Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate

B. Renee Bozard, Paresh P. Chothe, Amany Tawfik, Cory Williams, Sadanand Fulzele, Puttur D. Prasad, Pamela M. Martin, Vadivel Ganapathy, Sylvia B. Smith

Research output: Contribution to journalArticle

9 Citations (Scopus)

Abstract

Fumaric acid esters are used to treat psoriasis, an inflammatory skin disease characterized by keratinocyte proliferation. Inflammation and proliferation are hallmarks of retinal disease; hence, fumaric acid esters may have therapeutic value in retinal pathology. In diseased retinas, Müller glial cells (MCs) undergo reactive gliosis, a hyperproliferative state. MCs take up folate, a vitamin necessary for cell proliferation, via the proton-coupled folate transporter (PCFT). Here we examined the effect of monomethylfumarate (MMF), the active metabolite of fumaric acid esters, on expression and function of PCFT in MCs. Primary MCs, isolated from neonatal mouse retinas, were treated with MMF, and PCFT function was monitored by measuring uptake of radiolabeled methyltetrahydrofolate (MTF) at pH 5.5. Dose-response and time-course analyses were performed to identify optimal conditions for maximal effect. The influence of MMF treatment on kinetic parameters of PCFT was studied, and PCFT expression was analyzed at the mRNA and protein level. MTF uptake in MCs decreased by ̃50% following 18 h treatment with 1 mM MMF. This effect was specific to fumaric acid esters. MMF treatment decreased the maximal velocity of the transporter without altering substrate affinity. The decrease in PCFT function following MMF treatment was accompanied by attenuated PCFT expression. This is the first report that an antipsoriatic compound can regulate folate transport in MCs and may have potential for the treatment of reactive gliosis in retinal disease.

Original languageEnglish (US)
Pages (from-to)333-342
Number of pages10
JournalGlia
Volume60
Issue number3
DOIs
StatePublished - Mar 1 2012

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Proton-Coupled Folate Transporter
Neuroglia
Fumarates
Pharmaceutical Preparations
Retinal Diseases
Gliosis
Folic Acid
Retina
Therapeutics
citraconic acid
Keratinocytes
Psoriasis
Skin Diseases
Vitamins
Reaction Time
Cell Proliferation
Pathology
Inflammation

Keywords

  • Folic acid
  • Fumaric acid esters
  • Mouse
  • Müller cell gliosis
  • Vitamin transport

ASJC Scopus subject areas

  • Neurology
  • Cellular and Molecular Neuroscience

Cite this

Regulation of proton-coupled folate transporter in retinal Müller cells by the antipsoriatic drug monomethylfumarate. / Bozard, B. Renee; Chothe, Paresh P.; Tawfik, Amany; Williams, Cory; Fulzele, Sadanand; Prasad, Puttur D.; Martin, Pamela M.; Ganapathy, Vadivel; Smith, Sylvia B.

In: Glia, Vol. 60, No. 3, 01.03.2012, p. 333-342.

Research output: Contribution to journalArticle

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