Flupirtine as neuroprotective add-on therapy in autoimmune optic neuritis.
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system that results in persistent impairment in young adults. During chronic progressive disease stages, there is a strong correlation between neurodegeneration and disability. Current therapies fail to prevent progression of neurological impairment during these disease stages. Flupirtine, a drug approved for oral use in patients suffering from chronic pain, was used in a rat model of autoimmune optic neuritis and significantly increased the survival of retinal ganglion cells, the neurons that form the axons of the optic nerve. When flupirtine was combined with interferon-beta, an established immunomodulatory therapy for MS, visual functions of the animals were improved during the acute phase of optic neuritis. Furthermore, flupirtine protected retinal ganglion cells from degeneration in a noninflammatory animal model of optic nerve transection. Although flupirtine was shown previously to increase neuronal survival by Bcl-2 up-regulation, this mechanism does not appear to play a role in flupirtine-mediated protection of retinal ganglion cells either in vitro or in vivo. Instead, we showed through patch-clamp investigations that the activation of inwardly rectifying potassium channels is involved in flupirtine-mediated neuroprotection. Considering the few side effects reported in patients who receive long-term flupirtine treatment for chronic pain, our results indicate that this drug is an interesting candidate for further evaluation of its neuroprotective potential in MS.
Sättler
Muriel B
MB
Department of Neurology, University of Göttingen, Göttingen, Germany. msaettl@gwdg.de
Williams
Sarah K
SK
Neusch
Clemens
C
Otto
Markus
M
Pehlke
Jens R
JR
Bähr
Mathias
M
Diem
Ricarda
R
D000631:Aminopyridines / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001327:Autoimmune Diseases / Q000188:drug therapy* / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D019610:Cytoprotection / Q000187:drug effects; D018450:Disease Progression; D004359:Drug Therapy, Combination; D005074:Evoked Potentials, Visual / Q000187:drug effects; D005260:Female; D007249:Inflammation / Q000473:pathology; D016899:Interferon-beta / Q000627:therapeutic use; D015640:Ion Channel Gating / Q000187:drug effects; D018696:Neuroprotective Agents / Q000097:blood / Q000494:pharmacology / Q000627:therapeutic use*; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology; D009902:Optic Neuritis / Q000188:drug therapy* / Q000473:pathology; D024661:Potassium Channels, Inwardly Rectifying / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D017208:Rats, Wistar; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology
D000631:Aminopyridines; D018696:Neuroprotective Agents; D024661:Potassium Channels, Inwardly Rectifying; D019253:Proto-Oncogene Proteins c-bcl-2; D016899:Interferon-beta; C034161:flupirtine