Secondary Retinal Ganglion Cell Death and the Neuroprotective Effects of the Calcium Channel Blocker Lomerizine

Fitzgerald, Maria; Payne, Sophie C.; Bartlett, Carole A.; Evill, Lauren; Harvey, Alan R.; Dunlop, Sarah

doi:10.1167/iovs.09-3717

Cited by 76 publications

(104 citation statements)

References 68 publications

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“…However, it did not prevent demyelination of the ON. 86,87 Minocycline Minocycline, a broad spectrum tetracycline antibiotic has been investigated as a potential treatment for primary open angle glaucoma as it has been shown to promote trabecular meshwork cell and ON head astrocyte survival. 88 This antiapoptotic effect has also been demonstrated in the RGCs of rats with glaucomatous eyes and following ON transection.…”

Section: Lomerizinementioning

confidence: 99%

Traumatic Optic Neuropathy: A Review

Kumaran

Sundar

Chye

2015

Craniomaxillofacial Trauma & Reconstruction

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The aim of this article is to evaluate current literature on investigation and management of traumatic optic neuropathy (TON), propose recommendations for diagnosis and management, and explore novel future treatments. TON, though uncommon, causes substantial visual loss. Without clear guidelines, there is much ambiguity regarding its diagnosis and management. Investigation and treatment (conservative, medical, surgical, and combined) vary widely between centers. Electronic databases PubMed, MEDLINE, PROSPERO, CENTRAL, and EMBASE were searched for content that matched "Traumatic optic neuropathy." Articles with abstracts and full text available, published in the past 10 years, written English and limited to human adults, were selected. All study designs were acceptable except case reports and case series with fewer 10 patients. All abstracts were then evaluated for relevance. References of these studies were evaluated and if also relevant, included. A total of 2,686 articles were retrieved and 43 examined for relevance. Of these, 23 articles were included. TON is a clinical diagnosis. Visual-evoked potential is useful in diagnosis and prognosis. Computed tomography demonstrates canal fractures and concomitant injuries. Magnetic resonance images should be reserved for select and stable patients. Conservative treatment is appropriate in mild TON. Steroids are of questionable benefit and may be harmful. Surgery should be reserved for patients with radiological evidence of compression and individualized.

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Section: Lomerizinementioning

confidence: 99%

Traumatic Optic Neuropathy: A Review

Kumaran

Sundar

Chye

2015

Craniomaxillofacial Trauma & Reconstruction

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“…In the current partial ON transection study, we take advantage of the spatial separation of axons and somata undergoing primary versus secondary injury to identify, using semi-quantitative fluorescence immunohistochemistry, likely key contributors to the progression of secondary degeneration in this model. Finally, we have shown that the L-and T-type voltage-gated calcium channel blocker lomerizine is effective in reducing the amount of secondary RGC death from 2 weeks after partial ON transection (Fitzgerald et al, 2009a(Fitzgerald et al, , 2009b. Furthermore, lomerizine reduced secondary infiltration of macrophages at 7 days, and accumulation of aggregates of the oxidative stress marker manganese superoxide dismutase (MnSOD) at 1 month (Fitzgerald et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

“…Ventral axons of the ON, which are vulnerable only to secondary degeneration, are spatially separated from neurons and glia damaged by a dorsal primary ON injury (Fitzgerald et al, 2009a;Levkovitch-Verbin et al, 2003). After transection of dorsal axons in the Piebald Virol Glaxo (PVG) rat there is both primary and secondary death of retinal ganglion cells (RGCs) in the centrodorsal retina, while RGCs in the ventral retina exclusively undergo secondary degeneration (Fitzgerald, 2009b). The separation of optic axons from their parent somata, together with spatial separation of primary from secondary degeneration across the nerve, allows a comprehensive assessment of the sequence of events contributing specifically to secondary degenerative events in CNS tissue.…”

Section: Introductionmentioning

confidence: 99%

Early Events of Secondary Degeneration after Partial Optic Nerve Transection: An Immunohistochemical Study

