title: The transfection of BDNF to dopamine neurons potentiates the effect of dopamine D3 receptor agonist recovering the striatal innervation, dendritic spines and motor behavior in an aged rat model of Parkinson's disease.
abstract: The progressive degeneration of the dopamine neurons of the pars compacta of substantia nigra and the consequent loss of the dopamine innervation of the striatum leads to the impairment of motor behavior in Parkinson's disease. Accordingly, an efficient therapy of the disease should protect and regenerate the dopamine neurons of the substantia nigra and the dopamine innervation of the striatum. Nigral neurons express Brain Derived Neurotropic Factor (BDNF) and dopamine D3 receptors, both of which protect the dopamine neurons. The chronic activation of dopamine D3 receptors by their agonists, in addition, restores, in part, the dopamine innervation of the striatum. Here we explored whether the over-expression of BDNF by dopamine neurons potentiates the effect of the activation of D3 receptors restoring nigrostriatal innervation. Twelve-month old Wistar rats were unilaterally injected with 6-hydroxydopamine into the striatum. Five months later, rats were treated with the D3 agonist 7-hydroxy-N,N-di-n-propy1-2-aminotetralin (7-OH-DPAT) administered i.p. during 4½ months via osmotic pumps and the BDNF gene transfection into nigral cells using the neurotensin-polyplex nanovector (a non-viral transfection) that selectively transfect the dopamine neurons via the high-affinity neurotensin receptor expressed by these neurons. Two months after the withdrawal of 7-OH-DPAT when rats were aged (24 months old), immunohistochemistry assays were made. The over-expression of BDNF in rats receiving the D3 agonist normalized gait and motor coordination; in addition, it eliminated the muscle rigidity produced by the loss of dopamine. The recovery of motor behavior was associated with the recovery of the nigral neurons, the dopamine innervation of the striatum and of the number of dendritic spines of the striatal neurons. Thus, the over-expression of BDNF in dopamine neurons associated with the chronic activation of the D3 receptors appears to be a promising strategy for restoring dopamine neurons in Parkinson's disease.
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Luis F
authors.initials: LF
authors.lastname: Razgado-Hernandez
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Armando J
authors.initials: AJ
authors.lastname: Espadas-Alvarez
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Patricia
authors.initials: P
authors.lastname: Reyna-Velazquez
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Arturo
authors.initials: A
authors.lastname: Sierra-Sanchez
authors.affiliation: Neuromorphology Lab, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autonoma de México (UNAM), Tlalnepantla, Estado de México, México.
authors.forename: Veronica
authors.initials: V
authors.lastname: Anaya-Martinez
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Ismael
authors.initials: I
authors.lastname: Jimenez-Estrada
authors.affiliation: Department of Pharmacology, Wayne State University School of Medicine, Detroit, Michigan, United States of America.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bannon
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México; Programa de Nanociencias y Nanotecnología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Daniel
authors.initials: D
authors.lastname: Martinez-Fong
authors.affiliation: Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV), México D.F., México.
authors.forename: Jorge
authors.initials: J
authors.lastname: Aceves-Ruiz
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects / Q000235:genetics; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics*; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology*; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000473:pathology*; D005684:Gait / Q000187:drug effects / Q000235:genetics; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D009132:Muscles / Q000187:drug effects / Q000503:physiopathology; D017072:Neostriatum / Q000187:drug effects / Q000503:physiopathology*; D010300:Parkinson Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011597:Psychomotor Performance / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D050637:Receptors, Dopamine D3 / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000235:genetics; D012038:Regeneration / Q000187:drug effects / Q000235:genetics; D014162:Transfection; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D018491:Dopamine Agonists; D050637:Receptors, Dopamine D3; D014446:Tyrosine 3-Monooxygenase