Cyclosporine Immunomodulation Retards Regeneration of Surgically Transected Corneal Nerves

Namavari, Abed; Chaudhary, Shweta; Chang, Jin-Hong; Yco, Lisette; Sonawane, Snehal; Khanolkar, Vishakha; Yue, Beatrice Y.; Sarkar, Joy; Jain, Sandeep

doi:10.1167/iovs.11-8445

Cited by 31 publications

(42 citation statements)

References 53 publications

(42 reference statements)

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“…Further, in an in vivo mouse model of corneal abrasion, twicedaily 0.05% CsA retarded sprouting of transected stromal nerves while suppressing corneal inflammation [53]. This study also found that 0.0005% CsA directly inhibited neurite outgrowth in cultured mouse trigeminal ganglion cultures.…”

Section: Cyclosporine Asupporting

confidence: 59%

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Drug Treatment of Corneal Neuropathies: Mini Review

Tr¹,

Azuma²

2017

J Clin Exp Ophthalmol

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Section: Cyclosporine Asupporting

confidence: 59%

“…CsA is from the calcineurin family of immune suppressants. It blocks T-cell proliferation and down regulates IL-2 receptor expression and gene transcription [53].…”

Section: Cyclosporine Amentioning

confidence: 99%

Drug Treatment of Corneal Neuropathies: Mini Review

Tr¹,

Azuma²

2017

J Clin Exp Ophthalmol

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“…29 We, as well as others, have reported that regenerating nerves in the cornea do not follow pre-existing tracks; therefore, the appearance of new fluorescent nerve fibers in a new pattern signifies nerve regeneration. [14][15][16] We visualized two forms of stromal nerve neurotoxicity. Reversible neurotoxicity (axonopathy) was characterized by Western blot analyses of corneal lysate showed an increase in abundance of proteins associated with inflammation (IL6 and CD3) at 1 week and reduced abundance at 4 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…16,[24][25][26] On day 1, trigeminal neuronal cells (1 · 10 3 ) were plated in the central compartment. The side compartments were filled with a mixture that was identical except that it also contained cytosine arabinoside (AraC, 0.3 lM; Sigma).…”

Section: In Vitro Experimentsmentioning

confidence: 99%

“…14 We have recently described nerve regeneration events in these mice. 15,16 In the investigations reported here, we applied BAK to eyes of these mice and sequentially visualized the corneal nerves to characterize BAK-induced neurotoxicity. Furthermore, we confirmed BAK-induced neurotoxicity by molecular analyses of markers for nerve degeneration and regeneration and in cultured trigeminal ganglion cells.…”

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confidence: 99%

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Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

Sarkar¹,

Chaudhary²,

Namavari³

et al. 2012

Invest. Ophthalmol. Vis. Sci.

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121

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PURPOSE. The aim of this study was to determine and characterize the effect of topical application of benzalkonium chloride (BAK) on corneal nerves in vivo and in vitro.METHODS. Thy1-YFP+ neurofluorescent mouse eyes were treated topically with vehicle or BAK (0.01% or 0.1%). Widefield stereofluorescence microscopy was performed to sequentially image the treated corneas in vivo every week for 4 weeks, and changes in stromal nerve fiber density (NFD) and aqueous tear production were determined. Whole-mount immunofluorescence staining of corneas was performed with antibodies to axonopathy marker SMI-32. Western immunoblot analyses were performed on trigeminal ganglion and corneal lysates to determine abundance of proteins associated with neurotoxicity and regeneration. Compartmental culture of trigeminal ganglion neurons was performed in Campenot devices to determine whether BAK affects neurite outgrowth.RESULTS. BAK-treated corneas exhibited significantly reduced NFD and aqueous tear production, and increased inflammatory cell infiltration and fluorescein staining at 1 week (P < 0.05). These changes were most significant after 0.1% BAK treatment. The extent of inflammatory cell infiltration in the cornea showed a significant negative correlation with NFD. Sequential in vivo imaging of corneas showed two forms of BAK-induced neurotoxicity: reversible neurotoxicity characterized by axonopathy and recovery, and irreversible neurotoxicity characterized by nerve degeneration and regeneration. Increased abundance of beta III tubulin in corneal lysates confirmed regeneration. A dose-related significant reduction in neurites occurred after BAK addition to compartmental cultures of dissociated trigeminal ganglion cells. Although both BAK doses (0.0001% and 0.001%) reduced nerve fiber length, the reduction was significantly more with the higher dose (P < 0.001).CONCLUSION. Topical application of BAK to the eye causes corneal neurotoxicity, inflammation, and reduced aqueous tear production. (Invest Ophthalmol Vis Sci.

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Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

Asiedu

2023

J of Neuroscience Research

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The altered activity generated by corneal neuronal injury can result in morphological and physiological changes in the architecture of synaptic connections in the nervous system. These changes can alter the sensitivity of neurons (both second‐order and higher‐order projection) projecting pain signals. A complex process involving different cell types, molecules, nerves, dendritic cells, neurokines, neuropeptides, and axon guidance molecules causes a high level of sensory rearrangement, which is germane to all the phases in the pathomechanism of corneal neuropathic pain. Immune cells migrating to the region of nerve injury assist in pain generation by secreting neurokines that ensure nerve depolarization. Furthermore, excitability in the central pain pathway is perpetuated by local activation of microglia in the trigeminal ganglion and alterations of the descending inhibitory modulation for corneal pain arriving from central nervous system. Corneal neuropathic pain may be facilitated by dysfunctional structures in the central somatosensory nervous system due to a lesion, altered synaptogenesis, or genetic abnormality. Understanding these important pathways will provide novel therapeutic insight.

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Cyclosporine Immunomodulation Retards Regeneration of Surgically Transected Corneal Nerves

Abstract: Immunomodulation with CsA reduces the expression of cytokines (IL6) in the cornea and retards regenerative sprouting from transected corneal stromal nerve trunks. In addition, CsA has a direct growth inhibitory action on neurites as well.

Cited by 31 publications

References 53 publications

Drug Treatment of Corneal Neuropathies: Mini Review

Drug Treatment of Corneal Neuropathies: Mini Review

Corneal Neurotoxicity Due to Topical Benzalkonium Chloride

Neurophysiology of corneal neuropathic pain and emerging pharmacotherapeutics

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