title: Secondary degeneration of the optic nerve following partial transection: the benefits of lomerizine.
abstract: Secondary degeneration is a form of 'bystander' damage that can affect neural tissue both nearby and remote from an initial injury. Partial optic nerve transection is an excellent model in which to unequivocally differentiate events occurring during secondary degeneration from those resulting from primary CNS injury. We analysed the primary injury site within the optic nerve (ON) and intact areas vulnerable to secondary degeneration. Areas affected by the primary injury showed morphological disruption, loss of beta-III tubulin axonal staining, reduced myelinated axon density, greater proteoglycan expression (phosphacan), increased microglia and macrophage numbers and increased oxidative stress. Similar, but less extreme, changes were seen in areas of the optic nerve undergoing secondary degeneration. The CNS-specific L- and T-type calcium channel blocker lomerizine alleviated some of the changes in areas vulnerable to secondary degeneration. Lomerizine reduced morphological disruption, oxidative stress and phosphacan expression, and limited early increases in macrophage numbers. However, lomerizine failed to prevent progressive de-myelination of ON axons. Within the retina, secondary retinal ganglion cell (RGC) death was significant in areas vulnerable to secondary degeneration. Lomerizine protected RGCs from secondary death at 4 weeks but did not fully restore behavioural function (optokinetic nystagmus). We conclude that blockade of calcium channels is neuroprotective and limits secondary degenerative changes following CNS injury. However such an approach may need to be combined with other treatments to ensure long-term maintenance of full visual function.
authors.affiliation: Experimental and Regenerative Neurosciences, University of Western Australia, Crawley, WA, Australia. melfitz1@cyllene.uwa.edu.au
authors.forename: Melinda
authors.initials: M
authors.lastname: Fitzgerald
authors.forename: Carole A
authors.initials: CA
authors.lastname: Bartlett
authors.forename: Lauren
authors.initials: L
authors.lastname: Evill
authors.forename: Jenny
authors.initials: J
authors.lastname: Rodger
authors.forename: Alan R
authors.initials: AR
authors.lastname: Harvey
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Dunlop
mesh_terms: D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002121:Calcium Channel Blockers / Q000494:pharmacology / Q000627:therapeutic use; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D009900:Optic Nerve / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D020221:Optic Nerve Injuries / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D018384:Oxidative Stress / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5 / Q000378:metabolism; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D016896:Treatment Outcome; D014404:Tubulin / Q000187:drug effects / Q000378:metabolism; D014855:Wallerian Degeneration / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology
chemical_list: D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D018696:Neuroprotective Agents; D010879:Piperazines; D014404:Tubulin; C052424:lomerizine; D054633:Receptor-Like Protein Tyrosine Phosphatases, Class 5