N-Palmitoylethanolamine-Oxazoline as a New Therapeutic Strategy to Control Neuroinflammation: Neuroprotective Effects in Experimental Models of Spinal Cord and Brain Injury

Modulation of N-acylethanolamine-hydrolyzing acid amidase (NAAA) represents a potential alternative strategy in the treatment of neuroinflammation. Recent studies showed that pharmacological modulation of NAAA could be achieved with the oxazoline of palmitoylethanolamide (PEA; PEA-OXA). The aim of this study was to evaluate the neuroprotective effects of PEA-OXA in the secondary neuroinflammatory events induced by spinal and brain trauma in mice. Animals were subjected to spinal cord and brain injury models and PEA-OXA (10 mg/kg) was administered both intraperitoneally and orally 1 h and 6 h after trauma. PEA-OXA treatment markedly reduced the histological alterations induced by spinal cord injury (SCI) and traumatic brain injury (TBI) and ameliorated the motor function and behavioral deficits, as well. In addition, the expression of neurotrophic factors, such as glial cell line-derived neurotrophic factor, brain-derived neurotrophic factor, and neurotrophin-3 were increased by PEA-OXA treatment. Moreover, PEA-OXA also significantly decreased glial fibrillary acidic protein hyperexpression, the nuclear translocation of nuclear factor (NF)-kappa B, phosphorylation of Ser536 on the NF-kappa B subunit p65, and degradation of I kappa B-alpha, as well as diminished the expression of proinflammatory mediators such as cyclooxygenase-2 (COX-2), inducible nitric oxide synthase, tumor necrosis factor (TNF)-alpha and interleukin (IL)-1 beta. The modulation of intracellular NAAA by PEA-OXA treatment could thus represent a novel therapy to control neuroinflammatory conditions associated with SCI and TBI.