Adicciones y enfermedades neurodegenerativas: Dianas comunes en la búsqueda de nuevas terapias

Abstract

Pleiotrophin (PTN) is a neurotrophic factor for dopaminergic neurons whose levels of expression are increased in the brain of alcoholic patients, in rodents after the administration of amphetamine and in patients with different neurodegenerative diseases. PTN limits the neurotoxic effects of amphetamines in the nigrostriatal pathway which, in humans, can lead to Parkinson’s disease. Additionally, PTN limits the rewarding effects of alcohol. PTN is an endogenous inhibitor of the Receptor Protein Tyrosine Phosphatase Z1 (PTPRZ1, also known as RPTPβ/ζ or Phosphacan). We have shown that the effects of PTN can be reproduced with selective inhibitors of RPTPβ/ζ that we obtained through a rational drug design program. The leading RPTPβ/ζ inhibitory compound, MY10, significantly reduces alcohol consumption in animal models and regulates the neuroimmune response to this drug, blocking as a result the decrease in hippocampal neurogenesis produced by alcohol, revealing important differences between sexes. RPTPβ/ζ has been shown to be a key anchor for cell surface perineuronal nets (PNNs), which play an important role in alcohol addiction. In the hippocampus PNNs play a fundamental role in neurogenesis and learning, suggesting that the effects of MY10 on alcohol consumption and the decrease in hippocampal neurogenesis induced by this drug could be mediated by the actions of RPTPβ/ζ inhibition on the PNNs. Keywords: Alcohol; amphetamine; pleiotrophin; neuroinflammation; addiction; neurodegeneration