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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.
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Details
1 Changhua Christian Hospital, Vascular and Genomic Center, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372)
2 Changhua Christian Hospital, Vascular and Genomic Center, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372); Changhua Christian Hospital, Department of Neurology, Changhua, Taiwan (GRID:grid.413814.b) (ISNI:0000 0004 0572 7372); China Medical University, School of Chinese Medicine, Graduate Institute of Chinese Medicine, Graduate Institute of Integrated Medicine, College of Chinese Medicine, Research Center for Chinese Medicine and Acupuncture, Taichung, Taiwan (GRID:grid.254145.3) (ISNI:0000 0001 0083 6092)