title: Proactive transplantation of human neural stem cells prevents degeneration of striatal neurons in a rat model of Huntington disease.
abstract: We have investigated the effectiveness of transplantation of human neural stem cells into adult rat striatum prior to induction of striatal damage with the mitochondrial toxin 3-nitropropionic acid (3-NP). Systemic 3-NP administration caused widespread neuropathological deficits similar to ones found in Huntington disease (HD) including impairment in motor function (rotarod balance test) and extensive degeneration of neuron-specific nuclear antigen (NeuN)(+) neurons, calbindin(+) neurons and glutamic acid decarboxylase (GAD)(+) striatal neurons. Animals receiving intrastriatal implantation of human neural stem cells (hNSCs) 1 week before 3-NP treatments exhibited significantly improved motor performance and reduced damage to striatal neurons compared with control sham injections. In contrast, transplantation of hNSCs at 12 h after the initial 3-NP administration did not lead to any improvement in motor performance or protect striatal neurons from the 3-NP-induced toxicity. These results indicate that the presence of grafted hNSCs before 3-NP treatment is required for host striatal neuronal protection and enhanced motor function. Immunoreactivity of brain-derived neurotrophic factor (BDNF) was found in vitro in cultured hNSCs and in vivo in grafted NSCs with expression and secretion of BDNF demonstrated by RT-PCR, immunocytochemistry, dot-blot, and ELISA analyses. Thus, protective effects of proactive transplantation of hNSCs may be due, in part, to effects mediated by BDNF. The findings in this work have particular relevance to a rat model of HD in that proactive transplanted hNSCs protect host striatal neurons against neuronal injury and improve motor impairment induced by 3-NP toxicity.
authors.affiliation: Brain Disease Research Center, Ajou University School of Medicine, Suwon, South Korea.
authors.forename: Jae K
authors.initials: JK
authors.lastname: Ryu
authors.forename: Jean
authors.initials: J
authors.lastname: Kim
authors.forename: Sung J
authors.initials: SJ
authors.lastname: Cho
authors.forename: Kozo
authors.initials: K
authors.lastname: Hatori
authors.forename: Astushi
authors.initials: A
authors.lastname: Nagai
authors.forename: Hyun B
authors.initials: HB
authors.lastname: Choi
authors.forename: Min C
authors.initials: MC
authors.lastname: Lee
authors.forename: James G
authors.initials: JG
authors.lastname: McLarnon
authors.forename: Seung U
authors.initials: SU
authors.lastname: Kim
mesh_terms: D000818:Animals; D002461:Cell Line, Transformed; D003342:Corpus Striatum / Q000473:pathology / Q000637:transplantation*; D004195:Disease Models, Animal; D006801:Humans; D006816:Huntington Disease / Q000473:pathology / Q000601:surgery*; D008297:Male; D009410:Nerve Degeneration / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D009474:Neurons / Q000637:transplantation*; D051381:Rats; D011917:Rats, Inbred Lew; D033581:Stem Cell Transplantation / Q000379:methods*; D013234:Stem Cells / Q000502:physiology*; D013687:Telencephalon / Q000637:transplantation