Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

Fernandez-Parrilla, Manuel A.; Reyes-Corona, David; Flores-Martínez, Yazmin M.; Nadella, Rasajna; Bannon, Michael J.; Escobedo, Lourdes; Maldonado-Berny, Minerva; Santoyo-Salazar, J.; Soto-Rojas, Luis O.; Luna-Herrera, Claudia; Ayala-Dávila, José; González-Barrios, Juan Antonio; Flores, Gonzalo; Gutiérrez-Castillo, María Eugenia; Espadas-Álvarez, Armando J.; Martínez-Dávila, Irma A.; Nava, Porfirio; Martínez‐Fong, Daniel

doi:10.4103/1673-5374.321001

Cited by 3 publications

(6 citation statements)

References 70 publications

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“…Previous studies [ 4 , 5 , 11 ] suggest that features that block NTS-polyplex NPs from passing the BBB when injected via blood circulation are their size of around 100 nm, positive electrical charge, and the lack of specific transporters in the BBB [ 3 – 5 , 11 , 13 ]. Here, we explored the size and surface electrical charge of NTS-polyplex NPs resulting from compaction of the pEGFP-N1 plasmid with NTS carrier and with KPRa, KPSV40, or without KPs.…”

Section: Resultsmentioning

confidence: 99%

“…S6). Therefore, the presence of GFP in dopaminergic neurons and axonal projections proves that FUS overcame BBB blockage and preserved NTS-polyplex NPs specificity for dopaminergic neurons [ 4 , 6 , 17 , 22 , 23 ]. Because the plasmid pEGFP-N1 lacks a cell-specific promoter, the specificity of transfection is provided by the NTS ligand, which internalizes NTS-polyplex NPs through endocytosis of NTSR1, highly expressed in dopaminergic neurons, as previously demonstrated in primary neuron cultures and animals [ 2 , 8 , 9 , 15 , 16 ].…”

Section: Resultsmentioning

confidence: 99%

“…Neurotensin (NTS)-polyplex nanoparticles (NPs) constitute a specific gene delivery system to dopaminergic neurons that holds great promise for the therapy of Parkinson’s disease (PD) [ 1 ]. Those NPs result from the compaction of a plasmid DNA (pDNA) that contains the coding sequence of a neurotrophic factor gene under the control of dopamine transporter gene promoter (DAT) [ 2 , 3 ] or the synthetic NBRE3x promoter [ 4 – 6 ], both specific for dopaminergic neurons, or an eukaryotic promoter such as elongation factor α1 promoter [ 7 ]. pDNA compaction is mainly carried out by the electrostatic binding of linear poly-L-lysine conjugated with NTS and a fusogenic peptide [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

“…Specificity is another advantage of NTS-polyplex NPs provided by the NTS ligand, which internalizes them through endocytosis of NTSR1, highly expressed in dopaminergic neurons [ 2 , 8 , 9 , 15 , 16 ]. The ligand-mediated specificity can be additionally reinforced with a tissue-specific promoter for dopaminergic neurons, such as DAT or NBRE3x promoters [ 4 , 6 , 16 , 17 ]; furthermore, an inducible doxycycline-regulated system can control the transgene expression if needed [ 5 ]. Moreover, the ability of dual transfection with unilateral administration is another advantage [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

“…Preclinical studies with 6-hydroxydopamine (6-OHDA)-induced early parkinsonism have shown that the targeted delivery of genes coding for neurotrophic factors such as human (hGDNF) [ 22 ], rat brain-derived neurotrophic factor (rBDNF) [ 2 ], or hCDNF [ 6 ] can rescue dopaminergic neurons from neurodegeneration. Furthermore, gene delivery of hCDNF, rBDNF, or mNRTN in rats with 6-OHDA-induced advanced parkinsonism restores the structure and function of the dopaminergic nigrostriatal system [ 4 , 17 , 23 ]. A recent study in a novel PD model shows that the NTS-polyplex NP-mediated nurr1 gene transfection in dopaminergic neurons significantly reduces neuroinflammation, prion-like spreading of pathological α-synuclein aggregates, and degeneration of the dopaminergic nigrostriatal system, thus improving locomotor activity [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

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Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

Mascotte-Cruz,

Vera,

Leija

et al. 2024

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Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson’s disease because they do not cross the blood–brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson’s disease.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

Mascotte-Cruz,

Vera,

Leija

et al. 2024

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LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

