Inhibiting 15-PGDH restores redox homeostasis and confers neuroprotection in Parkinson's disease

Résumé fourni par la source

The prostaglandin- and autocoid-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) is shown here to be pathologically elevated in Parkinson's disease (PD) patients and mouse models of PD in the substantia nigra, the region of the brain where dopaminergic neurons are lost in PD. Inhibiting 15-PGDH by pharmacologic blockade or partial genetic reduction restores redox homeostasis and mitigates microglial and astrocyte activation, dopaminergic neuron loss, and motor impairment across three mouse models of PD. These models included systemic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), intranigral lipopolysaccharide (LPS), and intrastriatal AAV-α-synuclein with intra-ventral tegmental area α-synuclein preformed fibrils (PFFs). The neuroprotective efficacy of 15-PGDH inhibition in PD is shown to be mediated by downregulation of the dopaminergic neuronal cell death mediator lipocalin-2 (Lcn2), the pro-inflammatory cytokine interleukin-1β, the reactive oxygen generator Cybb/Nox2, and oxidative tissue damage. Mechanistically, in vitro exposure of BV2 microglia to LPS recapitulates induction of Lcn2, Cybb/N OX2 and superoxide, and all three of these effects are reversed by co-treating with prostaglandin E2 (PGE2), the prototypical degradation substrate of 15-PGDH. With a 15-PGDH inhibitor (MF-300) currently in human clinical trials for peripheral indications, these findings have translational relevance for PD.

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