Table 1B.
Summary of preclinical studies investigating palmitoylethanolamide and its correlations to neurocognitive disorders (NCDs).
| References (Country) | Aim of study | PEA type of study | Population | N | Outcome measure (test name or description) | Summary results |
|---|---|---|---|---|---|---|
| Scuderi et al. (29) (Italy) | To assess PEA effects on Aβ-exposed rat astrocytes | In vitro exposure in animals | 1. CTRL; 2. Aβ; 3. Aβ+PEA; 4. Aβ+PEA+MK; 4. Aβ+PEA+GW9662 |
X | 1. Astrocytes activation (Western blot, Immunofluorescence, RT-PCR, densitometric analysis, ELISA); 2. Neuroinflammation (Western blot, Immunofluorescence, spectrophotometric assay based on the Griess reaction, ELISA); 3. Anti-inflammatory effects (Western blot, EMSA analysis); 4. Effects on eCB system (Western blot analysis and densitometric analysis) |
1. PEA application reduces Aβ-induced neuroinflammation and astrocytes' activation; 2. PEA effects on atrocytes are counteracted by MK886 administration; 3. PEA application increases PPAR-α, CB1 and CB2 expression after Aβ exposure in astrocytes |
| Benito et al. (30) (Italy) | To assess PEA effects on Aβ-exposed FAAH-KO mice astrocytes | In vitro exposure in animals | 1. FAAH-WT group: (a) CTRL-WT; (b) Aβ-WT; (c) PEA; (d) Aβ+PEA; (e) Aβ+PEA+AEA+OEA; (f) OEA; (g) AEA; (h) Aβ+OEA; (i) Aβ+AEA; (j) URB; (k) Aβ+URB; (l) URB+SR1; (m) Aβ+URB+SR1; (n) URB+SR2; (o) Aβ+URB+SR2; 2. FAAH-KO group: (a) CTRL-KO; (b) Aβ-KO; (c) SR1; (d) Aβ+SR1; (e) SR2; (f) Aβ+SR2; (g) WY; (h) Aβ+WY; (i) TG; (j) Aβ+TG; (k) CPZ; (l) Aβ+CPZ |
X | 1. Anti-inflammatory effects (ELISA, Western blot, qRT-PCR); 2. Cell death (LDH dosage) |
PEA alone or combined with other eCBs/AEs decreases Aβ-induced inflammatory effects in astrocytes |
| D'Agostino et al. (31) (Italy) | To assess PEA effects on cognitive function and neuroprotection in AD mice | In vivo exposure in animals | 1. First set of mice (WT, PPARα-/-): (a) ScAb+VHI; (b) Ab+VHI; (c) Ab+PEA3; (d) Ab+PEA10; (e) Ab+PEA30; (f) Ab+GW7647; 2. Second, 3. Third sets of mice (WT): (a) ScAb+VHI; (b) Ab+VHI; (c) Ab+PEA30 |
8–10 per group | 1. Memory and cognition (YMT, MWM, WMT, NORT, Rotarod test); 2. Effects on brain function (Western blot, Lipid Peroxidation Measures) |
PEA administration restores learning and memory impairment and exerts a neuroprotective action at high dose in AD mice |
| Scuderi et al. (32) (Italy) | To assess PEA effects on Aβ-exposed rat neurons and astrocytes | 1. Ex vivo exposure in animals; 2. In vitro exposure in animals |
1. CTRL; 2. Aβ; 3. Aβ+PEA; 4. Aβ+PEA+MK; 5. Aβ+PEA+GW6471 |
X | Astrocyte proliferation and neuronal loss (Nissl staining, Immunofluorescence) | PEA application blunts Aβ-induced astrocyte activation and exerts a protective effect on neurons in rats |
| Scuderi and Steardo (33) (Italy) | To assess PEA effects on Aβ-exposed hippocampal tissue and neurons in rats | 1. Ex vivo exposure in animals; 2. In vitro exposure in animals |
1. Hippocampal slice cultures, 2. Cultures of primary neurons: (a) CTRL; (b) Aβ; (c) Aβ+PEA; (d) Aβ+PEA+GW6471 |
X | 1. Hippocampal tissue functioning, 2. Neuroinflammation (Nissl staining, Immunofluorescence, Western blot, ELISA); 3. Neuronal viability (Neutral red assay) |
PEA application blunts Aβ-induced astrocyte activation and exerts a protective effect on neurons in rats |
| Paterniti et al. (22) (Italy) | To assess PEA effects on Aβ-exposed mouse brain tissue | Ex vivo exposure in animals | 1. CTRL; 2. Aβ; 3. Aβ+PEA(0.27 + 0.027 μM); 4. Aβ+PEA(2.7 + 0.27 μM); 5. Aβ+PEA(27 + 2.7 μM) |
X | 1. Effects on neuronal viability (Vital staining); 2. Effects on brain function (Measurement fo nitrite concentration, Western blot, Comet analysis) |
