Sildenafil is currently licensed for erectile dysfunction and not chronic use to treat central nervous system disorders there is evidence that it may play a neuroprotective effect in stroke. There have been reports that the lesions observed in multiple sclerosis (MS) patients may have an ischemic component, and therefore it is possible that chronic administration of sildenafil may be beneficial as a neuroprotective agent in clinical and experimental demyelinating diseases. To test this hypothesis, experimental allergic encephalomyeolitis (EAE) was induced by adoptive transfer of proteolipid protein sensitized Tcells in SJL mice. Mice were treated with either placebo vehicle or twice daily sildenafil 2mgkg commencing on day 10 after disease induction and followed for 120 days with 10 sildenafil treated and placebo mice euthanized every month for pathological analysis. The primary outcome measure was clinical score, with brain atrophy and neuropathological measures being secondary outcome measures. EAE Clinical scores showed that while sildenafil had no measurable effect on relapses compared to placebo treated animals however, sildenafil treated animals showed significantly less disease progression compared to placebo mice (p0.016). Neuropathological analysis demonstrated a significant reduction in Tcell count in treated mice. Placebo mice were additionally found to have a greater degree of brain atrophy compared to sildenafil treated mice. These results suggest that sildenafil may have an effect in EAE and further work is needed to evaluate the longterm effects in animals with established or other EAE disease models.

Agency
National Institute of Health (NIH)
Institute
Clinical Center (CLC)
Type
Intramural Research (Z01)
Project #
1Z01CL090005-12
Application #
7593147
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2007
Total Cost
$94,955
Indirect Cost
Name
Clinical Center
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Anderson, Stasia A; Frank, Joseph A (2007) MRI of mouse models of neurological disorders. NMR Biomed 20:200-15
Pomeroy, Ian M; Matthews, Paul M; Frank, Joseph A et al. (2005) Demyelinated neocortical lesions in marmoset autoimmune encephalomyelitis mimic those in multiple sclerosis. Brain 128:2713-21
Anderson, Stasia A; Shukaliak-Quandt, Jacqueline; Jordan, Elaine K et al. (2004) Magnetic resonance imaging of labeled T-cells in a mouse model of multiple sclerosis. Ann Neurol 55:654-9
Bulte, Jeff W M; Ben-Hur, Tamir; Miller, Bradley R et al. (2003) MR microscopy of magnetically labeled neurospheres transplanted into the Lewis EAE rat brain. Magn Reson Med 50:201-5
Bulte, Jeff W M; Douglas, Trevor; Witwer, Brian et al. (2002) Monitoring stem cell therapy in vivo using magnetodendrimers as a new class of cellular MR contrast agents. Acad Radiol 9 Suppl 2:S332-5
Frank, Joseph A; Zywicke, Holly; Jordan, E K et al. (2002) Magnetic intracellular labeling of mammalian cells by combining (FDA-approved) superparamagnetic iron oxide MR contrast agents and commonly used transfection agents. Acad Radiol 9 Suppl 2:S484-7
Bulte, Jeff W M; Duncan, Ian D; Frank, Joseph A (2002) In vivo magnetic resonance tracking of magnetically labeled cells after transplantation. J Cereb Blood Flow Metab 22:899-907
McFarland, H I; Lobito, A A; Johnson, M M et al. (2001) Effective antigen-specific immunotherapy in the marmoset model of multiple sclerosis. J Immunol 166:2116-21
Bulte, J W; Douglas, T; Witwer, B et al. (2001) Magnetodendrimers allow endosomal magnetic labeling and in vivo tracking of stem cells. Nat Biotechnol 19:1141-7