Protective Effects of N-Oleoylglycine in a Mouse Model of Mild Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) is one of the main causes of death in young people for which currently no efficacious treatment exists. Recently, we have reported that mice with mild-TBI with a specific injury in the insula showed elevated levels of a little investigated N-acyl amino acid, N-oleoylglycine (OlGly). Nacyl amino acids have recently experienced an increased interest because of their important biological activities. They belong to the endocannabinoidome family of lipids with structural similarities with the endocannabinoids (eCBs). The aim of this study was to test the neuroprotective and antihyperalgesic actions of OlGly in a model of mouse mild-TBI (mTBI) and its effect on levels of eCBs and N-acylethanolamines at the end of treatment. Following mTBI, mice were administered a daily injection of OlGly (10−50−100 mg/kg i.p.) for 14 days. Treatment with OlGly normalized motor impairment and behavior in the light/dark box test, ameliorated TBI-induced thermal hyperalgesia and mechanical allodynia, and normalized aggressiveness and depression. Moreover, levels of eCBs and some N-acylethanolamines underwent significant changes 60 days after TBI, especially in the prefrontal cortex and hypothalamus, and OlGly reversed some of these changes. In conclusion, our findings reveal that OlGly ameliorates the behavioral alterations associated with mTBI in mice, while concomitantly modulating eCB and eCB-like mediator tone.

Spontaneous and Naloxone-Precipitated Withdrawal Behaviors From Chronic Opiates are Accompanied by Changes in N-Oleoylglycine and N-Oleoylalanine Levels in the Brain and Ameliorated by Treatment With These Mediators

“…The suppression of endogenous OlGly following spontaneous withdrawal from chronic morphine is noteworthy given its previously described neuroprotective properties. In fact, OlGly is elevated in the insular cortex in mice following traumatic brain injury (TBI; Donvito et al, 2019 ) and systemic administration of this compound reduces the behavioral impairments produced by TBI (i.e., motor, anxiety) ( Piscitelli et al, 2020 ) and nicotine withdrawal ( Donvito et al, 2019 ). We ( Petrie et al, 2019 ) have previously reported that ex vivo analysis of tissue from rats experiencing acute naloxone-precipitated MWD revealed that OlGly is elevated in the NAc (but not in the amygdala, PFC and IIC), whereas levels of the endocannabinoids, 2-AG and AEA, and the other endogenous PPARα ligands, OEA, and PEA, were not affected in any of the brain regions evaluated.…”

“…Tissues were dounce-homogenized and extracted with chloroform/methanol/Tris-HCl 50 mM pH 7.5 (2:1:1, v/v) containing internal deuterated standards for AEA, 2-AG, PEA, OEA, AraGly, OlGly, and OlAla and N -acylserotonin quantification by isotope dilution (5 pmol for [2H]8AEA; 50 pmol for [2H]52-AG, [2H]4 PEA, [2H]2 OEA; 10 pmol for [2H]4 DHEA and [2H]4 EPEA; 50 pmol for [2H]8AraGly and [2H]2OlGly; 100 pmol for [2H]8OlAla; 50 pmol for [2H]8 AA5HT). Then, the lipid extract was dissolved in 100 ul of CH 3 OH and analyzed by either LC-APCI-MS for AEA, 2-AG, PEA, OEA, DHEA, and EPEA quantification, which were calculated based on their area ratio with the internal deuterated standard signal areas ( Bisogno et al, 1997 ; Piscitelli et al, 2020 ), and by LC-MS-IT-TOF (Shimadzu Corporation, Kyoto, Japan) for N -acylglycine, N -oleoylalanine and N -acylserotonin identification and quantification, using multiple reaction monitoring (MRM). The chromatograms of the high-resolution [M-H]- values were extracted and used for calibration and quantification.…”

“…A new member of the increasing family of endocannabinoid (eCB)-like mediators, which, together with their receptors and metabolic enzymes, constitute the endocannabinoidome (eCBome) ( Di Marzo 2018 ), N -Oleoylglycine (OlGly) is an endogenous lipoaminoacid produced in the brain following mild trauma and has been shown to reduce the behavioral consequences of this condition ( Piscitelli et al, 2020 ) as well as the abuse-related effects of nicotine addiction in mouse models ( Donvito al., 2019 ). OlGly also reduced responses produced by acute naloxone-precipitated morphine withdrawal (MWD) in rats as assessed by conditioned place aversion (CPA; Petrie et al, 2019 ) and somatic withdrawal behaviors ( Rock et al, 2020 ).…”

N-Oleoyl Glycine and N-Oleoyl Alanine Attenuate Alcohol Self-Administration and Preference in Mice

“…To evaluate the role of the eCBs and eCB-Ls in alcohol use and abuse, we tested the effect of EtOH chronic self-administration on the levels of different eCBs and eCB-Ls, some were shown to have neuroprotective properties [10,17,24,25]. Therefore, female and male mice were tested for EtOH consumption and preference using an intermittent access to EtOH-two bottle choice (IA2BC) procedure, designed to simulate the repeated episodes of heavy drinking and withdrawal that characterize alcohol abuse [26].…”

(Wh)olistic (E)ndocannabinoidome-Microbiome-Axis Modulation through (N)utrition (WHEN) to Curb Obesity and Related Disorders

“…N -oleoyl-glycine (NOleG) has been reported to counteract some of the behavioural consequences of mild trauma in mice [ 120 ]. Importantly, this condition causes elevation of the levels of this compound in the insula [ 121 ]. NOleG also reduces nicotine self-administration as well as some of the signs of withdrawal from chronic or acute morphine administration in rats [ 120 , 122 ].…”