Metabolomics and biochemical alterations caused by pleiotrophin in the 6-hydroxydopamine mouse model of Parkinson\u2019s disease

Esther Gramage,Coral Barbas,Rosalía Fernández-Calle,Yasmina B Martín,Jorge Sáiz,María Uribarri,Gonzalo Herradón,Marcel Ferrer-Alcón

doi:10.1038/s41598-022-07419-6

Esther Gramage, Coral Barbas + Show 6 more

Open Access

https://doi.org/10.1038/s41598-022-07419-6

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Abstract

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.

Highlights

Pleiotrophin (PTN) is a cytokine involved in nerve tissue repair processes, neuroinflammation and neuronal survival
To test the possibility that Ptn-Tg mice may be protected against 6-OHDA-induced neurotoxicity in the substantia nigra (SN), we assessed the number of tyrosine hydroxylase (TH)+ cells in this area of vehicle- and 6-OHDA-treated PtnTg and Wild type (Wt) mice
We found a significant decrease in the number of TH+ cells in the substantia nigra of Wt mice treated with 6-OHDA compared to vehicle-treated mice (Fig. 1, P = 0.0106)

Summary

Introduction

Pleiotrophin (PTN) is a cytokine involved in nerve tissue repair processes, neuroinflammation and neuronal survival. 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 These effects of 6-OHDA were absent in Ptn-Tg mice. Loss of pericytes in PD, AD, amyotrophic lateral sclerosis (ALS), human immunodeficiency virus (HIV)-associated neurocognitive disorder and Huntington’s disease has been linked to PTN depletion causing neuronal loss[19]. These different disorders are characterized by overt neuroinflammation and PTN has been recently found to modulate the neuroimmune response in different pathological contexts. Ptn overexpression potentiates microglial activation and increases of pro-inflammatory cytokines in the brain induced by an acute administration of lipopolysaccharide (LPS)[21]

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