236(2):125-36
8046311
Atherosclerosis. 2005 Sep;182(1):47-55
16115474
Neuropsychopharmacology. 2005 Jun;30(6):1216-21
15841111