Limited restoration of visual function after partial optic nerve injury; a time course study using the calcium channel blocker lomerizine.
Secondary degeneration is a process encompassing damage adjacent to a primary injury, usually involving increased Ca(2+) influx into neurons and glia. Lomerizine dihydrochloride is a calcium channel blocker with relatively selective CNS effects, currently in clinical trials for glaucoma. We have recently demonstrated that, following partial transection of the optic nerve (ON), 1 month of lomerizine treatment protects retinal ganglion cells (RGCs), incompletely preserves visual function and also limits elements of secondary degeneration, including macrophage infiltration. However, under some circumstances macrophages have been shown to have different supportive effects on RGC protection and regeneration, casting doubt on the benefit of longer term therapies that reduce macrophage numbers. Here, we determined whether shorter treatment times (1 day or 1 week) result in improved effects on RGC survival and visual function, and whether benefits are maintained after cessation of treatment. We demonstrate that 1 month of lomerizine is the minimum period required to restore the fast reset phase of the optokinetic nystagmus and maintain it for a further 2 months after cessation of treatment (p>0.05, not different from normal). While 1 week of lomerizine treatment results in temporary recovery of numbers of fast reset phases, the recovery is not maintained after treatment cessation. Similarly, protection of RGC densities requires 1 month of lomerizine treatment, but protection is not maintained after treatment cessation. Importantly, none of the lomerizine treatment protocols resulted in full restoration of visual function, confirming the necessity of combining lomerizine with other treatment modalities.
Selt
Marion
M
Experimental and Regenerative Neurosciences, The University of Western Australia, Crawley, 6009 WA, Australia.
Bartlett
Carole A
CA
Harvey
Alan R
AR
Dunlop
Sarah A
SA
Fitzgerald
Melinda
M
D000818:Animals; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000627:therapeutic use*; D002452:Cell Count; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D007150:Immunohistochemistry; D008264:Macrophages / Q000187:drug effects / Q000502:physiology; D009410:Nerve Degeneration / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D009760:Nystagmus, Physiologic; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D010879:Piperazines / Q000008:administration & dosage / Q000627:therapeutic use*; D011698:Pursuit, Smooth; D051381:Rats; D011919:Rats, Inbred Strains; D020127:Recovery of Function / Q000187:drug effects*; D012160:Retina / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D013997:Time Factors; D016896:Treatment Outcome; D014786:Vision Disorders / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
D002121:Calcium Channel Blockers; D010879:Piperazines; C052424:lomerizine