title: Thiazolidinediones promote axonal growth through the activation of the JNK pathway.
abstract: The axon is a neuronal process involved in protein transport, synaptic plasticity, and neural regeneration. It has been suggested that their structure and function are profoundly impaired in neurodegenerative diseases. Previous evidence suggest that Peroxisome Proliferator-Activated Receptors-γ (PPARγ promote neuronal differentiation on various neuronal cell types. In addition, we demonstrated that activation of PPARγby thiazolidinediones (TZDs) drugs that selectively activate PPARγ prevent neurite loss and axonal damage induced by amyloid-β (Aβ). However, the potential role of TZDs in axonal elongation and neuronal polarity has not been explored. We report here that the activation of PPARγ by TZDs promoted axon elongation in primary hippocampal neurons. Treatments with different TZDs significantly increased axonal growth and branching area, but no significant effects were observed in neurite elongation compared to untreated neurons. Treatment with PPARγ antagonist (GW 9662) prevented TZDs-induced axonal growth. Recently, it has been suggested that the c-Jun N-terminal kinase (JNK) plays an important role regulating axonal growth and neuronal polarity. Interestingly, in our studies, treatment with TZDs induced activation of the JNK pathway, and the pharmacological blockage of this pathway prevented axon elongation induced by TZDs. Altogether, these results indicate that activation of JNK induced by PPARγactivators stimulates axonal growth and accelerates neuronal polarity. These novel findings may contribute to the understanding of the effects of PPARγ on neuronal differentiation and validate the use of PPARγ activators as therapeutic agents in neurodegenerative diseases.
authors.affiliation: Centro de Envejecimiento y Regeneración (CARE), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
authors.forename: Rodrigo A
authors.initials: RA
authors.lastname: Quintanilla
authors.forename: Juan A
authors.initials: JA
authors.lastname: Godoy
authors.forename: Ivan
authors.initials: I
authors.lastname: Alfaro
authors.forename: Deny
authors.initials: D
authors.lastname: Cabezas
authors.forename: Rommy
authors.initials: R
authors.lastname: von Bernhardi
authors.forename: Miguel
authors.initials: M
authors.lastname: Bronfman
authors.forename: Nibaldo C
authors.initials: NC
authors.lastname: Inestrosa
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects* / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D045162:Thiazolidinediones / Q000494:pharmacology*; D051153:Wnt Proteins / Q000378:metabolism; D000071818:Wnt-5a Protein
chemical_list: D047495:PPAR gamma; D045162:Thiazolidinediones; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C491837:Wnt5a protein, rat; D048031:JNK Mitogen-Activated Protein Kinases