Palmitoyl Serine: An Endogenous Neuroprotective Endocannabinoid-Like Entity After Traumatic Brain Injury

Abstract

The endocannabinoid (eCB) system helps recovery following traumatic brain injury (TBI). Treatment with 2-arachidonoylglycerol (2-AG), a cerebral eCB ligand, was found to ameliorate the secondary damage. Interestingly, the fatty acid amino acid amide (FAAA) N-arachidonoyl-L-serine (AraS) exerts similar eCB dependent neuroprotective. The present study aimed to investigate the effects of the FAAA palmitoyl-serine (PalmS) following TBI. We utilized the TBI model in mice to examine the therapeutic potential of PalmS, injected 1 h following closed head injury (CHI). We followed the functional recovery of the injured mice for 28 days post-CHI, and evaluated cognitive and motor function, lesion volume, cytokines levels, molecular signaling, and infarct volume at different time points after CHI. PalmS treatment led to a significant improvement of the neurobehavioral outcome of the treated mice, compared with vehicle. This effect was attenuated in the presence of eCBR antagonists and in CB2-/- mice, compared to controls. Unexpectedly, treatment with PalmS did not affect edema and lesion volume, TNFα and IL1β levels, anti-apoptotic mechanisms, nor did it exert improvement in cognitive and motor function. Finally, co-administration of PalmS, AraS and 2-AG, did not enhance the effect of the individual drugs. We suggest that the neuroprotective action of PalmS is mediated by indirect activation of the eCB receptors following TBI. One such mechanism may involve receptor palmitoylation which has been reported to result in structural stabilization of the receptors and to an increase in their activity. Further research is required in order to establish this assumption.

Role of palmitoylation of cysteine 415 in functional coupling CB1 receptor to Gαi2 protein

“…However, as more is understood of the mechanisms that regulate CB 1 receptor, and in particular the dynamic covalent modifications that might endow tissue specific functions, these regulatory processes may provide alternative targets for CB 1 ‐based drug discovery. In this direction, palmitoyl serine has been demonstrated to have a neuroprotective activity after traumatic brain injury, possibly by increasing CB 1 receptor palmitoylation .…”

N-Acyl Amino Acids: Metabolism, Molecular Targets, and Role in Biological Processes

“…While NAraSer, as with 2-AG, caused improvement of neurological severity score as well as reduction of lesion volume, NPalSer only slightly affected neurological behavior and did not modify the typical neuropathology following TBI. Any improvement in neurological severity score nor on the cognitive function were reported for NOleSer [64]. It should be also noted that NAraSer increased proliferation and decreased differentiation of neural progenitor cells (NPC) into astrocytes and neurons after TBI.…”

“…Calcium mobilization [31] Cancer cell proliferation [58] Cell apoptosis and migration [34,35] Cell morphology [40] Inflammation [36] Intraocular pressure [38] Microglial-neuronal communication [39] Neuropathic pain [45] Thermal analgesia [46] Angiogenesis [59] Anti-microbial effect [60] Cell proliferation [61] Cytoskeleton reorganization [62] Neuroprotection [61,63,64] N-Oleoyl…”

“…Calcium mobilization [67] Primary dysmenorrhea [68] Neuroprotection [64] NPalGly was identified in murine cells and tissues [50] and human fluids [68]. Notably, it was detected in Drosophila melanogaster that also expressed acyl derivatives of Val, Leu, Ala, Tryr, Phe, Ser and GABA [11,69].…”

“…Of note, NAraSer-induced signal transduction and endothelial functions were partly reduced in GPR55 knockdown mice [75]. Several members of NASer family, including NAra, NPal, and NOle derivatives, have been tested as neuroprotective agents after traumatic brain injury (TBI) [61,63,64]. While NAraSer, as with 2-AG, caused improvement of neurological severity score as well as reduction of lesion volume, NPalSer only slightly affected neurological behavior and did not modify the typical neuropathology following TBI.…”