Thiazolidinediones Promote Axonal Growth through the Activation of the JNK Pathway

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-gamma (PPAR gamma promote neuronal differentiation on various neuronal cell types. In addition, we demonstrated that activation of PPAR gamma by thiazolidinediones (TZDs) drugs that selectively activate PPAR gamma prevent neurite loss and axonal damage induced by amyloid-beta (A beta). However, the potential role of TZDs in axonal elongation and neuronal polarity has not been explored. We report here that the activation of PPAR gamma 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 PPAR gamma 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 PPAR gamma activators stimulates axonal growth and accelerates neuronal polarity. These novel findings may contribute to the understanding of the effects of PPAR gamma on neuronal differentiation and validate the use of PPAR gamma activators as therapeutic agents in neurodegenerative diseases.