Oleoylethanolamide Treatment Modulates Both Neuroinflammation and Microgliosis, and Prevents Massive Leukocyte Infiltration to the Cerebellum in a Mouse Model of Neuronal Degeneration

Abstract

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.

Intracerebellar injection of monocytic immature myeloid cells prevents the adverse effects caused by stereotactic surgery in a model of cerebellar neurodegeneration

“…As both surgery and transplantation of IMCs changed the densities of microglial populations in PCD mice, the expression of several genes related to inflammation was examined using qPCR. In this case, it is necessary to consider that the cerebellar degeneration of PCD mice also changes the expression of these genes [ 46 ]. Therefore, to further investigate the possible variations triggered by either surgery or transplantation, we performed two sets of analyses: [ 1 ] comparing the qPCR results of the PCD groups with those of the untreated WT control mice (i.e., whose gene fold change corresponded approximately to 1; Fig.…”

“…In our specific model (PCD mouse), previous findings have shown an intensified inflammation in the cerebellum of PCD mice, which also impairs the ratio of the different microglial populations [ 37 , 46 ]. Indeed, the regulation of such inflammation is most likely based on neuroprotection [ 46 ].…”

“…In our specific model (PCD mouse), previous findings have shown an intensified inflammation in the cerebellum of PCD mice, which also impairs the ratio of the different microglial populations [ 37 , 46 ]. Indeed, the regulation of such inflammation is most likely based on neuroprotection [ 46 ]. Here, we have analyzed three common markers for microglial activity: CD45 (reactive), CD16/CD32 (pro-inflammatory), and CD206 (anti-inflammatory).…”

“…Here, we have analyzed three common markers for microglial activity: CD45 (reactive), CD16/CD32 (pro-inflammatory), and CD206 (anti-inflammatory). Although the dichotomy of a pro- or anti-inflammatory microglial phenotype can be considered simplistic [ 85 , 86 ], it has been classically used as it offers a clear idea about the behavior of microglia in the face of specific situations [ 46 , 87 ]. First, our results have shown there is a reduction in the density of reactive microglia in sham-operated PCD mice, whose values were restored after IMC transplantation.…”

“…These data suggest that the neuroprotective effect of IMCs in terms of cellular immunomodulation is based on an increased number of anti-inflammatory microglial cells. This type of neuroprotection might be specific to severe cerebellar damage, as it has recently been detected in the same region, but in conjunction with another completely different treatment [ 46 ]. Furthermore, it has also been ascertained that IMCs can exert direct neuroprotective effects by secreting NGF or osteopontin [ 14 , 90 ].…”