Intranasal Administration of Extracellular Vesicles Derived from Human Teeth Stem Cells Improves Motor Symptoms and Normalizes Tyrosine Hydroxylase Expression in the Substantia Nigra and Striatum of the 6-Hydroxydopamine-Treated Rats

Abstract

Parkinson's disease (PD) is the second most common neurodegenerative disorder affecting millions of people worldwide. At present, there is no effective cure for PD; treatments are symptomatic and do not halt progression of neurodegeneration. Extracellular vesicles (EVs) can cross the blood–brain barrier and represent promising alternative to the classical treatment strategies. In the present study, we examined therapeutic effects of intranasal administration of EVs derived from human exfoliated deciduous teeth stem cells (SHEDs) on unilateral 6‐hydroxydopamine (6‐OHDA) medial forebrain bundle (MFB) rat model of PD. CatWalk gait tests revealed that EVs effectively suppressed 6‐OHDA‐induced gait impairments. All tested gait parameters (stand, stride length, step cycle, and duty cycle) were significantly improved in EV‐treated animals when compared with 6‐OHDA‐lesion group rats. Furthermore, EVs slowed down numbers of 6‐OHDA‐induced contralateral rotations in apomorphine test. Improvements in motor function correlated with normalization of tyrosine hydroxylase expression in the striatum and substantia nigra. In conclusion, we demonstrated, for the first time, the therapeutic efficacy of intranasal administration of EVs derived from SHEDs in a rat model of PD induced by 6‐OHDA intra‐MFB lesion. Our findings could be potentially exploited for the development of new treatment strategies against PD.

Intranasal delivery of mesenchymal stem cell-derived extracellular vesicles exerts immunomodulatory and neuroprotective effects in a 3xTg model of Alzheimer's disease

“…IN administration of EVs has been tested in neurological disorders including Parkinson's disease 82 and status epilepticus (SE), both in pilocarpine‐induced 50 or kainate‐induced 83 models of SE, lipopolysaccharide (LPS)‐induced brain inflammation model, experimental autoimmune encephalomyelitis, GL26 tumor model, 84 and the autism BTBR T+tf/J (BTBR) mice model 85 . However, except for the LPS‐acute inflammatory model, 84 all these studies have exploited chronic EV treatment, with mice being sacrificed at the end of the treatment.…”

Dental Stem Cell-Derived Secretome/Conditioned Medium: The Future for Regenerative Therapeutic Applications

“…SHED-CM enhanced neurite outgrowth and repressed 6-hydroxydopamineinduced cell death [119]. Similarly, SHED-CM showed a positive outcome in a Parkinson's disease rat model [120,121]. A superior laryngeal nerve injury rat model was treated with systemic administration of SHED-CM and strikingly functional recovery was improved via two mechanisms: macrophage polarization and vascularization [122].…”

<p>Extracellular Vesicles As Nanomedicine: Hopes And Hurdles In Clinical Translation</p>

“…In this respect, EVs derived from bovine milk were found to remain intact under GI conditions 58 and were shown to escape the intestinal mucosal barrier. 59 The intranasal route is also used 60,61 and may reduce EV loss when targeting regions in the central nervous system, because it evades intestinal and hepatic metabolism. Using this route, curcumin loaded-EVs managed to induce a significant reduction in the number of activated microglial cells thus revealing this to be an effective carrier method for this anti-inflammatory compound.…”