A new co-ultramicronized composite including palmitoylethanolamide and luteolin to prevent neuroinflammation in spinal cord injury

Abstract

BackgroundIt has recently been demonstrated that palmitoylethanolamide (PEA), an endogenous lipid amide belonging to the N-acylethanolamine family, exerts neuroprotection in central nervous system (CNS) pathologies. In recent studies, we have demonstrated that treatment with PEA significantly reduced inflammatory secondary events associated with spinal cord injury (SCI). Since oxidative stress is considered to play an important role in neuroinflammatory disorders, in the present work we studied a new composite, a formulation including PEA and the antioxidant compound luteolin (Lut), subjected to an ultramicronization process, co-ultraPEALut. We investigated the effect of co-ultraPEALut (in the respective fixed doses of 10:1 in mass) in both an ex vivo organotypic spinal cord culture model and an in vivo model of SCI.MethodsFor the organotypic cultures, spinal cords were prepared from mice at postnatal day 6 and were cut into transverse slices of 400 μm thickness to generate the lumbar organotypic slice cultures. After 7 days of culturing, the slices were mechanically injured onto the center of the slice and the co-ultraPEALut was applied at different concentrations (0.00009, 0.0009 and 0.009 g/l) 1 hour before damage. For in vivo studies, SCI was induced in mice through spinal cord compression by the application of vascular clips (force of 24 g) to the dura via a four-level T5 to T8 laminectomy, and co-ultraPEALut (1 mg/kg ip) was administered at 1 and 6 hours after SCI. At 24 hours after SCI, mice were sacrificed and the spinal cords were collected for further evaluation. Additional animals were treated similarly and sacrificed 10 days after SCI.ResultsPretreatment with co-ultraPEALut significantly reduced cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) expression in a concentration-dependent manner, restored neuronal nitric oxide synthase (nNOS) expression at all three tested concentrations, and protected cells by cell death (MTT assay) in spinal cord organotypic cultures. Moreover, we demonstrated in vivo that co-ultraPEALut 1 mg/kg reduced the severity of trauma induced by compression and improved the motor activity evaluated at 10 days post-injury.ConclusionThe present study demonstrates that the protective effect of PEA on SCI-associated neuroinflammation could be improved by co-ultramicronization with Lut possibly due to its antioxidant properties.

B-Cell Depletion with CD20 Antibodies as New Approach in the Treatment of Inflammatory and Immunological Events Associated with Spinal Cord Injury

“…NO is a unique molecule involved in a variety of physiological processes in the CNS [65]. The effects of NO on spinal cord damage are correlated with several factors, such as concentration of NO production, activity of different synthase isoforms, cellular source of production, and time of release [35]. In this study, we demonstrated increased NO expression after injury, reduced by 18B12 pretreatment.…”

“…Total nitrite levels, as an indicator of nitric oxide (NO) synthesis, were measured in the supernatant as previously described [35].…”

Ultramicronized palmitoylethanolamide in spinal cord injury neuropathic pain: a randomized, double-blind, placebo-controlled trial

“…Our study included patients with different causes and levels of SCI, which could impact the outcome, and patients with concomitant medication which could have an impact on the effect of PEA-um, and it is likely that we included some patients that are refractory to pain treatment, which could also contribute to the lack of effect, also considering that more patients randomized to PEA were treated with concomitant medication. Finally it is possible, that the effect seen in experimental studies is driven mainly by reduced inflammation and neuroprotective mechanisms [13,29] and that treating spinal cord-injured individuals with PEA-um in early stages and before neuropathic pain and spasticity develop, may be beneficial.…”

PEA and luteolin synergistically reduce mast cell-mediated toxicity and elicit neuroprotection in cell-based models of brain ischemia

“…Previous studies have shown that PEAluteolin combination can reduce inflammatory processes associated with spinal cord injury and TBI by restoring basal expressions of peroxisome proliferator-activated receptors (PPARs) and by limiting nuclear factor-kB (NF-kB) activation Paterniti et al, 2013). Moreover, PEA-luteolin association Fig.…”