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.
Highlights
Abbreviations PD Parkinson’s disease Mito Mitochondria P-Mito Pep-1-labelled mitochondria mtDNA Mitochondrial DNA substantia nigra (SN) Substantia nigra ST Striatum corpus callosum (CC) Corpus callosum anterior commissure (AC) Anterior commissure accessory olfactory bulb (AOB) Accessory olfactory bulb OB Olfactory bulb rostral migratory stream (RMS) Rostral migratory stream glomerular layer (GL) Glomerular layer
Unlike our previous study, which employed local injections of mitochondria for treatment of PD-model rats lesioned with 6-hydroxydopamine, in the present study, we explored the feasibility of intranasal delivery of mitochondria for brain targeting and compared it to mitochondrial transplantation with or without Pep-1 pre-modification in same animal model
There was no significant difference in behavior between the Sham and Pep-1-only groups, or between the Mito and P-Mito groups (Fig. 1)
Summary
Abbreviations PD Parkinson’s disease Mito Mitochondria P-Mito Pep-1-labelled mitochondria mtDNA Mitochondrial DNA SN Substantia nigra ST Striatum CC Corpus callosum AC Anterior commissure AOB Accessory olfactory bulb OB Olfactory bulb RMS Rostral migratory stream GL Glomerular layer. The intranasal route of drug administration offers a new approach to treating brain/central nervous system (CNS) disorders, including Parkinson’s disease (PD), Alzheimer disease, Huntington’s disease, epilepsy, etc.[1]. It accelerates drug development because therapeutic substances traditionally delivered via intravenous, intraperitoneal, and oral routes are hampered from crossing the blood–brain barrier (BBB) to reach targets in the CNS. Mitochondrial transplantation via appropriate approaches may accelerate active, instead of passive uptake via interstitial pressure, osmosis, or endocytosis[13] It is especially suitable for diseases involving chronic neuroinflammation or pathogenic disruption of cytoskeletal function, decreasing the probability of mitochondrial intake via actin-dependent endocytosis[15,16]. In support of direct nose-to-brain drug/cell delivery for more effective PD t reatment[19,20], we propose that mitochondria may be a useful intranasal delivery system for non-invasive clinical treatment
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