Creatine and neurotrophin-4/5 promote survival of nitric oxide synthase-expressing interneurons in striatal cultures.
Nitric oxide (NO) mediates a variety of physiological functions in the central nervous system and acts as an important developmental regulator. Striatal interneurons expressing neuronal nitric oxide synthase (nNOS) have been described to be relatively spared from the progressive cell loss in Huntington's disease (HD). We have recently shown that creatine, which supports the phosphagen energy system, induces the differentiation of GABAergic cells in cultured striatal tissue. Moreover, neurotrophin-4/5 (NT-4/5) has been found to promote the survival and differentiation of cultured striatal neurons. In the present study, we assessed the effects of creatine and NT-4/5 on nNOS-immunoreactive (-ir) neurons of E14 rat ganglionic eminences grown for 1 week in culture. Chronic administration of creatine [5mM], NT-4/5 [10ng/ml], or a combination of both factors significantly increased numbers of nNOS-ir neurons. NT-4/5 exposure also robustly increased levels of nNOS protein. Interestingly, only NT-4/5 and combined treatment significantly increased general viability but no effects were seen for creatine supplementation alone. In addition, NT-4/5 and combined treatment resulted in a significant larger soma size and number of primary neurites of nNOS-ir neurons while creatine administration alone exerted no effects. Double-immunolabeling studies revealed that all nNOS-ir cells co-localized with GABA. In summary, our findings suggest that creatine and NT-4/5 affect differentiation and/or survival of striatal nNOS-ir GABAergic interneurons. These findings provide novel insights into the biology of developing striatal neurons and highlight the potential of both creatine and NT-4/5 as therapeutics for HD.
Ducray
Angélique
A
Department of Neurosurgery, University of Bern, Inselspital, CH-3010 Bern, Switzerland.
Kipfer
Stefan
S
Huber
Alexander W
AW
Andres
Robert H
RH
Seiler
Rolf W
RW
Schlattner
Uwe
U
Wallimann
Theo
T
Widmer
Hans Rudolf
HR
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D003401:Creatine / Q000008:administration & dosage*; D004338:Drug Combinations; D007395:Interneurons / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D009414:Nerve Growth Factors / Q000008:administration & dosage*; D052248:Nitric Oxide Synthase Type I / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D004338:Drug Combinations; D009414:Nerve Growth Factors; C071951:neurotrophin 5; D052248:Nitric Oxide Synthase Type I; D003401:Creatine; C073922:neurotrophin 4