Co-ultramicronized Palmitoylethanolamide/Luteolin in the Treatment of Cerebral Ischemia: from Rodent to Man

Abstract

Acute ischemic stroke, the most frequent cause of permanent disability in adults worldwide, results from transient or permanent reduction in regional cerebral blood flow and involves oxidative stress and inflammation. Despite the success of experimental animal models of stroke in identifying anti-inflammatory/neuroprotective compounds, translation of these putative neuroprotectants to human clinical trials has failed to produce a positive outcome. Tissue injury and stress activate endogenous mechanisms which function to restore homeostatic balance and prevent further damage by upregulating the synthesis of lipid signaling molecules, including N-palmitoylethanolamine (PEA or palmitoylethanolamide). PEA exerts neuroprotection and reduces inflammatory secondary events associated with brain ischemia reperfusion injury (middle cerebral artery occlusion (MCAo)). Here, we examined the neuroprotective potential of a co-ultramicronized composite containing PEA and the antioxidant flavonoid luteolin (10:1 by mass), nominated co-ultraPEALut. The study consisted of two arms. In the first, rats subjected to MCAo and treated with co-ultraPEALut post-ischemia showed reduced edema and brain infract volume, improved neurobehavioral functions, and reduced expression of pro-inflammatory markers and astrocyte markers. In the second arm, a cohort of 250 stroke patients undergoing neurorehabilitation on either an inpatient or outpatient basis were treated for 60 days with a pharmaceutical preparation of co-ultraPEALut (Glialia®). At baseline and after 30 days of treatment, all patients underwent a battery of evaluations to assess neurological status, impairment of cognitive abilities, the degree of spasticity, pain, and independence in daily living activities. All indices showed statistically significant gains at study end. Despite its observational nature, this represents the first description of co-ultraPEALut administration to human stroke patients and clinical improvement not otherwise expected from spontaneous recovery. Further, controlled trials are warranted to confirm the utility of co-ultraPEALut to improve clinical outcome in human stroke.

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

“…In this study we did not explore the effects of the drugs when added to MCs just after the OGD exposure, though we showed that MCs can release neurotoxic factors synthetized ex novo in the post-OGD period and that PEA-luteolin can limit the cell death when added to cultured neurons after the OGD. These findings, together with the evidence that PEA-luteolin are neuroprotective when administered to rats after the onset of brain ischemia (Caltagirone et al, 2015), raise the possibility that the drug combination may be of therapeutical value even when administered in the acute post ischemic phase.…”

“…Finally, it has been recently shown that the combination PEA-luteolin is able to reduce the ischemia-induced MCs infiltration in a rat model of brain ischemia (Caltagirone et al, 2015).…”

“…A body of evidence points out the involvement of MCs in the pathophysiology of brain ischemia (Lindsberg et al, 2010;Strbian et al, 2009). After ischemia, MCs translocate from brain perivascular positions and can be more abundantly found in the ischemic cerebral area where they release their granules contents and mediators of inflammation (Caltagirone et al, 2015;Hu et al, 2004;Lindsberg et al, 2010;Silverman et al, 2000;Strbian et al, 2006). In rodent models of brain ischemia, both genetic deficiency or pharmacological inhibition of MCs led to a significant reduction of ischemic damages, including brain blood barrier (BBB) disruption, cerebral edema, and neutrophil infiltration (Mattila et al, 2011;Strbian et al, 2006).…”

“…Moreover, recent findings indicate that the combination PEAluteolin is effective in reducing inflammation in animal models of spinal cord injury , AD (Paterniti et al, 2014), traumatic brain injury (TBI) , anxiety/depression (Crupi et al, 2013), arthritis , PD ) and brain ischemia (Caltagirone et al, 2015), and in promoting the maturation of oligodendrocytes precursor cells in vitro (Barbierato et al, 2015). Finally, it has been recently shown that the combination PEA-luteolin is able to reduce the ischemia-induced MCs infiltration in a rat model of brain ischemia (Caltagirone et al, 2015).…”

Longitudinal modeling using log-gamma mixed model: case of memory deterioration after chronic cerebral hypoperfusion associated with diabetes in rats

“…The GLMM has been used to quantify the longitudinal benefits of different strategies after hypoxic/ischemic brain damage. They include investigations on the neuroprotective effects of the antineuroinflammatory lipid signaling molecule N-palmitoylethanolamine associated with the antioxidant agent luteolin in rats and humans (Caltagirone et al, 2016), the effects of prophylactic triple-H therapy on hemodynamic variables in humans victims of subarachnoid hemorrhage (Tagami et al, 2014), the impact of reducing the time window of treatment with intravenous tissue plasminogen activator (tPA) and the complicating effects of bleeding in patients that underwent acute ischemic stroke (Ido et al, 2016). Overall, these studies indicate the importance of using GLMM to evaluate experimental data related to the longterm outcomes of cerebral ischemia.…”