Fitzgerald¹,

Bartlett²,

Harvey

et al. 2010

Journal of Neurotrauma

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118

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Secondary degeneration in the central nervous system involves indirect damage to neurons and glia away from the initial injury. Partial transection of the dorsal optic nerve (ON) results in precise spatial separation of the primary trauma from delayed degenerative events in ventrally placed axons and parent somata. Here we conduct an immunohistochemical survey of secondary cellular changes in and around axons and their parent retinal ganglion cell (RGC) somata during the first 3 days after a restricted, dorsal ON transection. This is before the secondary loss of RGCs and axons projecting through the uninjured, ventral portion of the ON. Within 5 min, manganese superoxide dismutase (MnSOD; a marker of oxidative stress) co-localizes within the astrocytic network across the entire profile of the ON. Secondary astrocyte hypertrophy of immunofluorescent labeling was evident from 3 h, with sustained increases in myelin basic protein immunoreactivity across the nerve by 24 h. Increases in NG-2-positive oligodendrocyte precursor cells, ED-1-positive activated microglia/macrophages, and Iba1-positive reactive resident microglia/macrophage numbers were only seen in ON vulnerable to secondary degeneration by 3 days. Changes within RGC somata exclusively vulnerable to secondary degeneration were detected at 24 h, as evidenced by increases in MnSOD immunoreactivity, followed by increases in c-jun immunoreactivity at 3 days. Treatment with the voltage-gated calcium channel blocker lomerizine did not alter any measured outcome. We conclude that oxidative stress spreading via the astrocytic network and from injured axons to parent RGC somata is an early event during secondary degeneration, and containment is likely to be required in order to prevent further damage to the nerve.

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“…Nifedipine, verapamil, and diltiazem have been shown to be effective in normal tension glaucoma 44,45 and nilvadipine in open angle glaucoma. 46 Other calcium channel blockers, such as flunarizine and lomerizine, have shown to be effective in animal models but not in humans. 47 Calcium channel blockers should be used with caution because of their systemic hypotensive effect which may be potentially detrimental to optic nerve head perfusion.…”

Section: Calcium Channel Blockersmentioning

confidence: 99%

Emerging Therapeutic Regimens for Glaucoma and Ocular Hypertension

2011

Clinical Medicine Reviews in Therapeutics

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Glaucoma is the name given to a group of diseases characterized by incurable, progressive, multifactorial optic neuropathy. It is the second leading cause of blindness worldwide. Ocular hypertension (OH) is the term used to describe the presence of raised intraocular pressure (the most important risk factor for the development of glaucoma) in the absence of demonstrable glaucomatous optic neuropathy. The management of glaucoma and OH requires a holistic and rational approach, taking into account a number of factors. Treatment needs to be individualized depending on patient age, the severity and type of glaucoma, associated medical conditions, the condition of the ocular surface, tolerability of topical medication, and patient wishes. An understanding of the mechanism of glaucoma and its etiology in a particular patient is crucial for the initiation of appropriate treatment. This review article summarizes the existing medical management of glaucoma and OH, including pharmacology, mode of action, and safety profile for each major group of medication, and reviews current advances and future developments in treatment for glaucoma, including experimental medications, together with a summary of their modes of action, pharmacology, and safety profiles. It is hoped that readers will become more aware of the evolution of the next generation glaucoma and OH medications.

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Secondary Retinal Ganglion Cell Death and the Neuroprotective Effects of the Calcium Channel Blocker Lomerizine

Abstract: Lomerizine had differential effects on necrotic and apoptotic death with time, but its inability to completely prevent secondary death suggests that full neuroprotection will require combinatorial treatments.

Cited by 76 publications

References 68 publications

Traumatic Optic Neuropathy: A Review

Traumatic Optic Neuropathy: A Review

Early Events of Secondary Degeneration after Partial Optic Nerve Transection: An Immunohistochemical Study

Emerging Therapeutic Regimens for Glaucoma and Ocular Hypertension

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