Neuroprotective activities of palmitoylethanolamide in an animal model of Parkinson's disease

PLoS One. 2012;7(8):e41880. doi: 10.1371/journal.pone.0041880. Epub 2012 Aug 17.


The biochemical and cellular changes that occur following treatment with 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine (MPTP) are remarkably similar to that seen in idiopathic Parkinson's disease (PD). PD is characterized by the degeneration of dopaminergic nigrostriatal neurons, which results in disabling motor disturbances. Activation of glial cells and the consequent neuroinflammatory response is increasingly recognized as a prominent neuropathological feature of PD. There is currently no effective disease-modifying therapy. Targeting the signaling pathways in glial cells responsible for neuroinflammation represents a promising new therapeutic approach designed to preserve remaining neurons in PD. Chronic treatment with palmitoylethanolamide (PEA, 10 mg/kg, i.p.), initiated 24 hr after MPTP injection (20 mg/kg), protected against MPTP-induced loss of tyrosine hydroxylase positive neurons in the substantia nigra pars compacta. Treatment with PEA reduced MPTP-induced microglial activation, the number of GFAP-positive astrocytes and S100β overexpression, and protected against the alterations of microtubule-associated protein 2a,b-, dopamine transporter-, nNOS- positive cells in the substantia nigra. Furthermore, chronic PEA reversed MPTP-associated motor deficits, as revealed by the analysis of forepaw step width and percentage of faults. Genetic ablation of peroxisome proliferator activated receptor (PPAR)-α in PPAR-αKO mice exacerbated MPTP systemic toxicity, while PEA-induced neuroprotection seemed be partially PPARα-dependent. The effects of PEA on molecules typically involved in apoptotic pathways were also analyzed. Our results indicate that PEA protects against MPTP-induced neurotoxicity and the ensuing functional deficits even when administered once the insult has been initiated.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amides
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / pathology
  • Behavior, Animal / drug effects
  • Catalepsy / chemically induced
  • Catalepsy / drug therapy
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Disease Models, Animal
  • Dopamine Plasma Membrane Transport Proteins / metabolism
  • Endocannabinoids / pharmacology*
  • Endocannabinoids / therapeutic use
  • Ethanolamines / pharmacology*
  • Ethanolamines / therapeutic use
  • Gene Expression Regulation, Enzymologic / drug effects
  • MPTP Poisoning
  • Male
  • Mice
  • Nerve Growth Factors / metabolism
  • Neuroprotective Agents / pharmacology*
  • Neuroprotective Agents / therapeutic use
  • PPAR alpha / metabolism
  • Palmitic Acids / pharmacology*
  • Palmitic Acids / therapeutic use
  • Parkinson Disease / drug therapy*
  • Parkinson Disease / etiology
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins / metabolism
  • bcl-2-Associated X Protein / metabolism


  • Amides
  • Dopamine Plasma Membrane Transport Proteins
  • Endocannabinoids
  • Ethanolamines
  • Nerve Growth Factors
  • Neuroprotective Agents
  • PPAR alpha
  • Palmitic Acids
  • Proto-Oncogene Proteins c-bcl-2
  • S100 Calcium Binding Protein beta Subunit
  • S100 Proteins
  • bcl-2-Associated X Protein
  • palmidrol

Grant support

This study was supported by Programma Operativo Nazionale “Ricerca e Competitività 2007–2013" (PON R&C) 01_02512. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.