1. PEA administration increases neuronal viability in Aβ exposed mouse hippocampus; 2. PEA administration restores BDNF and GDNF levels in Aβ exposed mouse hippocampus; 3. PEA administration reduces GFAP activation in Aβ exposed mouse hippocampus; 4. PEA administration decreases nitrite production in Aβ exposed mouse hippocampus; 5. PEA administration rescues programmed cellular death in Aβ exposed mouse hippocampus; 6. PEA administration reduces DNA damage in Aβ exposed mouse hippocampus |
| Scuderi et al. (34) (Italy) | To assess PEA anti-inflammatory and neuro-protective effects in Aβ-exposed rats | In vivo exposure in animals | 1. VHI; 2. VHI+Aβ; 3. PEA+VHI; 4. PEA+Aβ; 5. PEA+GW6471+VHI; 6. PEA+GW6471+Aβ |
9–12 per group | 1. Glia activation, 2. Neuroinflammation (RT-PCR, Immunofluorescence, Western blot, ELISA); 3. Effect on the amyloidogenic and Wnt pathway (Western blot); 4. Neuronal viability (Immunofluorescence); 5. Memory and cognition (MWM) |
1. PEA administration counteracts Aβ-induced reactive gliosis and amyloidogenesis in rats; 2. PEA administration improves neuronal integrity after Aβ-exposure in rats; 3. PEA administration prevents Aβ-induced memory impairment in rats; 4. PEA exerts neuroprotective and anti-inflammatory effects through PPAR-α activation |
| Cipriano et al. (25) (Italy) | To assess PEA anti-inflammatory and anti-angiogenic effects on Aβ-exposed rat glioma cells | In vitro exposure in animals | 1. CTRL; 2. Aβ; 3. Aβ+PEA10∧−6; 4. Aβ+PEA10∧−7; 5. Aβ+PEA10∧−8; 6. Aβ+PEA10∧−6+GW6471(2.5); 7. Aβ+PEA10∧−6+GW6471(5); 8. Aβ+PEA10∧−6+GW6471(10) |
X | 1. Glia activation (Cell Vitality assay, Griess reaction, Western blot); 2. Effect on pro-angiogenic factors production and release (Western blot, ELISA) |
PEA concentration-dependently reduces the expression of 1. pro-inflammatory and 2. pro-angiogenic markers in Aβ treated cells. |
| Tomasini et al. (35) (Italy) | To assess PEA effects on Aβ exposed AD mouse neurons and astrocytes | In vitro exposure in animals | 1. Primary cerebral cortex neurons (3xTg-AD, Non-Tg): (a) CTRL; (b) PEA; (c) Aβ; (d) PEA+Aβ; 2. Primary cerebral cortex astrocytes (3xTg-AD, Non-Tg): (a) CTRL; (b) PEA; (c) Aβ; (d) PEA+Aβ |
X | 1. Cell viability (Neutral red assay); 2. Endogenous extracellular glutamate levels (High-performance liquid chromatography/fluorimetric detection system); 3. Cell morphology (Immunocytochemistry) |
PEA administration exerts protective properties in Non-Tg but not in 3xTg-AD Aβ-exposed mouse neuronal cultured cells |
| Caltagirone et al. (24) (Italy) | To assess PEA neuro-protective and behavioral effects in MCAo rats | In vivo exposure in animals | 1. MCAo+VHI; 2. MCAo+PEA; 3. sham+VHI; 4. sham+PEA |
1. First set of experiment: 20 per group; 2. Second set of experiment: 10 per group |
1. First set of experiment: (a) Motor behavior (Mean rotation number/h, Neurological scoring); (b) Brain tissue damage (Histological evaluation); 2. Second set of experiment: (a) Astrocyte activation (Immunohistochemistry, Western blot); (b) BDNF, GDNF expression (Western blot); (c) Mast cells infiltration, (d) Enzymatic expression (Immunohistochemistry); (e) Programmed cell death (Western blot) |
PEA administration improves neurobehavioural function, reduces neuroinflammation and counteracts histological damage in ischemic rats |
| Siracusa et al. (36) (Italy) | To assess PEA anti-inflammatory and neuroprotective effects in VaD mice | 1. In vivo exposure in animals; 2. Quantitative brain assessment |
