Nasal delivery of stem cell vesicles carrying phloroglucinol reduces movement and non-movement problems and supports new brain cell growth in a rat model of Parkinson’s disease
BACKGROUND: Parkinson's disease (PD) is characterized by dopaminergic (DA) neuron degeneration in the substantia nigra pars compacta (SNpc) driven by oxidative stress, inflammation, and impaired . , a polyphenolic antioxidant, has demonstrated neuroprotective effects in PD models but suffers from limited clinical applicability due to poor blood-brain barrier (BBB) permeability. (sEV) derived from dental pulp stem cells (DPSCs) exhibit neuroprotective and immunomodulatory properties and serve as promising vehicles for targeted drug delivery across the BBB. This study aimed to evaluate the therapeutic efficacy of intranasally administered sEV-encased phloroglucinol (sEV-Phl) in a chronic MPTP rat model of PD.
METHODS: DPSC-derived sEV were isolated via density gradient ultracentrifugation and characterized using Transmission Electron Microscopy (TEM), Dynamic-Light-Scattering (DLS), and CD marker expression. Phloroglucinol was encased in sEV (sEV-Phl) using sonication. Antioxidant properties were tested in vitro using an HDCF.DA assay in SH-SY5Y cells exposed to 6-OHDA. Chronic MPTP-treated male Wistar rats received intranasal sEV-Phl, with motor and non-motor behaviours evaluated up to 4-weeks post-MPTP treatment. TH-positive neurons, neurogenesis (Ki67, BrdU and FOXA2), lipid-peroxidation, and neurotransmitter-levels were analyzed. sEV biodistribution was tracked via near-infrared imaging and localization in neuronal and glial cells was confirmed with PKH-26 labelling, with confocal-imaging further verifying localization in neuronal and glial cells. TNF-α expression was assessed as a marker of neuroinflammation. 2
RESULTS: sEV displayed high purity and homogeneity. sEV-Phl significantly reduced oxidative stress both in vitro and in vivo, as indicated by decreased ROS and lipid peroxidation levels. sEV-Phl treated MPTP rats demonstrated marked improvement in motor and non-motor behaviours compared to MPTP rats. Immunohistochemical analysis revealed increased TH-positive neurons and enhanced neurogenesis in the SNpc of sEV-Phl-treated animals. Biodistribution studies confirmed efficient midbrain targeting of sEV, which were localized to dopaminergic-neurons, astrocytes and microglia. sEV-Phl also significantly reduced TNF-α expression, indicating decreased neuroinflammation.
CONCLUSION: This study provides the first instance of using DPSC-derived sEV as a delivery vehicle for phloroglucinol in a PD model. sEV-Phl demonstrated significant neuroprotective-effects, enhanced DA-neuron survival and neurogenesis, and reduced neuroinflammation. Intranasal delivery of sEV-Phl represents a promising non-invasive therapeutic strategy for PD, offering a dual benefit of antioxidative and neurogenic support.
Key numbers
significantly higher
Increase in TH-positive neurons
Compared to MPTP-treated rats
significantly reduced
Reduction in TNF-α levels
In the midbrain of treated rats
marked improvement
Improvement in motor behavior
Compared to untreated MPTP rats
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Declarations. Ethics approval and consent to participate: For the animal experiments ethics approval was taken from the Institutional Animal Ethics Committee (IAEC) of NIMHANS, Bengaluru, India for the project title “Cell-free therapeutic approach to Parkinson’s disease using exosomes of human dental pulp stem cells as drug delivery tool through intranasal route in in vivo PD model targeting efficacy and bio-distribution” of approval number AEC/69/446/BP dated May 10, 2019 and Institutional Bio-safety Committee (IBSC) of approval number NIMHANS/DO/IBSC MEETING/2018 dated April 18, 2018. Approval for use of commercially available human dental pulp stem cells was obtained from Institutional Committee for Stem Cell and Research (IC-SCR) for the same project title on May 27, 2019 of approval number SEC/03/018/BP. For the commercially procured DPSCs, the original source (HiMedia Laboratories) has confirmed that all procedures related to this product have been reviewed and approved by IEC and IC-SCR at HiMedia Laboratories Private Limited and the donors had signed informed consent. Competing interest: The authors declare that they have no competing interests. Declarations: The authors declare that they have not use AI-generated work in this manuscript.
PubMed
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