Search Results (4)

Background: Gastrointestinal (GI) disturbances occur frequently in the early premotor stage of Parkinson’s disease (PD). These GI impairments are associated, at least in part, with dopaminergic dysfunction in the myenteric plexus. However, the enteric nervous system (ENS) pathophysiology underlying GI dysfunction in PD has been overlooked. Objectives: The aim of this study was to evaluate the premotor GI disturbances in rats submitted to intranasal (i.n.) MPTP, a valid experimental model of the premotor stage of PD. Methods: Ileum segments from male Wistar rats (21 weeks old) were collected 12 days following the i.n. MPTP administration for functional studies. Isometric contractile concentration–response (CR) curves (cumulative) for dopamine (DA) were performed in both the presence and absence of sulpiride, a selective dopamine D2-like receptor (D2R) antagonist. Results: Functional studies showed that DA induced a concentration-dependent contractile response in the ileum, which exhibited marked contraction at lower concentrations (0.01–0.9 µM) and relaxation at higher concentrations (3–90 µM). MPTP significantly attenuated both the contraction and the ensuing relaxation. Furthermore, sulpiride significantly reduced the contractile response to DA in the control group and blocked the relaxation in the MPTP group. The MPTP-induced dysmotility occurred with preserved DA homeostasis, as shown by normal DA, TH, and D2R ileal levels in the MPTP group. However, MPTP seemed to impose a decrease in S100β and GFAP (enteroglial markers) immunostaining in the ileal myenteric plexus. Conclusions: In summary, we provide pioneering functional, neurochemical, and morphological evidence showing that rats submitted to the i.n. MPTP model exhibited premotor DA-dependent ileum motile dysfunction accompanied by enteroglial disturbance within the myenteric plexus, but with preserved DA markers. Full article

The intranasal delivery of exogenous mitochondria is a potential therapy for Parkinson’s disease (PD). The regulatory mechanisms and effectiveness in genetic models remains uncertain, as well as the impact of modulating the mitochondrial permeability transition pore (mPTP) in grafts. Utilizing UQCRC1 (p.Tyr314Ser) knock-in mice, and a cellular model, this study validated the transplantation of mitochondria with or without cyclosporin A (CsA) preloading as a method to treat mitochondrial dysfunction and improve disease progression through intranasal delivery. Liver-derived mitochondria were labeled with bromodeoxyuridine (BrdU), incubated with CsA to inhibit mPTP opening, and were administered weekly via the nasal route to 6-month-old mice for six months. Both treatment groups showed significant locomotor improvements in open-field tests. PET imaging showed increased striatal tracer uptake, indicating enhanced dopamine synthesis capacity. The immunohistochemical analysis revealed increased neuron survival in the dentate gyrus, a higher number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) and striatum (ST), and a thicker granule cell layer. In SN neurons, the function of mitochondrial complex III was reinstated. Additionally, the CsA-accumulated mitochondria reduced more proinflammatory cytokine levels, yet their therapeutic effectiveness was similar to that of unmodified mitochondria. External mitochondria were detected in multiple brain areas through BrdU tracking, showing a 3.6-fold increase in the ST compared to the SN. In the ST, about 47% of TH-positive neurons incorporated exogenous mitochondria compared to 8% in the SN. Notably, GFAP-labeled striatal astrocytes (ASTs) also displayed external mitochondria, while MBP-labeled striatal oligodendrocytes (OLs) did not. On the other hand, fewer ASTs and increased OLs were noted, along with lower S100β levels, indicating reduced reactive gliosis and a more supportive environment for OLs. Intranasally, mitochondrial transplantation showed neuroprotective effects in genetic PD, validating a noninvasive therapeutic approach. This supports mitochondrial recovery and is linked to anti-inflammatory responses and glial modulation. Full article

Background: Parkinson’s disease (PD) is a neurodegenerative disorder marked by motor deficits and non-motor symptoms, such as depression, which are associated with dopaminergic loss and α-synuclein aggregation in the brain. Objectives: This study investigated the neuroprotective effects of a hydroalcoholic extract of the purple fruit of Eugenia uniflora (PFEU) on motor ability and depressive-like behaviors in a PD model induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in female Wistar rats. Methods: Rats received intranasal administration of MPTP or vehicle, followed by 14 days of oral administration of PFEU (300 or 2000 mg/kg, administered once daily) or vehicle. Depressive-like behavior was assessed using the splash and forced swimming tests, while motor ability was evaluated using the rotarod and open field tests. On day 15, hippocampal tissue was collected for immunoreactivity analysis. Results: MPTP treatment induced depressive-like behavior, which was significantly reversed by PFEU, as evidenced by increased grooming and decreased immobility. No motor coordination or locomotion deficits were observed. Furthermore, PFEU treatment prevented the MPTP-induced increase in hippocampal α-synuclein, p-p53, and Bax while restoring Bcl-2 levels, suggesting neuroprotective effects through the modulation of apoptotic pathways and α-synuclein. Conclusions: These findings support PFEU’s potential as a neuroprotective agent for MPTP-induced depressive-like behavior in female rats, highlighting its molecular mechanisms. Full article

Parkinson’s disease (PD) is a neurodegenerative disorder defined by progressive deterioration of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Dental pulp stem cells (DPSCs) have been proposed to replace the degenerated dopaminergic neurons due to its inherent neurogenic and regenerative potential. However, the effective delivery and homing of DPSCs within the lesioned brain has been one of the many obstacles faced in cell-based therapy of neurodegenerative disorders. We hypothesized that DPSCs, delivered intranasally, could circumvent these challenges. In the present study, we investigated the therapeutic efficacy of intranasally administered DPSCs in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced mouse model of PD. Human deciduous DPSCs were cultured, pre-labelled with PKH 26, and intranasally delivered into PD mice following MPTP treatment. Behavioural analyses were performed to measure olfactory function and sensorimotor coordination, while tyrosine hydroxylase (TH) immunofluorescence was used to evaluate MPTP neurotoxicity in SNpc neurons. Upon intranasal delivery, degenerated TH-positive neurons were ameliorated, while deterioration in behavioural performances was significantly enhanced. Thus, the intranasal approach enriched cell delivery to the brain, optimizing its therapeutic potential through its efficacious delivery and protection against dopaminergic neuron degeneration. Full article