David Díaz

Neurodegenerative diseases involve an exacerbated neuroinflammatory response led by microglia that triggers cytokine storm and leukocyte infiltration into the brain. PPARα agonists partially dampen this neuroinflammation in some models of brain insult, but neuronal loss was not the triggering cause in any of them. This study examines the anti-inflammatory and immunomodulatory properties of the PPARα agonist oleoylethanolamide (OEA) in the Purkinje Cell Degeneration (PCD) mouse, which exhibits striking neuroinflammation caused by aggressive loss of cerebellar Purkinje neurons. Using real-time quantitative polymerase chain reaction and immunostaining, we quantified changes in pro- and anti-inflammatory markers, microglial density and marker-based phenotype, and overall leukocyte recruitment at different time points after OEA administration. OEA was found to modulate cerebellar neuroinflammation by increasing the gene expression of proinflammatory mediators at the onset of neurodegeneration and decreasing it over time. OEA also enhanced the expression of anti-inflammatory and neuroprotective factors and the Pparα gene. Regarding microgliosis, OEA reduced microglial density—especially in regions where it is preferentially located in PCD mice—and shifted the microglial phenotype towards an anti-inflammatory state. Finally, OEA prevented massive leukocyte infiltration into the cerebellum. Overall, our findings suggest that OEA may change the environment to protect neurons from degeneration caused by exacerbated inflammation.

The cerebellum is an encephalic region classically known for its central role in the control of movement, although recent research has revealed its involvement in other cognitive and affective tasks. Several different pathologies are known to affect this structure, causing a wide range of behavioral and gait impairments. Intriguingly, although the neurodegenerative factors affect all Purkinje cells of the cerebellum uniformly, certain neurodegeneration patterns can be distinguished, in which some Purkinje cells persist longer than other cell types. Specifically, there is a cerebellar region, lobe X, which is more resistant to different types of neurodegeneration, regardless of the injury. Degeneration patterns of the cerebellum have been described in several models, but this review goes further, as it aims at describing a phenomenon not so described: the resistance of the lobe X to neurodegeneration. For this purpose, the main models of cerebellar degeneration will be reviewed and a common origin for the lobe X resistance will be sought.