1. Healthy rats: only used to test PEA pharmacokinetics; 2. Mice: (a) sham+VHI; (b) sham+PEA; (c) VaD+VHI; (d) VaD+PEA |
40 (10 per group) | 1. PEA brain levels (LC-APCI-MS); 2. Memory and cognition (NORT); 3. Social behavior (Social Interaction test); 4. Locomotor activity (OFT); 5. Effects on brain function (Immunohistochemistry, Immunofluorescence, Western blot) |
1. PEA oral administration results in low-medium PEA brain concentrations shortly after in healthy rats; 2. PEA administration rescues injured hippocampal CA1 and CA3 neurons in VaD mice; 3. PEA administration rescues impaired memory, social behavior and locomotor activity in VaD mice; 4. PEA administration exerts anti-inflammatory and neuroprotective effects in VaD mice |
| Beggiato et al. (37) (Italy) | To assess PEA effects on Aβ exposed mouse neurons and astrocytes | In vitro exposure in animals | 1. CTRL; 2. Aβ; 3. Aβ+PEA; 4. PEA | X | 1. Cell viability (Neutral red assay); 2. Cell morphology (Immunofluorescence); 3. Programmed cell death (% of neurons' apoptotic nuclei, DNA staining) |
PEA administration improves neuronal survival and morphology, by blunting Aβ-induced mouse astrocyte activation |
| Bronzuoli et al. (38) (Italy) | To assess PEA anti-inflammatory and neuro-protective effects in AD mice | 1. In vivo exposure in animals; 2. In vitro exposure in animals |
1. In vivo (n = 18 3xTg-AD, n = 18 Non-Tg): (a) CTRL; (b) PEA(0.01); (c) PEA(0.1); (d) PEA(1); 2. In vitro (n = 36 3xTg-AD, n = 12 Non-Tg): (a) CTRL; (b) PEA |
84 | 1. Primary astrocytes activation (Immunofluorescence, Western blot); 2. Astrocytes and neuronal viability (Neutral red assay); 3. Reactive astrogliosis, 4. Neuronal support and survival (RNA isolation, RT-PCR, Western blot, Immunofluorescence) |
PEA in vitro application and in vivo administration supports neuronal viability and reduces gliosis in AD mice |
| Crupi et al. (39) (Italy) | To assess PEA anti-inflammatory and neuroprotective effects in PD mice | In vivo exposure in animals | 1. sham+VHI; 2. sham+PEA; 3. MPTP+VHI; 4. MPTP+PEA |
40 (10 per group) | Effects on brain function (Immunofluorescence) | PEA administration prevents the decrease in adult hippocampal cell proliferation and β3-tubulin aggregation in PD mice |
| Scuderi et al. (20) (Italy) | 1. To assess chronic PEA effects on cognitive function in AD mice; 2. To assess chronic PEA effects on brain function in AD mice |
In vivo exposure in animals | 1. First set of mice (3 months): (a) PEA (3 × Tg-AD/Non-Tg); (b) placebo (3 × Tg-AD/Non-Tg); 2. Second set of mice (9 months): (a) PEA (3 × Tg-AD/Non-Tg); (b) placebo (3 × Tg-AD/Non-Tg) |
1. First set of mice (3 months): 9–11 per group; 2. Second set of mice (9 months): 7–9 per group |
1. Memory and cognition (NORT, IA, MWM); 2. Depressive-/Anhedonia-like behavior (TST, FST, SPT); 3. Effects on brain function (RT-PCR, Western blot, Immunohistochemistry, Cytokine array, HPLC, MRI/MRS) |
1. PEA administration rescues early learning and memory deficits in 6-mo AD mice; 2. PEA administration improves short-term memory in 12-mo AD mice, with no significant effects on long-term memory; 3. PEA administration reverses the depressive-like phenotype in 6-mo AD mice, with no significant effects in 12-mo AD mice; 4. PEA administration attenuates the anhedonia-like phenotype in 6- and 12-mo AD mice; 5. PEA administration reduces hippocampal Aβ expression in 12-mo AD mice, with no significant effects in 6-mo AD mice; 6. PEA administration reduces abnormal hippocampal tau phosphorylation in 6- and 12-mo AD mice; 7. PEA administration promotes MAP2 expression in the CA1 subregion of hippocampus of AD mice; 8. PEA administration stabilizes astrocyte function and restrains neuroinflammation in AD mice; 9. PEA administration increases Glx levels as a response to disrupted glutamatergic functionin 6-mo AD mice |
