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Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine.

ABSTRACT: The feasibility of delivering mitochondria intranasally so as to bypass the blood-brain barrier in treating Parkinson's disease (PD), was evaluated in unilaterally 6-OHDA-lesioned rats. Intranasal infusion of allogeneic mitochondria conjugated with Pep-1 (P-Mito) or unconjugated (Mito) was performed once a week on the ipsilateral sides of lesioned brains for three months. A significant improvement of rotational and locomotor behaviors in PD rats was observed in both mitochondrial groups, compared to sham or Pep-1-only groups. Dopaminergic (DA) neuron survival and recovery > 60% occurred in lesions of the substantia nigra (SN) and striatum in Mito and P-Mito rats. The treatment effect was stronger in the P-Mito group than the Mito group, but the difference was insignificant. This recovery was associated with restoration of mitochondrial function and attenuation of oxidative damage in lesioned SN. Notably, P-Mito suppressed plasma levels of inflammatory cytokines. Mitochondria penetrated the accessory olfactory bulb and doublecortin-positive neurons of the rostral migratory stream (RMS) on the ipsilateral sides of lesions and were expressed in striatal, but not SN DA neurons, of both cerebral hemispheres, evidently via commissural fibers. This study shows promise for intranasal delivery of mitochondria, confirming mitochondrial internalization and migration via RMS neurons in the olfactory bulb for PD therapy.

SUBMITTER: Chang JC

PROVIDER: S-EPMC8136477 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundLevodopa-induced dyskinesia (LID) is a troublesome problem in the treatment of Parkinson's disease (PD). The mechanisms of LID are still mysterious. Recently, the interaction between Shp-2 and D1 dopamine receptor (D1R) has been identified to be indispensable in the D1R-mediated extracellular signal-regulated kinases 1 and 2 (ERK1/2) activation and the occurrence of LID. However, the role of Shp-2 in the D1R-mediated signaling pathway of dyskinetic rat models is not fully clear. We designed this study with the purpose of exploring the role of D1R/Shp-2 complex in the D1R-mediated signaling pathway in the occurrence of LID.Materials and methodsThe 6-hydroxydopamine (6-OHDA) was injected unilaterally to produce the rat models of PD. Successful PD rat models were randomly divided into three groups to receive the treatment with L-3,4-dihydroxyphenylalanine (l-DOPA) + benserazide, l-DOPA + benserazide + D1R antagonist (SCH23390) or D1R agonist (SKF38393). Abnormal involuntary movements were assessed in different groups during the treatment. The interaction between D1R and Shp-2 was confirmed in the sham and LID rats through the methods of coimmunoprecipitation. In addition, the levels of p-Shp-2, p-ERK1/2 and p-mTOR were determined by Western blot in different groups.ResultsAfter the treatment with l-DOPA + benserazide for 22 days, PD rats presented with dyskinesia. D1R agonist, SKF38393, induced similar involuntary movements in PD rats. In contrast, the dyskinetic movements were not induced by coadministration of l-DOPA + D1R antagonist (SCH23390). The interaction between D1R and Shp-2 in the normal rats was kept stable after the long-term use of l-DOPA. Moreover, we found that the pulsatile levodopa administration induced hyperphosphorylation of Shp-2, ERK1/2 and mTOR, while the coadministration of l-DOPA and D1R antagonist, SCH23390, did not induce the hyperphosphorylation of these proteins.ConclusionThese data verified the existence of D1R/Shp-2 complex and its crucial role in the D1R-mediated signaling pathway in dyskinetic rats. Focus on the D1R/Shp-2 complex might be a potential treatment of LID in the future.

Project description:BackgroundParkinson's disease (PD) is a progressive neurodegenerative disease with characteristic pathological abnormalities, including the loss of dopaminergic (DA) neurons, a dopamine-depleted striatum, and microglial activation. Lipid accumulation exhibits a close relationship with these pathologies in PD.MethodsHere, 6-hydroxydopamine (6-OHDA) was used to construct a rat model of PD, and the lipid profile in cerebrospinal fluid (CSF) obtained from model rats was analyzed using lipidomic approaches.ResultsEstablishment of this PD model was confirmed by apomorphine-induced rotation behaviors, loss of DA neurons, depletion of dopamine in the striatum, and microglial activation after 6-OHDA-induced lesion generation. Unsupervised and supervised methods were employed for lipid analysis. A total of 172 lipid species were identified in CSF and subsequently classified into 18 lipid families. Lipid families, including eicosanoids, triglyceride (TG), cholesterol ester (CE), and free fatty acid (FFA), and 11 lipid species exhibited significantly altered profiles 2 weeks after 6-OHDA administration, and significant changes in eicosanoids, TG, CE, CAR, and three lipid species were noted 5 weeks after 6-OHDA administration. During the period of 6-OHDA-induced lesion formation, the lipid families and species showed concentration fluctuations related to the recovery of behavior and nigrostriatal abnormalities. Correlation analysis showed that the levels of eicosanoids, CE, TG families, and TG (16:0_20:0_18:1) exhibited positive relationships with apomorphine-induced rotation behaviors and negative relationships with tyrosine hydroxylase (TH) expression in the midbrain.ConclusionThese results revealed that non-progressive nigrostriatal degeneration induced by 6-OHDA promotes the expression of an impairment-related lipidomic signature in CSF, and the level of eicosanoids, CE, TG families, and TG (16:0_20:0_18:1) in CSF may reveal pathological changes in the midbrain after 6-OHDA insult.

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Intranasal delivery of mitochondria for treatment of Parkinson's Disease model rats lesioned with 6-hydroxydopamine.

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