Neurotensin-polyplex-mediated brain-derived neurotrophic factor gene delivery into nigral dopamine neurons prevents nigrostriatal degeneration in a rat model of early Parkinson's disease

The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson's disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF ex...

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Published in:Journal of biomedical science 2015-07, Vol.22 (1), p.59-59, Article 59
Main Authors: Hernandez-Chan, Nancy G, Bannon, Michael J, Orozco-Barrios, Carlos E, Escobedo, Lourdes, Zamudio, Sergio, De la Cruz, Fidel, Gongora-Alfaro, Jose L, Armendáriz-Borunda, Juan, Reyes-Corona, David, Espadas-Alvarez, Armando J, Flores-Martínez, Yazmin M, Ayala-Davila, Jose, Hernandez-Gutierrez, Maria E, Pavón, Lenin, García-Villegas, Refugio, Nadella, Rasajna, Martinez-Fong, Daniel
Format: Article
Language:English
Subjects:
Animals
Brain-Derived Neurotrophic Factor - biosynthesis
Brain-Derived Neurotrophic Factor - genetics
Disease Models, Animal
Dopamine
Dopaminergic Neurons - metabolism
Dopaminergic Neurons - pathology
Fluorescence
Gene therapy
Genes
Genetic Therapy - methods
Male
Neurochemistry
Neurons
Neuropeptides
Neurotensin
Neurotensin - chemistry
Neurotensin - pharmacology
Parkinson Disease - genetics
Parkinson Disease - metabolism
Parkinson Disease - pathology
Parkinson Disease - therapy
Parkinson's disease
Phenols
Physiological aspects
Prevention
Rats
Rats, Wistar
Receptors, Neurotensin - metabolism
Substantia Nigra - metabolism
Substantia Nigra - pathology
Transfection - methods
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Summary:The neurotrophin Brain-Derived Neurotrophic Factor (BDNF) influences nigral dopaminergic neurons via autocrine and paracrine mechanisms. The reduction of BDNF expression in Parkinson's disease substantia nigra (SN) might contribute to the death of dopaminergic neurons because inhibiting BDNF expression in the SN causes parkinsonism in the rat. This study aimed to demonstrate that increasing BDNF expression in dopaminergic neurons of rats with one week of 6-hydroxydopamine lesion recovers from parkinsonism. The plasmids phDAT-BDNF-flag and phDAT-EGFP, coding for enhanced green fluorescent protein, were transfected using neurotensin (NTS)-polyplex, which enables delivery of genes into the dopaminergic neurons via neurotensin-receptor type 1 (NTSR1) internalization. Two weeks after transfections, RT-PCR and immunofluorescence techniques showed that the residual dopaminergic neurons retain NTSR1 expression and susceptibility to be transfected by the NTS-polyplex. phDAT-BDNF-flag transfection did not increase dopaminergic neurons, but caused 7-fold increase in dopamine fibers within the SN and 5-fold increase in innervation and dopamine levels in the striatum. These neurotrophic effects were accompanied by a significant improvement in motor behavior. NTS-polyplex-mediated BDNF overexpression in dopaminergic neurons has proven to be effective to remit hemiparkinsonism in the rat. This BDNF gene therapy might be helpful in the early stage of Parkinson's disease.
ISSN:1423-0127
1021-7770
1423-0127
DOI:10.1186/s12929-015-0166-7