| Boccella et al. (40) (Italy) | To assess PEA effects on cognitive function and their mGluR-mediated modulation in SNI mice | In vivo exposure in animals | 1. sham: (a) VHI; (b) PEA; (c) MPEP; (d) MPEP+PEA; (e) MDCPG; (f) MDCPG+PEA; 2. SNI: (a) VHI; (b) PEA; (c) MPEP; (d) MPEP+PEA; (e) MDCPG; (f) MDCPG+PEA |
96 | Memory and cognition (NORT) | 1. PEA administration rescues discriminative memory in SNI mice; 2. PEA beneficial effects on discriminative memory are prevented by the mGluR5 blockade, but not the mGluR8 blockade in SNI mice |
| Boccella et al. (41) (Italy) | To assess PEA effects on cognitive function in SNI mice | 1. In vivo exposure in animals; 2. Quantitative brain assessment |
1. sham+VHI; 2. sham+PEA; 3. SNI+VHI; 4. SNI+PEA |
10 per group | 1. Memory and cognition (NORT, MWM); 2. Effects eCBs/AEs system (LC-APCI-MS) |
1. PEA administration rescues discriminative and spatial memory deficits in SNI mice, by restoring LTP and synaptic maladaptative changes in the LEC-DG pathway; 2. PEA administration affects 2-AG, but not PEA nor AEA LEC levels in sham and SNI mice |
| Impellizzeri et al. (42) (Italy) | To assess PEA anti-inflammatory and neuroprotective effects in VaD mice | 1. In vivo exposure in animals; 2. Quantitative brain assessment |
1. sham+VHI; 2. sham+PEA; 3. VaD+VHI; 4. VaD+PEA |
40 (10 per group) | 1. Memory and cognition (NORT, MWM); 2. Effects on brain function and 3. eCBs/AEs system (Light microscospy, Immunohistochemistry, Immunofluorescence, TUNEL staining, LP-APCI-MS, Western blot) |
1. Endogenous PEA levels decrease after VaD induction; 2. PEA administration increases PEA endogenous levels in VaD mice; 3. PEA administration rescues injured hippocampal CA1 and CA3 neurons in VaD mice; 4. PEA administration exerts anti-inflammatory and neuroprotective effects in VaD mice; 5. PEA administration rescues learning and memory deficits in VaD mice |
| Piscitelli et al. (43) (Italy) | To assess PEA and other eCBs/AEs brain and plasma levels in AD-like Tg mice | Quantitative tissue assessment | 1. WT; 2. Tg |
10 | 1. Brain tissue eCBs/AEs levels (LP-APCI-MS); 2. Plasma levels |
1. PEA and other eCBs/AEs levels are not altered in AD-like Tg mouse model compared to WT mice; 2. PEA and other eCBs/AEs levels show no overt alterations from presymptomatic, mild symptomatic to symptomatic disease stages in AD-like Tg mouse model |
| Zimmermann et al. (44) (Germany) | To assess PEA/AEA signaling alterations and related effects on cognitive function in AAV-Glu-FAAH mice | Quantitative brain assessment | 1. AAV-Glu-FAAH; 2. AAV-Glu-empty; 3. AAV-WT |
3–16 per group | 1. Memory and cognition (spatial object recognition test); 2. PEA and other AEs brain levels (LC-MS/MS) |
Impaired PEA signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses |
| Beggiato et al. (45) (Italy) | To assess PEA neuroprotective effects in AD mice | In vitro exposure in animals | Mature cerebral cortex astrocytes: 1. Non-Tg: (a) CTRL; (b) Aβ; (c) Aβ+PEA; 2. 3xTg-AD: (a) CTRL; (b) Aβ; (c) Aβ+PEA |
4–5 animals per condition | 1. Effects on neuronal viability (Neutral red assay); 2. Effects on neuronal morphology (Immunohistochemistry); 3. Effects on apoptotic neuronal death (Immunofluorescence) |
PEA application prevents Aβ-induced astrogliosis, thus improving neuronal survival in AD mice |
| Beggiato et al. (46) (Italy) | 1. To assess PEA effects on cognitive function in AD mice; 2. To assess PEA anti-inflammatory and neuroprotective effects in AD mice; 3. To assess PEA effects on glutamate levels in AD mice |
