Molecular Neurobiology

, Volume 55, Issue 11, pp 8455–8472 | Cite as

N-palmitoylethanolamide Prevents Parkinsonian Phenotypes in Aged Mice

  • Rosalia Crupi
  • Daniela Impellizzeri
  • Marika Cordaro
  • Rosalba Siracusa
  • Giovanna Casili
  • Maurizio Evangelista
  • Salvatore Cuzzocrea


Parkinson’s disease (PD) is a neurodegenerative disease characterized by degeneration of dopaminergic neurons. Aging is a major risk factor for idiopathic PD. Several prior studies examined the neuroprotective effects of palmitoylethanolamide (PEA), alone or combined with antioxidants, in a model of PD induced by the dopaminergic toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Here, we analyzed the pretreatment effect of micronized PEA (PEAm) on neuroinflammation and neuronal cell death in the MPTP model. Male CD mice (21 months of age) were pre-treated for 60 days with PEAm. After this time, they received four intraperitoneal injections of MPTP over a 24-h period and were killed 7 days later. On the 8th day, brains were processed. Pretreatment with PEAm ameliorated behavioral deficits and the reductions in expression of tyrosine hydroxylase and dopamine transporter, while blunting the upregulation of α-synuclein and β3-tubulin in the substantia nigra after MPTP induction. Moreover, PEAm reduced proinflammatory cytokine expression and showed a pro-neurogenic effect in hippocampus. These findings propose this strategy as a valid approach to prevent neurodegenerative diseases associated with old age.


Age Mice Neuroinflammation Palmitoylethanolamide Parkinson’s disease 



The authors would like to thank Mr. Soraci Francesco for secretarial and administrative assistance, Medici Maria Antonietta for excellent technical assistance, and Miss Malvagni Valentina for editorial support with the manuscript.

