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

AbstractThe 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.

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Nose ‐To ‐Brain Delivery of Mitochondria for Treatment of Parkinson’s Disease Model Rats With 6-Hydroxydopamine

10.21203/rs.3.rs-96275/v1 ◽

2020 ◽

Author(s):

Jui-Chih Chang ◽

Yi-Chun Chao ◽

Huei-Shin Chang ◽

Yu-Ling Wu ◽

Hui-Ju Chang ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Olfactory Bulb ◽

Disease Model ◽

Organelle Transport ◽

Brain Delivery ◽

Ipsilateral Side ◽

6 Hydroxydopamine ◽

Locomotor Behaviors ◽

Migratory Stream

Abstract BackgroundFeasibility of mitochondrial organelle transport via the olfactory bulb route for Parkinson's disease (PD) therapy was evaluated in the unilateral 6-OHDA-lesioned rats due to the distinct difference based on payload properties. MethodsAn intranasal infusion with 200 μg of allogeneic mitochondria conjugated with Pep-1 (P-Mito) or not (Mito) was executed once a week at the ipsilateral side of lesioned brain for three months of treatments.Results A significant improvement of rotational and locomotor behaviors in PD rats was found in both mitochondria-treating groups in contrast to Sham group or Pep-1 group. There was more than 60% recovery survival of dopaminergic (DA) neurons in substantia nigra (SN) and striatum (ST) of lesioned sides compared to the intact sides in groups of Mito and P-Mito. Treatment effect in P-Mito group was higher in the P-Mito group than Mito group but not significant. The mechanism was associated with the restoration of mitochondrial function and attenuation of oxidative damage in lesioned SN. Notably, Pep-1 modification suppressed the plasma level of inflammatory cytokines induced by infused mitochondria. The 5-bromo-2-deoxyuridine-labelled tracks showed the mitochondrial penetrating into doublecortin-positive neurons of rostral migratory stream (RMS) along with the accessory olfactory bulb in ipsilateral side of lesion and it was expressed in striatal DA neurons, but not in SN, of two cerebral hemispheres via commissural fibers. Conclusion This study showed a promising approach of nose-to-brain delivery for mitochondrial transplantation by confirming the mitochondrial internalization via RMS neurons migration in olfactory bulb for therapeutic action of PD in rats.

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Locomotor Assessment of 6-Hydroxydopamine-induced Adult Zebrafish-based Parkinson's Disease Model

Journal of Visualized Experiments ◽

10.3791/63355 ◽

2021 ◽

Author(s):

Naemah Md Hamzah ◽

Siong Meng Lim ◽

Yuganthini Vijayanathan ◽

Fei Tieng Lim ◽

Abu Bakar Abdul Majeed ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Model ◽

Adult Zebrafish ◽

6 Hydroxydopamine

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Parallel Movement-suppressing Striatal Output Pathways

10.1101/2020.09.02.273615 ◽

2020 ◽

Author(s):

Qiaoling Cui ◽

Xixun Du ◽

Isaac Y. M. Chang ◽

Arin Pamukcu ◽

Varoth Lilascharoen ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Basal Ganglia ◽

Body Movement ◽

Disease Model ◽

Projection Neurons ◽

Indirect Pathway ◽

Direct Pathway ◽

Striatal Projection Neurons ◽

6 Hydroxydopamine

AbstractThe classic basal ganglia circuit model asserts a complete segregation of the two striatal output pathways. Empirical data argue that, in addition to indirect-pathway striatal projection neurons (iSPNs), direct-pathway striatal projection neurons (dSPNs) innervate the external globus pallidus (GPe). However, the functions of the latter were not known. In this study, we interrogated the organization principles of striatopallidal projections and how they are involved in full-body movement in mice (both males and females). In contrast to the canonical motor-promoting role of dSPNs in the dorsomedial striatum (DMSdSPNs), optogenetic stimulation of dSPNs in the dorsolateral striatum (DLSdSPNs) suppressed locomotion. Circuit analyses revealed that dSPNs selectively target Npas1+ neurons in the GPe. In a chronic 6-hydroxydopamine lesion model of Parkinson’s disease, the dSPN-Npas1+ projection was dramatically strengthened. As DLSdSPN-Npas1+ projection suppresses movement, the enhancement of this projection represents a circuit mechanism for the hypokinetic symptoms of Parkinson’s disease that has not been previously considered.Significance statementIn the classic basal ganglia model, the striatum is described as a divergent structure—it controls motor and adaptive functions through two segregated, opponent output streams. However, the experimental results that show the projection from direct-pathway neurons to the external pallidum have been largely ignored. Here, we showed that this striatopallidal sub-pathway targets a select subset of neurons in the external pallidum and is motor-suppressing. We found that this sub-pathway undergoes plastic changes in a Parkinson’s disease model. In particular, our results suggest that the increase in strength of this sub-pathway contributes to the slowness or reduced movements observed in Parkinson’s disease.

