Neuroprotective effects of palmitoylethanolamide in Alzheimer’s disease

Current treatments for Alzheimer’s Disease (AD) provide only inadequate symptomatic relief, without affecting its progressive course, then there is urgent need for agents able to prevent onset and delay illness progression. Increasing evidence suggests an age-related process leading to the accumulation of abnormally misfolded protein aggregates, resulting in neuronal loss, in vulnerable brain areas associated with memory and cognitive functions. It is commonly accepted that progressive (intra- and extra-neuronal) accumulation of beta amyloid (Aβ) peptide initiates a complex cascade of events. Given the complex heterogeneity of pathological changes occurring in AD, any therapeutic effort absolutely requires a multi-targeted approach, since attempts addressing only a single event may result ineffective. Palmitoylethanolamide (PEA), the naturally occurring lipid amide between palmitic acid and ethanolamine, seems to meet the criteria of a multifactorial approach. Here we describe the neuroprotective effects of systemic administration of PEA in adult male rats given intrahippocampal injection of Aβ (1-42). In order to investigate the molecular mechanisms responsible for the effects induced by PEA, we co-administered PEA with the GW6471, an antagonist of peroxisome proliferator-activated receptor-α (PPAR-α). We found that Aβ (1-42) injection results in severe changes of biochemical markers related to reactive gliosis and tau protein hyperphosphorylation. Interestingly PEA was able to restore the Aβ 1-42-induced alterations through PPAR-α involvement. In addition, results from the Morris water maze task showed a mild cognitive deficit during the reversal learning phase of the behavioral study, reduced by PEA treatment. These data suggest novel strategies that hopefully could have the potential not just to alleviate the symptoms but also to modify disease processes.