Brain-derived neurotrophic factor, neurotrophin-3, and neurotrophin-4/5 prevent the death of striatal projection neurons in a rodent model of Huntington's disease.
Intrastriatal injection of quinolinate has been proven to be a very useful animal model to study the pathogenesis and treatment of Huntington's disease. To determine whether growth factors of the neurotrophin family are able to prevent the degeneration of striatal projection neurons, cell lines expressing brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) were grafted in the adult rat striatum before quinolinate injection. Three days after lesioning, ongoing cell death was assessed by in situ detection of DNA fragmentation. In animals grafted with the control cell line, quinolinate injection induced a gradual cell loss that was differentially prevented by intrastriatal grafting of BDNF-, NT-3-, or NT-415-secreting cells. Seven days after lesioning, we characterized striatal projection neurons that were protected by neurotrophins. Quinolinate injection, alone or in combination with the control cell line, induced a selective loss of striatal projection neurons. Grafting of a BDNF-secreting cell line pre-vented the loss of all types of striatal projection neurons analyzed. Glutamic acid decarboxylase 67-, preproenkephalin-, and preprotachykinin A- but not prodynorphin-expressing neurons were protected by grafting of NT-3- or NT-4/5-secreting cells but with less efficiency than the BDNF-secreting cells. Our findings show that neurotrophins are able to promote the survival of striatal projection neurons in vivo and suggest that BDNF might be beneficial for the treatment of striatonigral degenerative disorders, including Huntington's disease.
Pérez-Navarro
E
E
Departament de Biologia Cel.lular i Anatomia Patològica, Facultat de Medicina, IDIBAPS, Universitat de Barcelona, Spain.
Canudas
A M
AM
Akerund
P
P
Alberch
J
J
Arenas
E
E
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D017690:Cell Transplantation; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004745:Enkephalins / Q000096:biosynthesis; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D005968:Glutamate Decarboxylase / Q000096:biosynthesis; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007527:Isoenzymes / Q000096:biosynthesis; D008297:Male; D009414:Nerve Growth Factors / Q000096:biosynthesis / Q000494:pharmacology*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D020933:Neurotrophin 3 / Q000096:biosynthesis / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011498:Protein Precursors / Q000096:biosynthesis; D017378:Quinolinic Acid; D051381:Rats; D011916:Rats, Inbred F344; D020813:Receptor, trkB / Q000378:metabolism; D015320:Tachykinins / Q000096:biosynthesis
D019208:Brain-Derived Neurotrophic Factor; D004745:Enkephalins; D007527:Isoenzymes; D009414:Nerve Growth Factors; D020933:Neurotrophin 3; D011498:Protein Precursors; D015320:Tachykinins; C044206:preprotachykinin; C071951:neurotrophin 5; C033660:preproenkephalin; D020813:Receptor, trkB; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D017378:Quinolinic Acid; C073922:neurotrophin 4