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