Modification of the number and phenotype of striatal dopaminergic cells by carotid body graft.
In non-human primates, striatal tyrosine hydroxylase-immunoreactive (TH-ir) cells are increased in number after dopamine depletion and in response to trophic factor delivery. As carotid body cells contain the dopaminotrophic glial cell line-derived neurotrophic factor (GDNF), we evaluated the number, morphology and neurochemistry of these TH-ir cells, in the anterior and posterior striatum of five monkeys treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which received a graft of carotid body cell aggregates (CBCA) (n = 3) or sham surgery (n = 2), and six MPTP-monkeys that were sacrificed 6 months and 3 years after the last MPTP dose [MPTP I (n = 3) and MPTP II (n = 3), respectively]. Three intact monkeys served as controls. A disability rating scale was used for the assessment of parkinsonism in all lesioned animals, both before and after surgery. For the neurochemical examination, tissue sections were double-labelled with antibodies to TH, dopamine transporter, dopa decarboxylase-67, vesicular monoamine transporter 2, glutamic acid decarboxylase -67, calbindin, parvalbumin, calretinin, neuronal nitric oxide synthase and GDNF. Only animals receiving CBCA graft showed a moderate but significant recovery of parkinsonism that persisted 12 months after the graft. The grafted striatum contained the greatest TH-ir cell density (120.4 +/- 10.3 cells/100 mm2), while the control striatum displayed the lowest (15.4 +/- 6.8 cells/100 mm2), and MPTP I, MPTP II and sham-operated monkeys showed a similar intermediate value (66.1 +/- 6.2, 58.3 +/- 17.2 and 57.7 +/- 7.0 cells/100 mm2, respectively). In addition, in the post-commissural striatum, only CBCA graft induced a significant increase in the TH-ir cell density compared to control animals (47.9 +/- 15.9 and 7.9 +/- 3.2, respectively). Phenotypically, TH-ir cells were striatal dopaminergic interneurons. However, in the grafted animals, the phenotype was different from that in control, MPTP and sham-operated monkeys, with the appearance of TH/GDNF-ir cells and the emergence of two TH-ir subpopulations of different size as the two main differentiating features. Our data confirm and extend previous studies demonstrating that striatal CBCA grafts produce a long-lasting motor recovery of MPTP-monkeys along with an increase in the number and phenotype changes of the striatal TH-ir interneurons, probably by the action of the trophic factors contained in carotid body cells. The increased number of striatal TH-ir cells observed in the grafted striatum may contribute to the improvement of parkinsonism observed after the graft.
San Sebastián
W
W
Laboratory of Regenerative Therapy, Center for Applied Medical Research, University of Navarra, Avenida de Pío XII, 55, Pamplona, Navarra, Spain.
Guillén
J
J
Manrique
M
M
Belzunegui
S
S
Ciordia
E
E
Izal-Azcárate
A
A
Garrido-Gil
P
P
Vázquez-Claverie
M
M
Luquin
M R
MR
D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002344:Carotid Body / Q000637:transplantation*; D002452:Cell Count; D002454:Cell Differentiation; D003342:Corpus Striatum / Q000378:metabolism* / Q000473:pathology*; D004298:Dopamine / Q000378:metabolism*; D019084:Fluorescent Antibody Technique, Indirect; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000032:analysis; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D023421:Models, Animal; D020734:Parkinsonian Disorders / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis
D015415:Biomarkers; D051100:Glial Cell Line-Derived Neurotrophic Factor; D015632:1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine