Palmitoylethanolamide interaction with dopamine and acetylcholine: promise for extrapiramidal disorders?

Dr Miriam Melis and her coworkers explored the physiological roles of Peroxisome Proliferator-Activated Receptors Type Alpha agonists such as palmitoylethanolamide on the dopaminergic system. This study is important, because dopaminergic disbalances can be found in a number of disorders, from Parkinsonism up to dystonia.

The role of PEA, as well as of other related molecules in the brain has been elucidated only recently, when the interest in lipid messengers was rekindled by the discovery that anadamide is an endogenous ligand to cannabinoid receptors. The highest concentration of these compounds in the brain however is palmitoylethanolamide (PEA), a non-cannabinoid and a lipid messengers produced “on demand” in case of danger for the cell. PEA is not stored in vesicles, but released from membrane phospholipids. PEA lack binding affinity at cannabinoid
receptors and is considered to be endogenous agonists at the PPAR’s and other non-cannabinoid targets.

PEA has neuroprotective effects, based at least in part, on its anti-inflammatory and anti-oxidative actions, as well as from its modulation of neuronal activity.

Meli suggests that reduced PEA levels might be a hallmark of neurodegenrative/neuroinflammatory diseases in active such as in multiple sclerosis or Huntington’s disease, thus highlighting the possibility that enhanced PEA levels in the brain can be therapeutically useful.

Despite the fact that evidence of the role of PEA in the modulation of dopamine functions was already known, it is only with the discovery that PEA could prevent nicotine-induced excitation of midbrain dopamine neurons via PPAR that its role as fine regulators of the brain dopaminergic system emerged.

The FAAH inhibitor URB597 effects on nicotine-induced excitation of the dopamine system were due to the enhancement in the intracellular levels of PEA within this pathway, and to the activation of PPAR. PPAR ligands not only prevent nicotine-induced excitation of dopamine neurons and increase extracellular
dopamine levels in the shell of the nucleus accumbens but also have a potential therapeutic use in Parkinson’s disease.

The researchers end:

As mitochondrial dysfunction appears to be critical to the pathogenesis of Parkinson’s disease, due to degeneration of dopamine neurons within the midbrain (whereas those dopamine neurons within the VTA are spared). Therefore, whether dopamine neurons of the substantia nigra are under PPAR regulation similar to the VTA is an important issue. Additionally, elucidating whether PPAR
may regulate nAChRs in other brain regions, thus contributing to fine regulation of ion influx, cell excitability, and ultimately of network activity, opens new possibilities to treat diverse neurological and/or psychiatric disorders.

Melis M, Carta G, Pistis M, Banni S. Physiological role of peroxisome proliferator-activated receptors type α on dopamine systems.CNS Neurol Disord Drug Targets. 2013 Feb 1;12(1):70-7.

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