1. In vivo exposure in animals; 2. Quantitative tissue assessment |
1.3 × Tg-AD+VHI; 2. 3 × Tg-AD+PEA; 3. Non-Tg+VHI; 4. Non-Tg+PEA |
4–11 per group | 1. Memory and cognition (NORT); 2. Effects on neuroinflammation, 3. Effects on neuroprotective factors expression (Immunofluorescence); 4. Hippocampal glutamate levels (HPLC coupled to fluorescence detection) |
1. PEA administration improves learning and memory in 5-mo AD mice; 2. PEA administration partially restrains neuroinflammation in 5-mo AD mice; 3. PEA administration reduces oxidative stress in 5-mo AD mice; 4. PEA administration does not affect Synaptophysin hippocampal levels in 5-mo AD mice; 5. PEA administration partially rescues increased glutamate levels in the hippocampus of 5-mo AD mice |
| Facchinetti et al. (47) (Italy) | To assess PEA anti-inflammatory and neuroprotective effects in prodromal AD rats | In vivo exposure in animals | 1. VHI; 2. VHI(Aβ); 3. PEA(VHI); 4. PEA(Aβ) |
4–5 per group | Effects on brain function (Immunofluorescence, qRT-PCR) | 1. Early PEA administration prevents Aβ-induced astrogliosis and microgliosis in AD rats; 2. Early PEA administration prevents the increased gene expression of pro-inflammatory cytokines and enzymes in AD rats; 3. Early PEA administration improves hippocampal neuronal survival in AD rats |
| Lama et al. (48) (Italy) | To assess PEA effects on cognitive function in HFD mice | In vivo exposure in animals | 1. STD; 2. HFD; 3. HFD+PEA |
≥ 15 per group | Memory and cognition (NORT) | PEA administration restores recognition memory in HFD mice |
| Boccella et al. (49) (Italy) | To assess PEA effects on cognitive function in SNI mice | In vivo exposure in animals | 1. sham+VHI; 2. sham+PEA; 3. SNI+VHI; 4. SNI+PEA |
120 | Memory and cognition (MWM, Y-maze) | PEA administration rescues spatial memory and working-memory in SNI mice |
| Campolo et al. (28) (Italy) | 1. To assess PEA anti-inflammatory and neuroprotective effects in TBI mice; 2. To assess PEA effects on cognitive function in TBI mice |
In vivo exposure in animals | 1. sham; 2. sham+PEA; 3. TBI; 4. TBI+PEA |
40 (10 per group) | 1. Memory and cognition (MWM); 2. Effects on brain function (Histological analysis, Immunohistochemistry, Immunofluorescence, FluoroJade, Western blot) |
1. PEA administration rescues learning and memory deficits in TBI mice; 2. PEA administration modulates neurogenesis processes in TBI mice; 3. PEA administration accelerates NSCs proliferation in TBI mice |
| D'Antongiovanni et al. (50) (Italy) | To assess PEA effects on enteric inflammation and bowel motor dysfunctions in AD mice | 1. In vivo exposure in animals; 2. In vitro exposure in animals |
1. In vivo/In vitro exposure: (a) SAMR1; (b) SAMP8; (c) SAMP8+PEA; 2. In vitro exposure: (a) CTRL; (b) LPS+Aβ; (c) LPS+Aβ+PEA |
X | 1. Effects on colonic contractile activity (ES, chemical stimulation); 2. Effects on misfolded proteins (ELISA assay); 3. Effects on enzymatic activity (Enzymatic assay); 4. Effects on colonic inflammation (ELISA, Western blot) |
1. PEA administration/application prevents the enteric glial hyperactivation in AD mice; 2. PEA administration/application reduces misfolded protein accumulation and counteracts colonic inflammatory condition in AD mice; 3. PEA administration/application relieves intestinal motor dysfunctions in AD mice; 4. PEA administration/application improves the intestinal epithelial barrier integrity in AD mice |
