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Effects of Palmitoylethanolamide on Neurodegenerative Diseases
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Palmitoylethanolamide (PEA) stands out among endogenous lipid mediators for its neuroprotective, anti-inflammatory, and analgesic functions. PEA belonging to the N-acetylanolamine class of phospholipids was first isolated from soy lecithin, egg yolk, and peanut flour. It is currently used for the treatment of different types of neuropathic pain, such as fibromyalgia, osteoarthritis, carpal tunnel syndrome, and many other conditions. 

PEA ALIAmides neuroinflammation
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Update Date: 19 May 2022
Table of Contents

    1. PEA, an Anti-Inflammatory and Neuroprotective Substance

    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].

    2. PEA Action in the Presence of Aging and Neurodegeneration

    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].
    Figure 1. Neurodegenerative diseases share common pathological hallmarks leading to cell dysfunction and death.
    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, researchers 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.
    Table 1. Summary of human studies using PEA in the presence of neurodegeneration.
    Study Disease Sample um PEA
    (Alone or
    In Combination)
    Dosage Duration Main Outcomes of PEA Treatment
    [47] MCI 1 patient co-um-PEALut 700/70 mg daily T3: 3 months treatment T9: 9 months follow-up T3: mild (though not significant) cognitive improvement;
    T9: near-normal neuropsychological assessment; improvement in test scores; brain SPECT near-normal.
    [48] PD 30 patients PEA added to
    regular levodopa
    600 mg daily 12 months Progressive reduction in the total MDS-UPDRS score;
    reduction in most nonmotor and motor symptoms.
    [49] PD 1 patient co-um-PEALut added to regular carbidopa/levodopa 700/70 mg daily 4 months Complete resolution of leg and trunk dyskinesia and marked reduction in the onset of camptocormia during the “off” state.
    [50] FTD 17 patients co-um-PEALut 700 mg/2 daily 4 weeks Improvement in test scores and neurophysiological evaluation; increase in TMS-evoked frontal lobe activity and of high-frequency oscillations in the beta/gamma range.
    [51] ALS 1 patient PEA 600 mg/2 daily ∼40 days Improvement in clinical picture.
    [52] ALS 28 treated and 36 untreated
    PEA + 50 mg riluzole
    or 50 mg riluzole only
    600 mg/2 daily 6 months Lower decrease in forced vital capacity over time as compared with untreated ALS patients.
    [53] MS 24 patients
    17 healthy controls
    eCBs levels in blood _ _ eCB system is altered in MS.
    [54] MS 1 patient PEA 600 mg/2 daily ∼9 months Pain reduction; increased
    interval between acupuncture sessions.
    [55] MS 29 patients PEA added to
    IFN-β1a or placebo
    600 mg daily 12 months Improvement in pain sensation, no reduction of erythema at the injection site, improved evaluation of quality of life, increase in PEA, AEA and OEA plasma levels, reduction of interferon-γ, tumor necrosis factor-α, and interleukin-17 serum profile.
    [56] Myasthenia gravis 22 patients PEA 600 mg/2 daily 1 week Reduced level of disability and decremental muscle
    AEA-Anandamide; ALS-Amyotrophic Lateral Sclerosis; co-um-PEALut-combined ultra-micronized PEA/Lutein; eCB-endocannabinoid; FTD-Frontotemporal Dementia; IFN-β1-Interferon-beta-1; MCI-Mild Cognitive Impairment; MDS-UPDRS-Movement Disorder Society-Unified Parkinson’s Disease Rating Scale; MS-Multiple Sclerosis; OEA-Oleoylethanolamide; PD-Parkinson Disease; um-ultra-micronized.
    Table 2. Summary of experimental studies using PEA in the presence of neurodegeneration.
    Study Disease Sample um PEA
    (Alone or In Combination)
    Dosage Duration Main Outcomes of PEA
    [57] AD model
    (Aβ 1–42
    intra-hippocampal injection)
    Male adult
    Sprague-Dawley rats (9–12/group)
    PEA added to GW6471
    PEA:10 mg/kg;
    GW647: 2 mg/kg
    7 days Restoration of Aβ 1–42-induced alterations;
    reduced mnestic deficits.
    [58] AD model
    (Aβ 25–35 i.c.v. injection)
    Male PPAR-α/(B6.129S4-SvJaePparatm
    1Gonz) and WT mice (9–10/group)
    PEA and GW7647
    PEA: 3–30 mg/kg daily, GW7647: 5 mg/kg daily 1–2 weeks
    or a single dose
    Reduction (10 mg/kg) or prevention (30 mg/kg) of
    behavioral impairments. No rescue of memory deficits. PEA acute treatment was ineffective.
    [59] AD model 3-month-old male 3 × Tg-AD
    and WT mice
    or vehicle
    10 mg/kg daily 90 days Counteraction of disease progression, improvement of trophic support to neurons, in the absence of astrocytes and neuronal toxicity.
    [60] AD model 3-month-old or 9-month-old male 3 × Tg-AD or WT mice
    or vehicle
