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.

Axonal PPARγ promotes neuronal regeneration after injury

“…Increased PGC‐1α expression in neurons increases mitochondrial density and regulates mitochondrial transport and oxidation state after injury (O'Donnell et al, ; van Spronsen et al, ; Corona and Duchen, ). Another possibility is that downstream targets of PPARγ modulate the c‐jun‐NH2 terminal kinase (JNK) pathway to modulate axonal growth, as previously shown for long‐term treatment of hippocampal neurons with TZDs (Quintanilla et al, ). The JNK pathway is known to affect a series of transcription factors and cytoskeleton substrates in axonal regeneration (Waetzig et al, ; Coffey, ).…”

“…The mechanism(s) underlying PPARγ‐mediated neuroprotection are unclear, and might be associated with anti‐inflammatory effects on glial cells (Garcia‐Bueno et al, ) although other studies have shown that neuronal expression of PPARγ is protective in cerebral ischemia (Bernardo and Minghetti, ; Zhao et al, ). Moreover, TZDs can promote neuronal protection and axonal extension in neural cell lines and primary neuron cultures in vitro (Fuenzalida et al, ; Quintanilla et al, ; Chiang et al, ). Taken together, these studies suggest that PPARγ might be involved in axonal physiology in normal and pathological conditions.…”

Role of PPARγin the Differentiation and Function of Neurons

“…Studies made on hippocampal neurons indicated that activation of PPAR γ by TZDs drugs enhanced axonal growth [61]. This effect on axonal growth was accompanied by an increase in PPAR γ expression and was completely prevented by the use of GW9662, a specific PPAR γ antagonist [61].…”

The role of brain PPARγ in regulation of energy balance and glucose homeostasis

“…Consistent with its role in regulating neural precursor cell differentiation, PPARγ has also been demonstrated to play an important role in increasing dendritic spine densities 286 and inducing neuronal polarity 287 . Brodbeck el al.…”

“…Addition of GW9662 completely blocked axon elongation, suggesting that this effect was mediated through the induction of PPARγ. Interestingly, the increase in axonal growth was also prevented by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK), indicating that the effect of PPARγ on neuronal polarity involves the activation of JNK pathway 287 .…”