Compliance with Ethical Standards

Disclosure Statement

Salvatore Cuzzocrea is co-inventor on patent WO2013121449 A8 (Epitech Group Srl) which deals with methods and compositions for the modulation of amidases capable of hydrolysing N-acylethanolamines employable in the treatment of inflammatory diseases. This invention is wholly unrelated to the present study. Moreover, Prof. Cuzzocrea is also, with Epitech Group, a co-inventor on the following patent: EP 2821083; MI2014 A001495; 102015000067344 that are however unrelated to the study.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Lee YI, Kang H, Ha YW, Chang KY, Cho SC, Song SO, Kim H, Jo A et al (2016) Diaminodiphenyl sulfone-induced parkin ameliorates age-dependent dopaminergic neuronal loss. Neurobiol Aging 41:1–10. CrossRefPubMedGoogle Scholar
  2. 2.
    Cascianelli S, Tranfaglia C, Fravolini ML, Bianconi F, Minestrini M, Nuvoli S, Tambasco N, Dottorini ME, Palumbo B (2017) Right putamen and age are the most discriminant features to diagnose Parkinson's disease by using (123)I-FP-CIT brain SPET data by using an artificial neural network classifier, a classification tree (ClT). Hell J Nucl Med 20 Suppl:165Google Scholar
  3. 3.
    Calabrese V, Santoro A, Monti D, Crupi R, Di Paola R, Latteri S, Cuzzocrea S, Zappia M et al (2018) Aging and Parkinson's disease: inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis. Free Radic Biol Med 115:80–91. CrossRefPubMedGoogle Scholar
  4. 4.
    Baluchnejadmojarad T, Eftekhari SM, Jamali-Raeufy N, Haghani S, Zeinali H, Roghani M (2017) The anti-aging protein klotho alleviates injury of nigrostriatal dopaminergic pathway in 6-hydroxydopamine rat model of Parkinson's disease: Involvement of PKA/CaMKII/CREB signaling. Exp Gerontol 100:70–76. CrossRefPubMedGoogle Scholar
  5. 5.
    Olanow CW, Tatton WG (1999) Etiology and pathogenesis of Parkinson's disease. Annu Rev Neurosci 22:123–144. CrossRefPubMedGoogle Scholar
  6. 6.
    Becker G (2003) Methods for the early diagnosis of Parkinson's disease. Nervenarzt 74(Suppl 1):S7–11. CrossRefPubMedGoogle Scholar
  7. 7.
    Rodriguez M, Rodriguez-Sabate C, Morales I, Sanchez A, Sabate M (2015) Parkinson's disease as a result of aging. Aging Cell 14(3):293–308. CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Branch SY, Sharma R, Beckstead MJ (2014) Aging decreases L-type calcium channel currents and pacemaker firing fidelity in substantia nigra dopamine neurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 34(28):9310–9318. CrossRefGoogle Scholar
  9. 9.
    Esposito E, Di Matteo V, Benigno A, Pierucci M, Crescimanno G, Di Giovanni G (2007) Non-steroidal anti-inflammatory drugs in Parkinson's disease. Exp Neurol 205(2):295–312. CrossRefPubMedGoogle Scholar
  10. 10.
    Schulz JB, Falkenburger BH (2004) Neuronal pathology in Parkinson's disease. Cell Tissue Res 318(1):135–147. CrossRefPubMedGoogle Scholar
  11. 11.
    Liberatore GT, Jackson-Lewis V, Vukosavic S, Mandir AS, Vila M, McAuliffe WG, Dawson VL, Dawson TM et al (1999) Inducible nitric oxide synthase stimulates dopaminergic neurodegeneration in the MPTP model of Parkinson disease. Nat Med 5(12):1403–1409. CrossRefPubMedGoogle Scholar
  12. 12.
    Huang D, Wang Z, Tong J, Wang M, Wang J, Xu J, Bai X, Li H et al (2018) Long-term changes in the nigrostriatal pathway in the MPTP mouse model of Parkinson's disease. Neuroscience 369:303–313. CrossRefPubMedGoogle Scholar
  13. 13.
    Kohutnicka M, Lewandowska E, Kurkowska-Jastrzebska I, Czlonkowski A, Czlonkowska A (1998) Microglial and astrocytic involvement in a murine model of Parkinson's disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Immunopharmacology 39(3):167–180CrossRefGoogle Scholar
  14. 14.
    Liu J, Huang D, Xu J, Tong J, Wang Z, Huang L, Yang Y, Bai X et al (2015) Tiagabine protects dopaminergic neurons against neurotoxins by inhibiting microglial activation. Sci Rep 5:15720. CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Shimoi K, Masuda S, Furugori M, Esaki S, Kinae N (1994) Radioprotective effect of antioxidative flavonoids in gamma-ray irradiated mice. Carcinogenesis 15(11):2669–2672CrossRefGoogle Scholar
