Cellular delivery of CNTF but not NT-4/5 prevents degeneration of striatal neurons in a rodent model of Huntington's disease.
The delivery of neurotrophic factors to the central nervous system (CNS) has gained considerable attention as a potential treatment strategy for neurodegenerative disorders such as Huntington's disease (HD). In the present study, we directly compared the ability of two neurotrophic factors, ciliary neurotrophic factor (CNTF), and neurotrophin-4/5 (NT-4/5), to prevent the degeneration of striatal neurons following intrastriatal injections of quinolinic acid (QA). Expression vectors containing either the human CNTF or NT-4/5 gene were transfected into a baby hamster kidney fibroblast cell line (BHK). Using a polymeric device, encapsulated BHK-control cells and those secreting either CNTF (BHK-CNTF) or NT-4/5 (BHK-NT-4/5) were transplanted unilaterally into the rat lateral ventricle. Seven days later, the same animals received unilateral injections of QA (225 nmol) into the ipsilateral striatum. Nissl-stained sections demonstrated that the BHK-CNTF cells significantly reduced the volume of striatal damage produced by QA. Quantitative analysis of striatal neurons further demonstrated that both choline acetyltransferase (ChAT)- and glutamic acid decarboxylase (GAD)-immunoreactive neurons were protected by CNTF implants. In contrast, the volume of striatal damage and loss of striatal ChAT and GAD-positive neurons in animals receiving BHK-NT-4/5 implants did not differ from control-implanted animals. These results help better define the scope of neuronal protection that can be afforded following cellular delivery of various neurotrophic factors. Moreover, these data further support the concept that implants of polymer-encapsulated CNTF-releasing cells can be used to protect striatal neurons from excitotoxic damage, and that this strategy may ultimately prove relevant for the treatment of HD.
Emerich
D F
DF
CytoTherapeutics, Inc., Providence, RI 02906, USA.
Bruhn
S
S
Chu
Y
Y
Kordower
J H
JH
D000818:Animals; D002460:Cell Line; D017690:Cell Transplantation; D020934:Ciliary Neurotrophic Factor; D003342:Corpus Striatum / Q000187:drug effects / Q000473:pathology; D006224:Cricetinae; D015194:Diffusion Chambers, Culture; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D006801:Humans; D006816:Huntington Disease / Q000139:chemically induced / Q000473:pathology / Q000628:therapy*; D008297:Male; D009410:Nerve Degeneration / Q000517:prevention & control; D009414:Nerve Growth Factors / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D011108:Polymers; D017378:Quinolinic Acid / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection
D020934:Ciliary Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D011108:Polymers; C071951:neurotrophin 5; D017378:Quinolinic Acid; C073922:neurotrophin 4