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Moxibustion Exerts a Neuroprotective Effect through Antiferroptosis in Parkinson’s Disease

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2019/2735492 ◽

2019 ◽

Vol 2019 ◽

pp. 1-10 ◽

Cited By ~ 1

Author(s):

Juan Lu ◽

Xuelei Liu ◽

Ye Tian ◽

Hang Li ◽

Zhenxing Ren ◽

...

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Neuroprotective Effect ◽

Disease Model ◽

Protective Mechanism ◽

Neural Cells ◽

Ferritin Heavy Chain ◽

Functional Pathway ◽

6 Hydroxydopamine ◽

The Right

The objective of this study was to explore the neuroprotective effect of moxibustion on rats with Parkinson’s disease (PD) and its mechanism. A Parkinson’s disease model was established in rats using a two-point stereotactic 6-hydroxydopamine injection in the right substantia nigra (SN) and ventral tegmental area. The rats received moxibustion at the Baihui (GV20) and Sishencong (EX-HN1) acupoints for 20 minutes, six times a week, for 6 weeks. The right SN tissue was histologically and immunohistochemically examined. Differentially expressed genes (DEGs) were identified through RNA sequencing. In addition, the levels of tyrosine hydroxylase (TH), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1) in SN were measured. In comparison to the model group, the moxibustion group showed a significantly greater TH immunoreactivity and a higher behavioural score. In particular, moxibustion led to an increase in the number and morphological stability of SN neural cells. The functional pathway analysis showed that DEGs are closely related to the ferroptosis pathway. GPX4 and FTH1 in the SN were significantly overexpressed in the moxibustion-treated rats with PD. Moxibustion can effectively reduce the death of SN neurons, decrease the occurrence of ferroptosis, and increase the TH activity to protect the neurons in rats with PD. The protective mechanism may be associated with suppression of the ferroptosis.

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AnIn VivoMicrodialysis Study of FLZ Penetration through the Blood-Brain Barrier in Normal and 6-Hydroxydopamine Induced Parkinson’s Disease Model Rats

BioMed Research International ◽

10.1155/2014/850493 ◽

2014 ◽

Vol 2014 ◽

pp. 1-11 ◽

Cited By ~ 6

Author(s):

Jinfeng Hou ◽

Qian Liu ◽

Yingfei Li ◽

Hua Sun ◽

Jinlan Zhang

Keyword(s):

Parkinson’S Disease ◽

Parkinson's Disease ◽

Disease Model ◽

Time Curve ◽

Liquid Chromatography Tandem Mass ◽

Bbb Permeability ◽

6 Hydroxydopamine ◽

The Brain ◽

Active Substances

FLZ (N-[2-(4-hydroxy-phenyl)-ethyl]-2-(2,5-dimethoxy-phenyl)-3-(3-methoxy-4-hydroxy-phenyl)-acrylamide) is a novel synthetic squamosamide derivative and a potential anti-Parkinson’s disease (PD) agent. The objective of the present study was to investigate the penetration of free FLZ across the BBB and the effects of P-gp inhibition on FLZ transport in normal and 6-hydroxydopamine (6-OHDA) induced PD model rats.In vivomicrodialysis was used to collect FLZ containing brain and blood dialysates following intravenous (i.v.) drug administration either with or without pretreatment with the specific P-gp inhibitor, zosuquidar trihydrochloride (zosuquidar·3HCl). A sensitive, rapid, and reliable ultraperformance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) technique was developed and validated to quantitate free FLZ levels in the dialysates. No significant differences were observed in the brain/blood FLZ area under the concentration-time curve (AUC) ratio between normal and PD model rats. However, pretreatment with zosuquidar·3HCl markedly increased the AUC ratio in both rat models. In addition, FLZ penetration was similar in zosuquidar·3HCl-pretreated normal and PD rats. These results suggest that P-gp inhibition increases BBB permeability to FLZ, thereby supporting the hypothesis that P-gp normally restricts FLZ transfer to the brain. These findings could provide reference data for future clinical trials and may aid investigation of the BBB permeability of other CNS-active substances.

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