  16. 16.
    Lin Y, Shi R, Wang X, Shen HM (2008) Luteolin, a flavonoid with potential for cancer prevention and therapy. Curr Cancer Drug Targets 8(7):634–646CrossRefGoogle Scholar
  17. 17.
    Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ (2002) The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem 9(6):663–674CrossRefGoogle Scholar
  18. 18.
    Hansen HS (2010) Palmitoylethanolamide and other anandamide congeners. Proposed role in the diseased brain. Exp Neurol 224(1):48–55. CrossRefPubMedGoogle Scholar
  19. 19.
    De Filippis D, D'Amico A, Iuvone T (2008) Cannabinomimetic control of mast cell mediator release: new perspective in chronic inflammation. J Neuroendocrinol 20(Suppl 1):20–25. CrossRefPubMedGoogle Scholar
  20. 20.
    Koch M, Kreutz S, Bottger C, Benz A, Maronde E, Ghadban C, Korf HW, Dehghani F (2011) Palmitoylethanolamide protects dentate gyrus granule cells via peroxisome proliferator-activated receptor-alpha. Neurotox Res 19(2):330–340. CrossRefPubMedGoogle Scholar
  21. 21.
    Sasso O, Russo R, Vitiello S, Raso GM, D'Agostino G, Iacono A, Rana GL, Vallee M et al (2012) Implication of allopregnanolone in the antinociceptive effect of N-palmitoylethanolamide in acute or persistent pain. Pain 153(1):33–41. CrossRefPubMedGoogle Scholar
  22. 22.
    Esposito E, Impellizzeri D, Mazzon E, Paterniti I, Cuzzocrea S (2012) Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson's disease. PLoS One 7(8):e41880. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Esposito E, Paterniti I, Mazzon E, Genovese T, Di Paola R, Galuppo M, Cuzzocrea S (2011) Effects of palmitoylethanolamide on release of mast cell peptidases and neurotrophic factors after spinal cord injury. Brain Behav Immun 25(6):1099–1112. CrossRefPubMedGoogle Scholar
  24. 24.
    Genovese T, Esposito E, Mazzon E, Di Paola R, Meli R, Bramanti P, Piomelli D, Calignano A et al (2008) Effects of palmitoylethanolamide on signaling pathways implicated in the development of spinal cord injury. J Pharmacol Exp Ther 326(1):12–23. CrossRefPubMedGoogle Scholar
  25. 25.
    Antzoulatos E, Jakowec MW, Petzinger GM, Wood RI (2011) MPTP neurotoxicity and testosterone induce dendritic remodeling of striatal medium spiny neurons in the C57Bl/6 mouse. Parkinson's disease 2011:138471–138410. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Fleming SM, Salcedo J, Fernagut PO, Rockenstein E, Masliah E, Levine MS, Chesselet MF (2004) Early and progressive sensorimotor anomalies in mice overexpressing wild-type human alpha-synuclein. The Journal of neuroscience : the official journal of the Society for Neuroscience 24(42):9434–9440. CrossRefGoogle Scholar
  27. 27.
    Hwang DY, Fleming SM, Ardayfio P, Moran-Gates T, Kim H, Tarazi FI, Chesselet MF, Kim KS (2005) 3,4-dihydroxyphenylalanine reverses the motor deficits in Pitx3-deficient aphakia mice: behavioral characterization of a novel genetic model of Parkinson's disease. The Journal of neuroscience : the official journal of the Society for Neuroscience 25(8):2132–2137. CrossRefGoogle Scholar
  28. 28.
    Pellow S, Chopin P, File SE, Briley M (1985) Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14(3):149–167CrossRefGoogle Scholar
  29. 29.
    Siracusa R, Paterniti I, Impellizzeri D, Cordaro M, Crupi R, Navarra M, Cuzzocrea S, Esposito E The Association of Palmitoylethanolamide with Luteolin Decreases Neuroinflammation and Stimulates Autophagy in Parkinson's Disease Model. CNS Neurol Disord Drug Targets 14 (10):1350–1365. doi:CNSNDDT-EPUB-69743 [pii]Google Scholar
  30. 30.
    Siracusa R, Paterniti I, Cordaro M, Crupi R, Bruschetta G, Campolo M, Cuzzocrea S, Esposito E (2017) Neuroprotective effects of Temsirolimus in animal models of Parkinson's disease. Mol Neurobiol. CrossRefGoogle Scholar
  31. 31.
