Targeting the noradrenergic system for anti-inflammatory and neuroprotective effects:implications for Parkinson's disease

Eoin O'Neill; Andrew Harkin

doi:10.4103/1673-5374.235219

摘要：Degeneration of the locus coeruleus noradrenergic system is thought to play a key role in the pathogenesis of Parkinson's disease (PD),whereas pharmacological approaches to increase noradrenaline bioavailability may provide neuroprotection.Noradrenaline inhibits microglial activation and suppresses pro-inflammatory mediator production (e.g.,tumor necrosis factor-α,interleukin-1β & inducible nitric oxide synthase activity),thus limiting the cytotoxicity of midbrain dopaminergic neurons in response to an inflammatory stimulus.Neighbouring astrocyte populations promote a neurotrophic environment in response to β2-adrenoceptor (β2-AR) stimulation via the production of growth factors (e.g.,brain derived neurotrophic factor,cerebral dopamine neurotrophic factor & glial cell derived neurotrophic factor which have shown promising neuroprotective and neuro-restorative effects in the nigrostriatal dopaminergic system.More recent findings have demonstrated a role for the β2-AR in down-regulating expression levels of the human α-synuclein gene SNCA and relative α-synuclein protein abundance.Given that αt-synuclein is a major protein constituent of Lewy body pathology,a hallmark neuropathological feature in Parkinson's disease,these findings could open up new avenues for pharmacological intervention strategies aimed at alleviating the burden of α-synucleinopathies in the Parkinsonian brain.In essence,the literature reviewed herein supports our hypothesis of a tripartite neuroprotective role for noradrenaline in combating PD-related neuropathology and motor dysfunction via (1) inhibiting nigral microglial activation & pro-inflammatory mediator production,(2) promoting the synthesis of neurotrophic factors from midbrain astrocytes and (3) downregulating α-synuclein gene expression and protein abundance in a β2-AR-dependent manner.Thus,taken together,either pharmacologically enhancing extra-synaptic noradrenaline bioavailability or targeting glial β2-ARs directly makes itself as a promising treatment option aimed at slowing/halting PD progression.