Although dysregulated substance P (SP) has been implicated in the pathophysiology of Parkinson's disease (PD), how SP affects the survival of dopaminergic neurons remains unclear. Here, we found that mice lacking endogenous SP (TAC1(-/-)), but not those deficient in the SP receptor (neurokinin-1 receptor, NK1R), were more resistant to lipopolysaccharide (LPS)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced nigral dopaminergic neurodegeneration than wild-type controls, suggesting a NK1R-independent toxic action of SP. In vitro dose-response studies revealed that exogenous SP enhanced LPS- and 1-methyl-4-phenylpyridinium (MPP(+))-induced dopaminergic neurodegeneration in a bimodal manner, peaking at submicromolar and subpicomolar concentrations, but was substantially less effective at intermediate concentrations. Mechanistically, the actions of submicromolar levels of SP were NK1R-dependent, whereas subpicomolar SP-elicited actions required microglial NADPH oxidase (NOX2), the key superoxide-producing enzyme, but not NK1R. Subpicomolar concentrations of SP activated NOX2 by binding to the catalytic subunit gp91(phox) and inducing membrane translocation of the cytosolic subunits p47(phox) and p67(phox). The importance of NOX2 was further corroborated by showing that inhibition or disruption of NOX2 blocked subpicomolar SP-exacerbated neurotoxicity. Together, our findings revealed a critical role of microglial NOX2 in mediating the neuroinflammatory and dopaminergic neurodegenerative effects of SP, which may provide new insights into the pathogenesis of PD.
Pubmed ID: 25209287 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
This polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets GAPDH antibody [6C5]
View all literature mentionsThis monoclonal targets IkappaB-alpha
View all literature mentionsThis monoclonal targets Phospho-I B (Ser32)
View all literature mentionsThis unknown targets IKK-beta
View all literature mentionsThis monoclonal targets Phospho-IKKα/β (Ser176/180)
View all literature mentionsThis monoclonal targets NF-κB p65
View all literature mentionsThis polyclonal targets Phospho-NF-kappaB p65 (Ser536)
View all literature mentionsThis polyclonal targets SAPK/JNK
View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis monoclonal targets Phospho-p38 MAPK (Thr180/Tyr182) (3D7) Rabbit mAb
View all literature mentionsThis polyclonal targets p38 MAPK
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis polyclonal targets Mouse p47-phox
View all literature mentionsThis monoclonal targets RAT ANTI MOUSE CD11b
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis polyclonal targets Tyrosine Hydroxylase
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsA provider for commercial products for analyzing neuronal morphology, stereology, etc.
View all literature mentionsThis monoclonal targets Phospho-I B (Ser32)
View all literature mentionsThis monoclonal targets NF-κB p65
View all literature mentionsThis unknown targets IKK-beta
View all literature mentionsThis polyclonal targets Phospho-NF-kappaB p65 (Ser536)
View all literature mentionsThis monoclonal targets Phospho-IKKα/β (Ser176/180)
View all literature mentionsThis monoclonal targets IkappaB-alpha
View all literature mentionsThis monoclonal targets Phospho-p38 MAPK (Thr180/Tyr182) (3D7) Rabbit mAb
View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis polyclonal targets p38 MAPK
View all literature mentionsThis polyclonal targets Erk1/2
View all literature mentionsThis polyclonal targets SAPK/JNK
View all literature mentionsThis monoclonal targets RAT ANTI MOUSE CD11b
View all literature mentionsThis polyclonal targets Iba1
View all literature mentionsThis polyclonal targets Mouse p47-phox
View all literature mentionsThis monoclonal targets GAPDH antibody [6C5]
View all literature mentionsThis monoclonal targets IkappaB-alpha
View all literature mentionsThis monoclonal targets Phospho-I B (Ser32)
View all literature mentionsThis polyclonal targets Tyrosine Hydroxylase
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis polyclonal targets p44/42 MAPK (Erk1/2)
View all literature mentionsThis monoclonal targets GAPDH antibody [6C5]
View all literature mentionsThis unknown targets IKK-beta
View all literature mentionsThis monoclonal targets Phospho-IKKα/β (Ser176/180)
View all literature mentions