An Orally Active Pharmacological Inhibitor Of Complement C5a Signalling Protects Against Dopaminergic Degeneration In Experimental Parkinson's Disease

Abstract

Parkinson's disease (PD) is the most common neurodegenerative movement disorder and imposes a severe socioeconomic burden on ageing populations. The pathological hallmark of PD is a progressive loss of dopaminergic neurons in the midbrain that manifests as a range of debilitating motor and non-motor symptoms. The chronic neuroinflammatory response that accompanies dopaminergic degeneration is known to drive disease progression. Activation of the innate immune complement system has been reported in PD patients, with early complement fragments upregulated in the nigrostriatal system. Given the potent inflammatory activity of the complement anaphylatoxin C5a, we hypothesized that microglial C5aR signalling could drive neuroinflammation in PD brains and exacerbate disease pathology. In this study, we demonstrate elevated C5a levels in serum and CSF samples from PD patients, suggesting widespread complement activation in PD. We also found that synuclein aggregates can activate the complement cascade to generate C5a in complement-sufficient blood. Further, in multiple experimental models of PD, C5aR is upregulated following dopaminergic degeneration. Significantly, pharmacological inhibition of C5a-C5aR signaling using our orally active CNS-permeable C5aR antagonist, PMX205, protected against behavioral deficits and dopaminergic degeneration in experimental PD. The studies indicate that selective targeting of C5aR may be a potential therapeutic strategy to reduce microglial inflammation, and thus slow disease progression in PD.