(W1018) INTRANASAL DELIVERY OF DENTAL PULP STEM CELL-DERIVED EXOSOME-ENCASED PHLOROGLUCINOL MITIGATES DEFICITS & PROMOTES NEUROGENESIS IN IN VIVO CHRONIC MODEL OF PARKINSON’S DISEASE
Additional Professor National Institute of Mental Health and Neurosciences Bengaluru, Karnataka, India
Abstract: 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 neurogenesis. Dopamine analogues lack antioxidative, anti-inflammatory, and regenerative effects, highlighting the need for non-invasive supportive therapies in PD. Phloroglucinol, a polyphenolic antioxidant, has demonstrated neuroprotective effects in PD models but suffers from limited clinical applicability due to poor blood-brain barrier (BBB) permeability. These compounds need a delivery system that bypasses the gut, crosses the BBB, targets injured regions via inflammatory cues, and ideally offers immunomodulatory benefits. Exosomes 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 exosome-encased phloroglucinol (Exo-Phl) in a chronic MPTP rat model of PD. Exosomes displayed high purity and homogeneity. Exo-Phl significantly reduced oxidative stress both in vitro and in vivo, as indicated by decreased ROS and lipid peroxidation levels. Exo-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 Exo-Phl-treated animals. Biodistribution studies confirmed efficient midbrain targeting of exosomes, which were localized to dopaminergic-neurons, astrocytes and microglia. Exo-Phl also significantly reduced TNF-α expression, indicating decreased neuroinflammation. This study provides the first instance of using DPSC-derived exosomes as a delivery vehicle for phloroglucinol in a PD model. Exo-Phl demonstrated significant neuroprotective-effects, enhanced DA-neuron survival and neurogenesis, and reduced neuroinflammation. Intranasal delivery of Exo-Phl represents a promising non-invasive therapeutic strategy for PD, offering a dual benefit of antioxidative and neurogenic support.
Funding Source: Funding source: Indian Council for Medical Research (ICMR)