Valenzuela-Arzeta

Soto-Rojas

Flores-Martínez

et al. 2023

IJMS

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Whether neuroinflammation leads to dopaminergic nigrostriatal system neurodegeneration is controversial. We addressed this issue by inducing acute neuroinflammation in the substantia nigra (SN) with a single local administration (5 µg/2 µL saline solution) of lipopolysaccharide (LPS). Neuroinflammatory variables were assessed from 48 h to 30 days after the injury by immunostaining for activated microglia (Iba-1 +), neurotoxic A1 astrocytes (C3 + and GFAP +), and active caspase-1. We also evaluated NLRP3 activation and Il-1β levels by western blot and mitochondrial complex I (CI) activity. Fever and sickness behavior was assessed for 24 h, and motor behavior deficits were followed up until day 30. On this day, we evaluated the cellular senescence marker β-galactosidase (β-Gal) in the SN and tyrosine hydroxylase (TH) in the SN and striatum. After LPS injection, Iba-1 (+), C3 (+), and S100A10 (+) cells were maximally present at 48 h and reached basal levels on day 30. NLRP3 activation occurred at 24 h and was followed by a rise of active caspase-1 (+), Il-1β, and decreased mitochondrial CI activity until 48 h. A significant loss of nigral TH (+) cells and striatal terminals was associated with motor deficits on day 30. The remaining TH (+) cells were β-Gal (+), suggesting senescent dopaminergic neurons. All the histopathological changes also appeared on the contralateral side. Our results show that unilaterally LPS-induced neuroinflammation can cause bilateral neurodegeneration of the nigrostriatal dopaminergic system and are relevant for understanding Parkinson’s disease (PD) neuropathology.

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Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy

Gatica-Garcia,

Bannon,

Martínez-Dávila

et al. 2023

Neural Regeneration Research

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JOURNAL/nrgr/04.03/01300535-990000000-00154/inline-graphic1/v/2023-12-22T072528Z/r/image-tiff Parkinsonism by unilateral, intranigral β-sitosterol β-D-glucoside administration in rats is distinguished in that the α-synuclein insult begins unilaterally but spreads bilaterally and increases in severity over time, thus replicating several clinical features of Parkinson’s disease, a typical α-synucleinopathy. As Nurr1 represses α-synuclein, we evaluated whether unilateral transfected of rNurr1-V5 transgene via neurotensin-polyplex to the substantia nigra on day 30 after unilateral β-sitosterol β-D-glucoside lesion could affect bilateral neuropathology and sensorimotor deficits on day 30 post-transfection. This study found that rNurr1-V5 expression but not that of the green fluorescent protein (the negative control) reduced β-sitosterol β-D-glucoside-induced neuropathology. Accordingly, a bilateral increase in tyrosine hydroxylase-positive cells and arborization occurred in the substantia nigra and increased tyrosine hydroxylase-positive ramifications in the striatum. In addition, tyrosine hydroxylase-positive cells displayed less senescence marker β-galactosidase and more neuron-cytoskeleton marker βIII-tubulin and brain-derived neurotrophic factor. A significant decrease in activated microglia (positive to ionized calcium-binding adaptor molecule 1) and neurotoxic astrocytes (positive to glial fibrillary acidic protein and complement component 3) and increased neurotrophic astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10) also occurred in the substantia nigra. These effects followed the bilateral reduction in α-synuclein aggregates in the nigrostriatal system, improving sensorimotor behavior. Our results show that unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neurodegeneration (senescence and loss of neuron-cytoskeleton and tyrosine hydroxylase-positive cells), neuroinflammation (activated microglia, neurotoxic astrocytes), α-synuclein aggregation, and sensorimotor deficits. Increased neurotrophic astrocytes and brain-derived neurotrophic factor can mediate the rNurr1-V5 effect, supporting its potential clinical use in the treatment of Parkinson’s disease.

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Cerebral dopamine neurotrophic factor transfection in dopamine neurons using neurotensin-polyplex nanoparticles reverses 6-hydroxydopamine-induced nigrostriatal neurodegeneration

Cited by 3 publications

References 70 publications

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

Focused ultrasound on the substantia nigra enables safe neurotensin-polyplex nanoparticle-mediated gene delivery to dopaminergic neurons intranasally and by blood circulation

LPS Triggers Acute Neuroinflammation and Parkinsonism Involving NLRP3 Inflammasome Pathway and Mitochondrial CI Dysfunction in the Rat

Unilateral rNurr1-V5 transgene expression in nigral dopaminergic neurons mitigates bilateral neuropathology and behavioral deficits in parkinsonian rats with α-synucleinopathy

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