PPAR agonists as therapeutics for CNS trauma and neurological diseases

Abstract

Traumatic injury or disease of the spinal cord and brain elicits multiple cellular and biochemical reactions that together cause or are associated with neuropathology. Specifically, injury or disease elicits acute infiltration and activation of immune cells, death of neurons and glia, mitochondrial dysfunction, and the secretion of substrates that inhibit axon regeneration. In some diseases, inflammation is chronic or non-resolving. Ligands that target PPARs (peroxisome proliferator-activated receptors), a group of ligand-activated transcription factors, are promising therapeutics for neurologic disease and CNS injury because their activation affects many, if not all, of these interrelated pathologic mechanisms. PPAR activation can simultaneously weaken or reprogram the immune response, stimulate metabolic and mitochondrial function, promote axon growth and induce progenitor cells to differentiate into myelinating oligodendrocytes. PPAR activation has beneficial effects in many pre-clinical models of neurodegenerative diseases and CNS injury; however, the mechanisms through which PPARs exert these effects have yet to be fully elucidated. In this review we discuss current literature supporting the role of PPAR activation as a therapeutic target for treating traumatic injury and degenerative diseases of the CNS.

Figure 1. PPARs modulate multiple pathways in the CNS

PPAR activation after CNS injury/trauma promotes recovery through multiple mechanisms by promoting (1) axon outgrowth, (2) mitochondrial bioenergetics, (3) inhibition of Th1 and Th17 T-cell differentiation, (4) OPC maturation, and (5) polarization of macrophages from an inflammatory ‘M1’ to an anti-inflammatory ‘M2’ activation state.

Figure 2. NG2+ oligodendrocyte progenitor cells express PPARδ

Spinal cord section from a normal rat spinal cord gray matter (ventral horn) immunolabeled for PPARδ (brown) and NG2 (gray), a marker for oligodendrocyte progenitor cells. In the normal spinal cord, PPARδ is expressed by NG2 cells (arrow, inset) and is also visible in NG2-negative motor neurons (arrowheads). Scale bar=50 μm; scale bar in inset=20 μm.