Administration of palmitoylethanolamide (PEA) protects the neurovascular unit and reduces secondary injury after traumatic brain injury in mice.

Traumatic brain injury (TBI) is a major cause of preventable death and morbidity in young adults. This 26 complex condition is characterized by significant blood brain barrier leakage that stems from cerebral 27 ischemia, inflammation, and redox imbalances in the traumatic penumbra of the injured brain. Recovery 28 of function after TBI is partly through neuronal plasticity. In order to test whether treatments that 29 enhance plasticity might improve functional recovery, a controlled cortical impact (CCI) in adult mice, 30 as a model of TBI, in which a controlled cortical impactor produced full thickness lesions of the forelimb 31 region of the sensorimotor cortex, was performed. Once trauma has occurred, combating these exacerba- 32 tions is the keystone of an effective TBI therapy. The endogenous fatty acid palmitoylethanolamide (PEA) 33 is one of the members of N-acyl-ethanolamines family that maintain not only redox balance but also inhi- 34 bit the mechanisms of secondary injury. Therefore, we tested whether PEA shows efficacy in a mice 35 model of experimental TBI. PEA treatment is able to reduced edema and brain infractions as evidenced 36 by decreased 2,3,5-triphenyltetrazolium chloride staining across brain sections. PEA-mediated improve- 37 ments in tissues histology shown by reduction of lesion size and improvement in apoptosis level further 38 support the efficacy of PEA therapy. The PEA treatment blocked infiltration of astrocytes and restored CCI- 39 mediated reduced expression of PAR, nitrotyrosine, iNOS, chymase, tryptase, CD11b and GFAP. PEA inhib- 40 ited the TBI-mediated decrease in the expression of pJNK and NF-jB. PEA-treated injured animals 41 improved neurobehavioral functions as evaluated by behavioral tests.