Opposing effects of β-2 and β-1 adrenergic receptor signaling on neuroinflammation and dopaminergic neuron survival in α-synuclein-mediated neurotoxicity

Abstract

Background Noradrenergic neurons in the locus coeruleus (LC) are the primary source of norepinephrine (NE) in the brain and degeneration of these neurons is reported in the early stages of Parkinson’s disease (PD), even prior to dopaminergic neuron degeneration in the substantia nigra (SN), which is a hallmark of PD pathology. NE depletion is generally associated with increased PD pathology in neurotoxin-based PD models. The effect of NE depletion in other models of PD like α-synuclein-based models is largely unexplored. In PD models and in human patients, β-adrenergic receptors (AR) signaling is associated with a reduction of neuroinflammation and PD pathology. However, the effect of NE depletion in the brain and the extent of NE and β-ARs signaling involvement in neuroinflammation, and dopaminergic neuron survival is poorly understood. Methods Two mouse models of PD, a 6OHDA neurotoxin-based model and a human α-synuclein (hα-SYN) virus-based model of PD were used. DSP-4 was used to deplete NE levels in the brain and its effect was confirmed by HPLC with electrochemical detection. A pharmacological approach was used to mechanistically understand the impact of DSP-4 in the hα-SYN model of PD using a norepinephrine transporter (NET) and a β-AR blocker. Epifluorescence and confocal imaging were used to study changes in microglia activation and T-cell infiltration after β1-AR and β2-AR agonist treatment in the hα-SYN virus-based model of PD. Results Consistent with previous studies we found that DSP-4 pretreatment increased dopaminergic neuron loss after 6OHDA injection. In contrast, DSP-4 pretreatment protected dopaminergic neurons after hα-SYN overexpression. DSP-4-mediated protection of dopaminergic neurons after hα-SYN overexpression was dependent on β-AR signaling since using a β-AR blocker prevented DSP-4-mediated dopaminergic neuron protection in this model of PD. Finally, we found that the β-2AR agonist, clenbuterol, reduced microglia activation, T-cell infiltration, and dopaminergic neuron degeneration whereas xamoterol a β-1AR agonist showed increased neuroinflammation and dopaminergic neuron degeneration in the context of hα-SYN-mediated neurotoxicity. Conclusion Our data demonstrate that the effects of DSP-4 on dopaminergic neuron degeneration are model specific, and suggest that in the context of α-SYN driven neuropathology β2-AR specific agonists may have therapeutic benefit in PD.

Locus coeruleus injury modulates ventral midbrain neuroinflammation during DSS-induced colitis

“…To elucidate the role of NE, future studies would combine our two-hit model with pharmacological drugs for adrenergic receptors or NE reuptake and examine the effects on neuroinflammation. This strategy has been employed in several mouse studies previously; two NE reuptake inhibitors, such as desipramine and atomoxetine, and β2-adrenergic receptor agonists, such as clenbuterol, have lessened neuroinflammation after immune insults and alpha-synuclein overexpression [118][119][120] , while β-adrenergic receptor blockers, like metoprolol and propranolol, have exacerbated aging-and proteinopathy-related neuroinflammation and subsequent cognitive dysfunction 54,121 . Based on these data, we expect that the loss of NE mediates most of the inflammatory phenotype we observe in our two-hit model, however the antiinflammatory effects of brain-derived neurotrophic factor 122 and galanin 123 , some of the LC's major co-transmitters, are also worth further consideration.…”

“…To elucidate the role of NE, future studies would combine our two-hit model with pharmacological drugs for adrenergic receptors or NE reuptake and examine the effects on neuroinflammation. This strategy has been employed in several mouse studies previously; two NE reuptake inhibitors, such as desipramine and atomoxetine, and β2-adrenergic receptor agonists, such as clenbuterol, have lessened neuroinflammation after immune insults and alpha-synuclein overexpression [118][119][120] , . CC-BY 4.0 International license available under a (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.…”