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

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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.

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Abbreviations

2-AG:

2-arachidonoyl glycerol

AraS:

N-arachidonoyl serine

CHI:

Closed head injury

eCB:

Endocannabinoid

FAAA:

Fatty acid amino acid amides

NF-kappaB:

Nuclear factor kappaB

PalmS:

Palmitoyl serine

TBI:

Traumatic brain injury

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Acknowledgments

This study was supported by a NIH grant DA-9789; RM thanks the Kessler Foundation for financial support.

Conflict of Interest

The authors declare no conflict of interests.

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Authors and Affiliations

  1. Institute for Drug Research, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, 91120, Israel

    Aniv Mann, Reem Smoum, Victoria Trembovler, Alexander Alexandrovich, Aviva Breuer, Raphael Mechoulam & Esther Shohami

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  1. Aniv Mann
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  2. Reem Smoum
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  3. Victoria Trembovler
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  4. Alexander Alexandrovich
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  5. Aviva Breuer
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  6. Raphael Mechoulam
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  7. Esther Shohami
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Correspondence to Esther Shohami.

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Mann, A., Smoum, R., Trembovler, V. et al. Palmitoyl Serine: An Endogenous Neuroprotective Endocannabinoid-Like Entity After Traumatic Brain Injury. J Neuroimmune Pharmacol 10, 356–363 (2015). https://doi.org/10.1007/s11481-015-9595-z

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  • DOI: https://doi.org/10.1007/s11481-015-9595-z

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