    Lee KW, Zhao X, Im JY, Grosso H, Jang WH, Chan TW, Sonsalla PK, German DC et al (2012) Apoptosis signal-regulating kinase 1 mediates MPTP toxicity and regulates glial activation. PLoS One 7(1):e29935. CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Siracusa R, Impellizzeri D, Cordaro M, Crupi R, Esposito E, Petrosino S, Cuzzocrea S (2017) Anti-inflammatory and neuroprotective effects of co-ultraPEALut in a mouse model of vascular dementia. Front Neurol 8:233. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Cordaro M, Paterniti I, Siracusa R, Impellizzeri D, Esposito E, Cuzzocrea S (2017) KU0063794, a dual mTORC1 and mTORC2 inhibitor, reduces neural tissue damage and locomotor impairment after spinal cord injury in mice. Mol Neurobiol 54(4):2415–2427. CrossRefPubMedGoogle Scholar
  34. 34.
    Demetrius L (2006) Aging in mouse and human systems: a comparative study. Ann N Y Acad Sci 1067:66–82. CrossRefPubMedGoogle Scholar
  35. 35.
    Dutta S, Sengupta P (2016) Men and mice: relating their ages. Life Sci 152:244–248. CrossRefPubMedGoogle Scholar
  36. 36.
    Erro R, Picillo M, Vitale C, Amboni M, Moccia M, Santangelo G, Pellecchia MT, Barone P (2016) The non-motor side of the honeymoon period of Parkinson's disease and its relationship with quality of life: a 4-year longitudinal study. Eur J Neurol 23(11):1673–1679. CrossRefPubMedGoogle Scholar
  37. 37.
    Hall H, Reyes S, Landeck N, Bye C, Leanza G, Double K, Thompson L, Halliday G et al (2014) Hippocampal Lewy pathology and cholinergic dysfunction are associated with dementia in Parkinson's disease. Brain : a journal of neurology 137(Pt 9):2493–2508. CrossRefGoogle Scholar
  38. 38.
    van Mierlo TJ, Chung C, Foncke EM, Berendse HW, van den Heuvel OA (2015) Depressive symptoms in Parkinson's disease are related to decreased hippocampus and amygdala volume. Movement disorders: official journal of the Movement Disorder Society 30(2):245–252. CrossRefGoogle Scholar
  39. 39.
    Ouchi Y, Yoshikawa E, Sekine Y, Futatsubashi M, Kanno T, Ogusu T, Torizuka T (2005) Microglial activation and dopamine terminal loss in early Parkinson's disease. Ann Neurol 57(2):168–175. CrossRefPubMedGoogle Scholar
  40. 40.
    McGeer PL, McGeer EG (2002) Innate immunity, local inflammation, and degenerative disease. Science of aging knowledge environment : SAGE KE 2002 (29):re3. CrossRefGoogle Scholar
  41. 41.
    Hald A, Lotharius J (2005) Oxidative stress and inflammation in Parkinson's disease: is there a causal link? Exp Neurol 193(2):279–290. CrossRefPubMedGoogle Scholar
  42. 42.
    Marchetti B, Abbracchio MP (2005) To be or not to be (inflamed)—is that the question in anti-inflammatory drug therapy of neurodegenerative disorders? Trends Pharmacol Sci 26(10):517–525. CrossRefPubMedGoogle Scholar
  43. 43.
    Calignano A, La Rana G, Piomelli D (2001) Antinociceptive activity of the endogenous fatty acid amide, palmitylethanolamide. Eur J Pharmacol 419(2–3):191–198CrossRefGoogle Scholar
  44. 44.
    Naccarato M, Chiodo Grandi F, Dennis M, Sandercock PA (2010) Physical methods for preventing deep vein thrombosis in stroke. The Cochrane database of systematic reviews 8:CD001922. CrossRefGoogle Scholar
  45. 45.
    Crupi R, Paterniti I, Ahmad A, Campolo M, Esposito E, Cuzzocrea S (2013) Effects of palmitoylethanolamide and luteolin in an animal model of anxiety/depression. CNS & neurological disorders drug targets 12(7):989–1001CrossRefGoogle Scholar
  46. 46.
    Palee S, Apaijai N, Shinlapawittayatorn K, Chattipakorn SC, Chattipakorn N (2016) Acetylcholine attenuates hydrogen peroxide-induced intracellular calcium dyshomeostasis through both muscarinic and nicotinic receptors in cardiomyocytes. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 39(1):341–349. CrossRefGoogle Scholar
  47. 47.
    Bertolino B, Crupi R, Impellizzeri D, Bruschetta G, Cordaro M, Siracusa R, Esposito E, Cuzzocrea S (2017) Beneficial effects of co-ultramicronized palmitoylethanolamide/luteolin in a mouse model of autism and in a case report of autism. CNS neuroscience & therapeutics 23(1):87–98. CrossRefGoogle Scholar
  48. 48.
    Asakawa T, Fang H, Sugiyama K, Nozaki T, Hong Z, Yang Y, Hua F, Ding G et al (2016) Animal behavioral assessments in current research of Parkinson's disease. Neurosci Biobehav Rev 65:63–94. CrossRefPubMedGoogle Scholar
  49. 49.