    10 mg/kg daily 90 days Improvement of learning and memory, amelioration of
    depressive and anhedonia-like symptoms, reduced Aβ
    formation, tau protein phosphorylation, promotion of hippocampal neuronal survival and astrocytic function,
    rebalancing of glutamatergic transmission, restraint of
    [61] AD model 2-month-old male 3 × Tg-AD or WT mice
    or vehicle
    single dose/sub-chronic/chronic:100 mg/kg daily 1–8–90 days Rescue of cognitive deficit, restraint of neuroinflammation and oxidative stress, reduced increase in hippocampal glutamate levels.
    [62] PD model (MPTP) 6–7-week-old male PPAR-αKO
    PPAR-αWT mice (10/group)
    10 mg/kg 8 days Reduction of MPTP-induced microglial activation, glial fibrillary acidic protein positive expression astrocyte numbers, overexpression of S100b; protection against alterations in microtubule-associated protein 2a,b, dopamine transporter, nNOS-positive cells in the substantia nigra. Reversal of motor deficits.
    [63] PD model (MPTP) 3/21-month-old male CD1 mice
    10 mg/kg 60 days Amelioration of behavioral deficits and of reduction of
    tyrosine hydroxylase and dopamine transporter in substantia nigra. Reduction of hippocampal proinflammatory cytokines and pro-neurogenic effects.
    [64] PD model
    Ten-week-old male Swiss CD1 mice (6 × group) s.c.
    or GW7647
    3–30 mg/kg/day; GW7647 5 mg/kg/day
    28 days Improvement of behavioral impairment. Increased tyrosine hydroxylase expression at striatal level. Reduction in the expression of pro-inflammatory enzymes, protective scavenging effect.
    [65] PD model (MPTP) 8-week-old male C57BL/6 (10/group) i.p.
    1 mg/kg daily 8 days Reduction of motor impairment, cataleptic response, immobility and anxiety levels. Reduction of neuronal degeneration and of specific PD markers, attenuation of
    inflammatory processes (activation of astrocytes, pro-inflammatory cytokines, and nitric oxide synthase), stimulation of autophagy.
    [66] PD model
    8-week-old male C57BL/6
    or vehicle
    10 mg/kg daily 8 days Prevention of MPTP-induced bradykinesia and anxiety, and neuronal degeneration of the dopaminergic tract, prevention of dopamine depletion, modulation of microglia and astrocyte activation.
    [67] HD model ∼32-day-old-R6/2 10-week-old R6/2
    mice and WT mice (4/group)
    Measurement of PEA, AEA and 2-AG
    _ _ Alteration of the eCB system, decreased levels of PEA in the striatum
    [68] MS model (EAE) 12-week-old
    female C57BL/6
    or CBD
    or in
    PEA 5 mg/kg
    CBD 5 mg/kg
    3 days Reduced severity of EAE neurobehavioral scores, diminished inflammation, demyelination, axonal damage and inflammatory cytokine expression.
    [69] MS model (chronic relapsing EAE) Biozzi ADH mice
    i.v. or i.p.
    1–10 mg/kg Single
    Amelioration of spasticity
    [70] MS model (EAE) C57BL/6 mice
    co-um-PEALut or vehicle
    0.1, 1, and 5 mg/kg 16 days Dose-dependent improvement of clinical signs through
    anti-inflammatory signals and pro-resolving circuits.
    [71] MS model (TMEV-IDD) Four-week
    female SJL/J mice
    or vehicle
    5 mg/kg 10 days Reduction of motor disability, anti-inflammatory effect.
    [72] Vascular
    CD1 mice Oral
    or vehicle
    10 mg/kg daily 15 days Improvement of behavioral deficits, reduction of histological alterations, decrease of markers of astrocyte and microglia activation and oxidative stress, modulation of antioxidant response, inhibition of apoptotic process.
    2-AG-2-Arachidonoylglycerol; 6-OHDA-6-hydroxydopamine; Aβ-amyloid beta; CBD-cannabidiol; EAE-Experimental Autoimmune Encephalomyelitis; i.c.v.-intracerebroventricular; i.p.-intraperitoneal; KO-knockout; MPTP-1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; nNOS-neuronal Nitric Oxide Synthase; PEA-OXA-2-pentadecyl-2-oxazoline; PPAR-α-peroxisome proliferator-activated receptor-α; s.c.-subcutaneous; TMEV-IDD-Theiler’s Murine Encephalomyelitis Virus-Induced Demyelinating Disease; WT-Wild Type.


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      Petrosini, L.; Landolfo, E.; Cutuli, D.; Caltagirone, C. Effects of Palmitoylethanolamide on Neurodegenerative Diseases. Encyclopedia. Available online: (accessed on 07 June 2023).
      Petrosini L, Landolfo E, Cutuli D, Caltagirone C. Effects of Palmitoylethanolamide on Neurodegenerative Diseases. Encyclopedia. Available at: Accessed June 07, 2023.
      Petrosini, Laura, Eugenia Landolfo, Debora Cutuli, Carlo Caltagirone. "Effects of Palmitoylethanolamide on Neurodegenerative Diseases" Encyclopedia, (accessed June 07, 2023).
      Petrosini, L., Landolfo, E., Cutuli, D., & Caltagirone, C. (2022, May 17). Effects of Palmitoylethanolamide on Neurodegenerative Diseases. In Encyclopedia.
      Petrosini, Laura, et al. "Effects of Palmitoylethanolamide on Neurodegenerative Diseases." Encyclopedia. Web. 17 May, 2022.