| Gaspar et al. (51) (Ireland) | 1. To assess PEA effects on inflammatory pain-related cognitive impairment in CFA-treated rats; 2. To assess PEA and other AEs brain levels in CFA-treated rats |
1. In vivo exposure in animals; 2. Quantitative brain assessment |
1. noCFA, 2. CFA: (a) VHI; (b) GW6471; (c) GSK; (d) GW9662; (e) PEA |
80 | 1. Memory and cognition (NORT); 2. PEA and other AEs brain levels (LC-MS/MS) |
1. PPARα antagonist impairs spatial memory in CFA-treated rats; 2. PEA levels are not modified in the Dorsal Hippocampus nor in the Entorhinal Cortex of CFA-Injected rats |
| Gatta et al. (52) (Italy) | To assess PEA anti-inflammatory and neuroprotective effects in AD-like mouse microglial cells | 1. In vitro exposure in animals; 2. Ex vivo exposure in animals |
1. BV2 microglial cell model: (a) CTRL; (b) LPS; (c) LPS+PEA; (d) Aβ; (e) Aβ+PEA; 2. Mature cerebral cortex microglial cells: (a) CTRL; (b) LPS; (c) LPS+PEA |
4–6 animals per condition | Effects on brain function (Western blot, semi-quantitative qRT-PCR) | PEA reduces LPS- or Aβ-induced neuroinflammation and TG2 overexpression in mouse microglial cells |
PEA, palmitoylethanolamide; Aβ, β-amyloid precursor protein; CTRL, control; MK, MK886 (PPARα antagonist); GW9662, PPARγ antagonist; RT-PCR, Reverse transcriptase-PCR analysis; ELISA, Enzyme-linked immunosorbent assay; EMSA, Electrophoretic mobility shift assay; eCB, endocannabinoid; FAAH, Fatty acid amide hydrolase; KO, Knock-out; WT, Wild-type; AEA, anandamide; OEA, oleoylethanolamide; URB, URB597; SR1, SR141716A; SR2, SR144528; WY, WY14643; TG, troglitazone; CPZ, capsazepine; qRT-PCR, RT quantitative-PCR; LDH, Lactate dehydrogenase; AE, acylethanolamine; AD, Alzheimer's disease; PPARα, Peroxisome proliferator-activated receptor alpha; ScAb, Scrambled Ab25-35 peptide; VHI, vehicle; Ab, Ab25-35 peptide; PEA(3, 10, 30), PEA (3, 10, 30 mg/Kg); GW7647, PPARα agonist; YMT, Y-Maze test; MWM, Morris Water Maze test; WMT, Working-memory test; NORT, Novel Object Recognition test; GW6471, PPARα antagonist; μM, micromolar; BDNF, Brain-Derived Neurotrophic Factor; GDNF, Glial cell line-derived neurotrophic factor; GFAP, Glial fibrillary acidic protein; DNA, Deoxyribonucleic acid; 3xTg-AD, triple-transgenic mouse model of AD; non-Tg, non-transgenic mouse model; MCAo, middle cerebral artery occlusion; VaD, vascular dementia; LC-APCI-MS, Liquid chromatography-atmospheric pressure chemical ionization-mass spectrometry; OFT, Open-field test; RNA, Ribonucleic acid; PD, Parkinson's disease; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; IA, Inhibitory passive avoidance; TST, Tail suspension test; FST, Forced swim test; SPT, Sucrose preference test; HPLC, High-performance liquid chromatography; MRI, Magnetic resonance imaging; MRS, Magnetic resonance spectroscopy; -mo, month-old; MAP2, Microtubule-associated protein 2; Glx, Glutamine/glutamate; mGluR, Metabotropic glutamate receptor; SNI, spare nerve injury; MPEP, 2-Methyl-6-(phenylethynyl) pyridine; MDCPG, (RS)-4-(1-amino-1-carboxyethyl)phthalic acid; LTP, long-term potentiation; LEC, lateral entorhinal cortex; DG, dentate gyrus; 2-AG, 2-arachidonoylglycerol; eCBs, endocannabinoids; AEs, acylethanolamines; Tg, transgenic; AAV, adeno-associated virus; Glu, glutamatergic neurons; AAV-Glu-FAAH, Animals overexpressing FAAH in glutamatergic neurons; LC-MS/MS, liquid chromatography–mass spectrometry; HFD, high-fat diet; TBI, traumatic brain injury; NSCs, neuronal stem cells; SAMR1, Senescence-Accelerated Mouse-Resistant 1; SAMP8, Senescence Accelerated Mouse-prone 8; LPS, lipopolysaccharide; ES, electrical stimulation; CFA, Complete Freund's Adjuvant; GSK, GSK0660 (PPARβ/δ antagonist); TG2, Tissue type 2 transglutaminase.