    Abeliovich A, Schmitz Y, Farinas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM et al (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25(1):239–252CrossRefGoogle Scholar
  50. 50.
    Nemani VM, Lu W, Berge V, Nakamura K, Onoa B, Lee MK, Chaudhry FA, Nicoll RA et al (2010) Increased expression of alpha-synuclein reduces neurotransmitter release by inhibiting synaptic vesicle reclustering after endocytosis. Neuron 65(1):66–79. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Scott D, Roy S (2012) Alpha-synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis. The Journal of neuroscience : the official journal of the Society for Neuroscience 32(30):10129–10135. CrossRefGoogle Scholar
  52. 52.
    Cameron HA, Woolley CS, McEwen BS, Gould E (1993) Differentiation of newly born neurons and glia in the dentate gyrus of the adult rat. Neuroscience 56(2):337–344CrossRefGoogle Scholar
  53. 53.
    Toni N, Laplagne DA, Zhao C, Lombardi G, Ribak CE, Gage FH, Schinder AF (2008) Neurons born in the adult dentate gyrus form functional synapses with target cells. Nat Neurosci 11(8):901–907. CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Parent JM, Jessberger S, Gage FH, Gong C (2007) Is neurogenesis reparative after status epilepticus? Epilepsia 48(Suppl 8):69–71CrossRefGoogle Scholar
  55. 55.
    Braak H, Del Tredici K, Rub U, de Vos RA, Jansen Steur EN, Braak E (2003) Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging 24(2):197–211CrossRefGoogle Scholar
  56. 56.
    Mayer RJ, Lowe J, Lennox G, Landon M, MacLennan K, Doherty FJ (1989) Intermediate filament-ubiquitin diseases: implications for cell sanitization. Biochem Soc Symp 55:193–201PubMedGoogle Scholar
  57. 57.
    Galloway PG, Mulvihill P, Perry G (1992) Filaments of Lewy bodies contain insoluble cytoskeletal elements. Am J Pathol 140(4):809–822PubMedPubMedCentralGoogle Scholar
  58. 58.
    Langston JW, Ballard P, Tetrud JW, Irwin I (1983) Chronic parkinsonism in humans due to a product of meperidine-analog synthesis. Science 219(4587):979–980CrossRefGoogle Scholar
  59. 59.
    Przedborski S, Jackson-Lewis V (1998) Mechanisms of MPTP toxicity. Movement disorders: official journal of the Movement Disorder Society 13(Suppl 1):35–38Google Scholar
  60. 60.
    Betarbet R, Sherer TB, MacKenzie G, Garcia-Osuna M, Panov AV, Greenamyre JT (2000) Chronic systemic pesticide exposure reproduces features of Parkinson's disease. Nat Neurosci 3(12):1301–1306. CrossRefPubMedGoogle Scholar
  61. 61.
    Cappelletti G, Pedrotti B, Maggioni MG, Maci R (2001) Microtubule assembly is directly affected by MPP(+)in vitro. Cell Biol Int 25(10):981–984. CrossRefPubMedGoogle Scholar
  62. 62.
    Cartelli D, Casagrande F, Busceti CL, Bucci D, Molinaro G, Traficante A, Passarella D, Giavini E et al (2013) Microtubule alterations occur early in experimental parkinsonism and the microtubule stabilizer epothilone D is neuroprotective. Sci Rep 3:1837. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Burke D, Gasdaska P, Hartwell L (1989) Dominant effects of tubulin overexpression in Saccharomyces cerevisiae. Mol Cell Biol 9(3):1049–1059CrossRefGoogle Scholar
  64. 64.
    Weinstein B, Solomon F (1990) Phenotypic consequences of tubulin overproduction in Saccharomyces cerevisiae: differences between alpha-tubulin and beta-tubulin. Mol Cell Biol 10(10):5295–5304CrossRefGoogle Scholar
  65. 65.
    Hirsch EC, Hunot S (2009) Neuroinflammation in Parkinson's disease: a target for neuroprotection? Lancet Neurol 8(4):382–397. CrossRefPubMedGoogle Scholar
  66. 66.
    McGeer PL, McGeer EG (2008) The alpha-synuclein burden hypothesis of Parkinson disease and its relationship to Alzheimer disease. Exp Neurol 212(2):235–238. CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Chemical, Biological, Pharmacological and Environmental SciencesUniversity of MessinaMessinaItaly
  2. 2.Institute of Anaesthesiology and ReanimationCatholic University of the Sacred HeartRomeItaly
  3. 3.Department of Pharmacological and Physiological ScienceSaint Louis UniversitySaint LouisUSA

Personalised recommendations