The Effect Of Peripheral Inflammation In Parkinson’s Disease And L-DOPA Induced Dyskinesia

Objective: Neuroinflammation plays an important role in the pathogenesis of Parkinson’s disease(PD).Inflammatory cytokines in the peripheral immune system can induce neuroinflammation in central nervous system(CNS).Whether the peripheral immune system is involved in PD is unclear.The present study investigated the contribution of the peripheral immune system to the neuronal loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)model of PD.Methods: MPTP was intraperitoneally injected into mice to generate a PD model.Mice received clodronate liposomes every 3 days to deplete peripheral macrophages.The percentages of macrophages were measured by flow cytometry at 1,3,7 days after MPTP injection.Neurobehavioral parameters,protein expression,inflammatory cytokines release,and microglia activation were measured by the open field test,western blotting,quantitative polymerase chain reaction(q PCR),and immunofluorescence staining,respectively at 7 days after MPTP injection.Results: Our study revealed that intraperitoneal injection of MPTP could increase peripheral M1 macrophages levels.It also can induce T cells infiltration and cytokine release.Depletion of M1 macrophages by clodronate liposomes suppressed these inflammatory effects and blunted the loss of TH+ nigral neurons and functional impairments caused by MPTP.Conclusion: Our results indicated the critical role of M1 macrophages in the pathogenesis of PD and proposed inhibition of M1 macrophages as a promising therapeutic approach for neurodegeneration.Background: Neuroinflammation with activation of microglia and production of proinflammatory cytokines in the striatum plays an active role in l-DOPA-induced dyskinesia(LID).These findings prompted investigation of non-neuronal mechanisms of LID involving activated glial cells and inflammatory cytokines.Peripheral inflammation may exacerbate neuroinflammation.This study examined the effects of peripheral inflammation on the involvement of neuroinflammation and in the development of LID.Methods: In order to evaluate a possible influence of peripheral inflammation in the appearance of LID,PD rats received an intraperitoneal injection of different concentrations of LPS(1,2,5mg/kg)or saline.One day later,animals started to receive a daily treatment with L-DOPA(6 mg/kg plus benserazide 6 mg/kg)or saline for 21 days,and dyskinesias were evaluated at several time-points.Moreover,the activation of microglia and astrocyte,as well as,molecular changes in NR2 B and m GLUR5 and PKC/MEK/ERK signaling pathways were measured.Results: Results showed that peripheral inflammatory stimulation with lipopolysaccharide(LPS)exacerbated the intensity of AIMs induced by L-DOPA treatment in 6-OHDAlesioned rats.LID rats that received injection of LPS showed the over-expression of pNR2 B and NR2 B,as well as activated PKC/MEK/ERK signal pathway compared to LID rats.On the contrary,clodronate encapsulated in liposomes(Clod Lip),which ameliorated the effect of LPS,improved behavioral dysfunction,prevented p-NR2 B and NR2 B overexpression。Conclusion: This study suggests that peripheral inflammation might represent a risk factor in the development of LID.Peripheral inflammatory stimulation caused an exacerbation of L-DOPA-induced motor behavior associated with higher levels of p-NR2 B and NR2 B in the ipsilateral striatum.