J Neurochem. 2004 Jun;89(6):1387-95.

A non-peptidyl neurotrophic small molecule for midbrain dopaminergic neurons.

Lin LF, Rubin LL, Xu M.

Curis Inc., 61 Moulton Street, Cambridge, MA 02138, USA. Leu-Fen.Lin@regeneron.com

Abstract A small organic molecule (CUR-162590) that selectively enhances survival of midbrain dopaminergic neurons was identified by screening small molecule compound libraries. In embryonic midbrain cultures, CUR-162590 increased dopamine uptake and the number of dopaminergic neurons without altering the number of total neurons or astroglia or the uptake of GABA or serotonin. CUR-162590 reduced apoptosis of cultured dopaminergic neurons and protected against death induced by toxins such as MPP(+). Several synthetic analogs of CUR-162590 also had similar bioactivities. CUR-162590 thus represents a new class of neurotrophic small molecules that may have utility in the treatment of Parkinson's disease, which is marked by degeneration of midbrain dopaminergic neurons.

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Curis, Incorporated, 61 Moulton Street, Cambridge, Massachusetts 02138, USA.

In ventromedial cells of the developing CNS, Sonic hedgehog (Shh) has been shown to affect precursor proliferation, phenotype determination, and survival. Here we show that Shh and its receptor, Ptc-1, are expressed in the adult rat basal forebrain, and that Ptc-1 is expressed specifically by cholinergic neurons. In basal forebrain cultures, Shh was added alone and in combination with nerve growth factor (NGF), and the number of cholinergic neurons was determined by choline acetyltransferase (ChAT) immunocytochemistry. By 8 days in vitro, Shh and NGF show a synergistic effect: the number of ChAT-positive cells after treatment with both factors is increased over untreated cultures or cultures treated with either factor alone. While Shh increases the overall basal level of proliferation, double-labeling of dividing neuronal precursors with [(3)H]thymidine followed by ChAT immunocytochemistry after they mature, demonstrates that the specific increase in cholinergic neurons is not due to this proliferation enhancement. These experiments imply a role for Shh in the development of postmitotic cholinergic neurons and suggest a therapeutic value for Shh in neurodegenerative disease. (c)2002 Elsevier Science.
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Curr Opin Genet Dev. 2001 Oct;11(5):575-80.

Differentiation potential of adult stem cells.

Clarke D, Frisen J.

Department of Cell and Molecular Biology, Medical Nobel Institute, Karolinska Institute, SE-171 77, Stockholm, Sweden. dclarke@curis.com

In many different adult tissues, stem cells generate new cells either continuously or in response to injury. Such cells were thought to be limited to generating the types of cells normally present in the tissue where the stem cell resides. However, several different stem-cell populations in the adult have been found recently to be capable of generating additional cell types under certain conditions.

Publication Types:
Review
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