Switching the microglial harmful phenotype promotes lifelong restoration of Subtantia Nigra dopaminergic neurons from inflammatory neurodegeneration in aged mice

Aging represents a major risk factor for the development and progression of Parkinson disease (PD), a chronic degenerative disorder characterized by the selective loss of dopaminergic (DAergic) neurons in the subtantia nigra pars compacta (SNpc). Emerging evidence highlights the glia as a pivotal factor in PD etiology, and epidemiological studies indicate that certain nonsteroidal antiinflammatory drugs (NSAIDs) may prevent or delay the progression of PD. Given that the exaggerated inflammatory response observed in old age may play a critical role in exacerbating DAergic vulnerability, we hypothesize here that switching the harmful glial response to inflammation and oxidative stress might increase the ability of the SN to resist inflammatory attacks. To this end, we developed a treatment in which we combined the effects of nitric oxide (NO) with nonsteroidal antiinflammatory activity by using HCT1026, a NO-donating derivative of flurbiprofen that has a safe profile and additional immunomodulatory properties. Young and aged mice fed with control or HCT1026 (30mg kg ^-1 day ^-1) diet were exposed to a single systemic injection of a subtoxic dose (0.2mg kg ^-1) of lipopolysaccharide (LPS), one of the most extensively used glial activators. HCT1026 efficiently reversed the age-dependent increase of microglial activation in response to LPS to levels measured in younger mice. In aged mice, LPS induced a progressive loss of DAergic neurons with no recovery for their entire life span, whereas younger mice or aged mice fed with HCT1026 were resistant to systemic LPS-induced DAergic neurodegeneration, underscoring glia as a key pharmacological target for DAergic neuroprotection.