Lipid molecules may play a primary role essential to fight, or at least delay, chronic neuroinflammation, a phenomenon underlying many neurodegenerative diseases. A class of anti-inflammatory molecules are the Autacoid Local Injury Antagonist (ALIA) amides [1]. This acronym, coined by the research group of Rita Levi Montalcini, describes a group of endogenous bioactive acyl ethanolamides with anti-inflammatory properties [2], generally referred to as N-acylethanolamines (NAEs). NAEs include PEA, an anti-inflammatory and analgesic substance, oleoylethanolamide (OEA), an anorectic substance, and anandamide (AEA), an endocannabinoid (eCB) substance with autocrine and paracrine signaling properties [3]. PEA cannot strictly be considered a classic eCB, because it has a low affinity for the cannabinoid receptors CB1 and CB2 [4,5]. However, the presence of PEA enhances the AEA activity, likely through an “entourage effect”. PEA is endowed with important anti-inflammatory, neuroprotective, and analgesic actions, and some of its effects are mediated by the peroxisome proliferator-activated receptor (PPAR)-α. PEA anti-inflammatory and neuroprotective functions have been attributed in particular to eCBs belonging to the acyl ethanolamide family, as well as to their congeners, since their production is significantly increased in the sites of neuronal damage [6]. PEA is naturally found in some foods, such as egg yolk, peanut flour, soybean oil, and corn [1,7]. In animal cells, PEA is synthesized from palmitic acid, the most common fatty acid present in many foods including palm oil, meats, cheeses, butter, and other dairy products [8]. Because of its high safety and tolerability [9,10,11,12], PEA is often used as an analgesic, anti-inflammatory, and neuroprotective mediator in the treatment of acute and chronic inflammatory diseases, alone or combined with antioxidant or analgesic molecules acting on molecular targets of central and peripheral nervous system and immune cells [11,13,14]. In the brain, PEA is produced “on demand” by neurons, microglia, and astrocytes, and thus plays a pleiotropic and pro-homeostatic role, when faced with external stressors provoking inflammation. PEA exerts a local anti-injury function by down-modulating mast cell activation and protecting neurons from excitotoxicity [15,16,17]. The synthesis of PEA takes place in the membranes of various cell populations and mainly involves the class of N-acylphosphatidylethanolamines (NAPEs). Similar to its eCB congeners, PEA acts as local neuroprotective mediator and its physiological tone depends on the finely regulated balance between biosynthesis (mainly catalyzed by NAPE-selective phospholipase D) and degradation (mainly catalyzed by fatty acid amide hydrolase (FAAH) and N-acylethanolamine-hydrolyzing acid amidase) [18,19,20].

It was proposed that PEA exerts its effects through three mechanisms, which are not mutually exclusive. The first mechanism advances that PEA acts by down-regulating mast-cell degranulation, via an ALIA effect [21,22,23]; the second one, the entourage effect, postulates that PEA acts by enhancing the anti-inflammatory and anti-nociceptive effects exerted by AEA [4,24,25]; and finally, the third one, the “receptor mechanism”, is based on PEA’s capability to directly stimulate either PPAR-α or the orphan receptor G-protein coupling, GPR55, which mediates many anti-inflammatory effects [26,27].

PEA lacks a direct antioxidant capacity to prevent the formation of free radicals and counteract the damage of DNA, lipids, and proteins [1]. With its lipid structure and the large size of heterogeneous particles in the naïve state, PEA has limitations in terms of solubility and bioavailability. To overcome these problems, PEA has been micronized (m-PEA) or ultra-micronized (um-PEA) [28]. Several in vitro and in vivo preclinical studies attest that PEA, especially in its micrometer-sized crystalline forms, may be a therapeutic agent for the effective treatment of neuroinflammatory pathologies [29]. m-PEA and um-PEA show enhanced rate of dissolution and absorption [30], better bioavailability, pharmacokinetics, and efficacy when compared to its naïve form [31,32]. Since, as already mentioned, PEA has no antioxidant effects per se, the combination of PEA’s ultra-micronized forms with an antioxidant agent, such as a flavonoid, results in more efficacious forms than either molecule alone, potentiating the pharmacological effects of both compounds [33]. In fact, among the natural molecules with excellent antioxidant and antimicrobial functions there are flavonoids, as firstly luteolin, and also polydatin, quercetin, and silymarin. These compounds possess marked antioxidant and neuroprotective pharmacological actions, by modulating apoptosis and release of cytokines and free radicals (reactive oxygen and nitrogen species), suppressing the production of tumor necrosis factor alpha, inhibiting autophagy, and controlling signal transduction pathways [1,34]. In particular, luteolin is able to improve the PEA morphology: while naïve PEA has a morphology featured by large flat crystals, very small quantities of luteolin stabilize the microparticles by inhibiting the PEA crystallization process [35]. The combination of PEA and luteolin makes co-um-PEALut a product able to tackle several neuroinflammatory conditions, and to have protective effects [33].

Aging is the result of a continuous interaction between biological mechanisms and environmental factors, such as life events, health conditions, and lifestyle habits. Although aging is not necessarily synonymous with disease, the deterioration in cell function that increases with advancing age progressively increments the risk of developing disease and disability, because bodily and brain cellular responses become less and less efficient [36]. Namely, aging is characterized by gradual and permanent accumulation of cellular and molecular damage (such as abnormal protein dynamics, mitochondrial dysfunction, DNA damage, oxidative stress, neurotrophin dysfunction), progressive structural changes of neurons (deregulation of neurotransmitters and neuro-signals), loss of tissue and organ function, and neuroinflammatory processes [37,38,39]. Unlike the normally beneficial acute inflammatory response, chronic neuroinflammation can lead to damage and destruction of tissues, and often results from inappropriate immune responses [40]. A fundamental principle behind neuroinflammation is the existence of numerous signaling pathways between glial cells and immune system. Notably, despite different triggering events, a common feature of several central and peripheral neuropathologies is chronic immune activation, particularly of the microglia, the resident macrophages of the central nervous system [41]. Individual neurodegenerative disorders are heterogeneous in etiopathogenesis and symptomatology, but biomedical research has revealed many similarities among them at the subcellular level. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well [42].

The most common neurodegenerative diseases encompass a wide range of conditions which impair mobility, muscle coordination and strength, mood, and cognition. They are amyloidosis, tauopathies, α-synucleinopathies, proteopathies (TAR DNA-binding protein 43, TDP-43), and include Alzheimer’s Disease (AD), Parkinson’s Disease (PD), Huntington’s Disease (HD), Frontotemporal Dementia (FTD), Amyotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS) (Figure 1) [43].

Up to now, the treatment of most of these neurodegenerative diseases was mainly symptomatic (dopaminergic treatment for PD, inhibitors of acetylcholinesterase for cognitive disorders, antipsychotics for dementia), despite significant attempts to find drugs reducing or rescuing the debilitating symptoms [44,45,46]. In this context, integrative treatments of these neurodegenerative diseases have been investigated through a number of in vitro and in vivo animal models of disease, and, when combined with classical drug therapies, are in the frontline of research in an attempt to protect against neuroinflammation and oxidative stress, and thereby improve symptomatology of the neurodegenerative patients [45]. Since most clinical studies on PEA are related to neuropathic pain or inflammation-related peripheral conditions, and there are fewer studies evaluating the possible beneficial effects of PEA on neurodegenerative diseases, we were interested to offer a general overview of the effects of PEA on different symptoms of neurodegeneration, taking into account both human (Table 1) and rodent (Table 2) studies.