Possible Anandamide and Palmitoylethanolamide involvement in human stroke

Abstract

BackgroundEndocannabinoids (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.MethodsA 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.Results1)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.ConclusionsThis 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.

Endocannabinoids and the Cardiovascular System in Health and Disease

“…Human and animal in vivo data have shown increases in neurological and circulating plasma levels of AEA, 2-AG, OEA and PEA after stroke (Schabitz et al 2002;Hillard 2008;Naccarato et al 2010). As in other cardiovascular disorders, the hypothesis is that upregulation of the endocannabinoid system is protective in stroke, and this is supported by numerous studies showing that 2-AG (Wang et al 2009), AEA (Wang et al 2009) as well as the endocannabinoid-like compounds, OEA (Sun et al 2007;Zhou et al 2012) and PEA (Schomacher et al 2008;Garg et al 2010;Ahmad et al 2012b), offer protection against ischaemic/reperfusion injury.…”

Antiepileptic action of N-palmitoylethanolamine through CB1 and PPAR-α receptor activation in a genetic model of absence epilepsy

“…Less understood are the functions of PEA in the central nervous system (CNS), where, it is normally present at detectable levels (Cadas et al, 1997) and its concentrations significantly increase under pathological conditions, such as excitotoxicity (Hansen et al, 1998), brain ischemia (Franklin et al, 2003;Schomacher et al, 2008), stroke (Naccarato et al, 2010) and neuroinflammation (Darmani et al, 2005;Garg et al, 2010). Other studies, indicate that PEA is normally produced and hydrolysed by microglia (Muccioli and Stella, 2008), it increases after focal cerebral ischemia potentiating microglial cell motility (Franklin et al, 2003), and protects cerebellar granule cells from glutamate excitotoxicity (Skaper et al, 1996).…”

New Targets in Pain, Non-Neuronal Cells, and the Role of Palmitoylethanolamide

“…[81][82][83][84][85][86][87]108,109] PEA affinity for PPAR-, coupled with the widespread presence of this receptor in CNS microglia and astrocytes (which play a key role in the winding up phenomena, based on peripheral and central sensitization [110]) provides a strong underlying rationale for PEA application in the treatment of neuropathic pain. [111][112][113][114] Further, PEA performed better in the so-called mice forced swimming test compared to the anti-depressant fluoxetine. [115] PEA antiinflammatory action counteracted reactive astrogliosis induced by beta-amyloid peptide in a rodent model relevant for neurodegeneration, most probably via PPAR-.…”

“…[116] In models of stroke, MS and other CNS trauma settings, PEA displayed neuroprotective properties. [59,87,112,113] At the clinical level, in Italy for example, neurologists have used this preclinical evidence as the impetus to treat patients suffering from a variety of disorders, from MS to neuropathic pain. [18, 61, 62, 65, 66, 84-88, 92-94, 111-113, 115] …”