title: Calcitriol imparts neuroprotection in vitro to midbrain dopaminergic neurons by upregulating GDNF expression.
abstract: During development a tightly controlled signaling cascade dictates the differentiation, maturation and survival of developing neurons. Understanding this signaling mechanism is important for developing therapies for neurodegenerative illnesses. In previous work we have sought to understand the complex signaling pathways responsible for the development of midbrain dopamine neurons using a proteomic approach. One protein we have identified as being expressed in developing midbrain tissue is the vitamin D receptor. Therefore we investigated the effect of the biologically active vitamin D3 metabolite, calcitriol, on primary fetal ventral mesencephalic cultures of dopamine neurons. We observed a dose responsive increase in numbers of rat primary dopamine neurons when calcitriol was added to culture media. Western blot data showed that calcitriol upregulated the expression of glial derived neurotrophic factor (GDNF). Blocking GDNF signaling could prevent calcitriol's ability to increase numbers of dopamine neurons. An apoptosis assay and cell birth dating experiment revealed that calcitriol increases the number of dopamine neurons through neuroprotection and not increased differentiation. This could have implications for future neuroprotective PD therapies.
authors.affiliation: Institute for Science and Technology in Medicine and Department of Life Sciences, Keele University, Keele, Staffordshire, England.
authors.forename: Rowan P
authors.initials: RP
authors.lastname: Orme
authors.forename: Manminder S
authors.initials: MS
authors.lastname: Bhangal
authors.forename: Rosemary A
authors.initials: RA
authors.lastname: Fricker
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002117:Calcitriol / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D008636:Mesencephalon / Q000196:embryology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D061251:Primary Cell Culture; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D018696:Neuroprotective Agents; D018167:Receptors, Calcitriol; D002117:Calcitriol