Effects of Palmitoylethanolamide on Neurodegenerative Diseases

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1		Laura Petrosini	--	2202	2022-05-17 12:41:00	\|
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3	format correction	Dean Liu	Meta information modification	2202	2022-05-19 04:21:38	\|

This entry is adapted from the peer-reviewed paper 10.3390/biom12050667

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

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 patients	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 response.

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 Treatment
^[57]	AD model (Aβ 1–42 intra-hippocampal injection)	Male adult Sprague-Dawley rats (9–12/group)	i.p. PEA 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)	s.c. 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 (9–10/group)	s.c. PEA 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 (7–11/group)	s.c. PEA 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 neuroinflammation.
^[61]	AD model	2-month-old male 3 × Tg-AD or WT mice (7–11/group)	oral PEA 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)	i.p. PEA	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/group)	oral PEA	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 (6-OHDA)	Ten-week-old male Swiss CD1 mice (6 × group)	s.c. PEA or GW7647	PEA 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. co-um-PEALut	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 (MPTP)	8-week-old male C57BL/6 (10/group)	oral PEA-OXA 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 endogenous levels	_	_	Alteration of the eCB system, decreased levels of PEA in the striatum
^[68]	MS model (EAE)	12-week-old female C57BL/6 (8/group)	i.p. PEA or CBD or in combination	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 (>6/group)	i.v. or i.p. PEA	1–10 mg/kg	Single injection	Amelioration of spasticity
^[70]	MS model (EAE)	C57BL/6 mice (8/group)	i.p. 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	i.p. PEA or vehicle	5 mg/kg	10 days	Reduction of motor disability, anti-inflammatory effect.
^[72]	Vascular dementia	CD1 mice	Oral PEA-OXA 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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1. PEA, an Anti-Inflammatory and Neuroprotective Substance

2. PEA Action in the Presence of Aging and Neurodegeneration

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