1. Investigación

Pleiotrophin (PTN) is a cytokine involved in nerve tissue repair processes, neuroinflammation and neuronal survival. PTN expression levels are upregulated in the nigrostriatal pathway of Parkinson’s Disease (PD) patients. We aimed to characterize the dopaminergic injury and glial responses in the nigrostriatal pathway of mice with transgenic Ptn overexpression in the brain (Ptn-Tg) after intrastriatal injection of the catecholaminergic toxic 6-hydroxydopamine (6-OHDA) at a low dose (5 μg). Ten days after surgery, the injection of 6-OHDA induced a significant decrease of the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra and of the striatal TH contents in Wild type (Wt) mice. In contrast, these effects of 6-OHDA were absent in Ptn-Tg mice. When the striatal Iba1 and GFAP immunoreactivity was studied, no statistical differences were found between vehicle-injected Wt and Ptn-Tg mice. Furthermore, 6-OHDA did not cause robust glial responses neither on Wt or Ptn-Tg mice 10 days after injections. In metabolomics studies, we detected interesting metabolites that significantly discriminate the more injured 6-OHDA-injected Wt striatum and the more protected 6-OHDA-injected Ptn-Tg striatum. Particularly, we detected groups of metabolites, mostly corresponding to phospholipids, whose trends were opposite in both groups. In summary, the data confirm lower 6-OHDA-induced decreases of TH contents in the nigrostriatal pathway of Ptn-Tg mice, suggesting a neuroprotective effect of brain PTN overexpression in this mouse model of PD. New lipid-related PD drug candidates emerge from this study and the data presented here support the increasingly recognized “lipid cascade” in PD.

La enfermedad de Parkinson (EP) es un proceso neurodegenerativo complejo, caracterizado por la presencia de rigidez, bradicinesia y temblor de reposo. La termoablación de la región motora del subtálamo mediante radiofrecuencia o ultrasonido focal guiado por resonancia magnética (MRgFUS) modula la actividad cortical patológica y disminuye las complicaciones motoras asociadas. No obstante, los mecanismos anatómicos y fisiológicos que soportan esta mejoría no han sido estudiados en detalle. Esta investigación utiliza avanzadas técnicas de adquisición, procesamiento y análisis de imágenes para caracterizar, por primera vez, los cambios en la arquitectura anatómica y funcional de los circuitos ganglios basales-tálamo corticales, inducidos por subtalamotomía. Nuestros resultados indican que la subtalamotomía es un método seguro, eficaz y mínimamente invasivo para el tratamiento de los síntomas motores de la EP. La topografía de la lesión ideal combina el impacto motor en el subtálamo con el efecto anti-discinético de la interrupción de las fibras pálido-fugales. Esta técnica desplaza el patrón metabólico relacionado con la EP hacia valores normales. La correlación de la mejoría en los signos motores con los cambios en distintos marcadores de neuroimágenes, indican que la subtalamotomía opera a través de un amplio efecto modulador sobre las redes anátomo-funcionales del cerebro.

Pleiotrophin (PTN) is a recently discovered cytokine which has been found highly upregulated in the substantia nigra and striatum of rodents in experimental models of Parkinson´s disease. Interestingly, immunohistochemical studies have shown increased levels of PTN expression in the substantia nigra of patients with Parkinson´s disease. Since, in other contexts, PTN has been shown to be critical in repair processes in the injured nervous system, the antecedents suggest that PTN could exhibit protective effects in Parkinson´s disease. This hypothesis was confirmed when PTN was shown to support survival of dopaminergic neurons and to promote the differentiation of neural stem cells to dopaminergic neurons. These findings suggest a new therapeutic approach in the treatment of Parkinson´s disease based on the molecular mechanism of action of PTN. Pleiotrophin receptor, receptor protein tyrosine phosphatase (RPTP) β/ζ, is found active in monomeric form in neurons and glia within the central nervous system. Pleiotrophin induces dimerization of RPTPβ/ζ inactivating its phosphatase activity, thus increasing the phosphorylation levels of its substrates such as β-catenin, Fyn and βadducin. These substrates have been shown to be critical for the proliferation of dopaminergic progenitors and the survival and differentiation of dopaminergic neurons. This review summarizes the strong scientific basis to consider blocking RPTPβ/ζ as a potentially novel therapeutic strategy in the treatment of Parkinson´s disease and discusses various starting points to design antagonists of this receptor.