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Changes in Rabbit Corneal Innervation Induced by the Topical Application of Benzalkonium Chloride

Chen, Wensheng MD; Zhang, Zhenhao; Hu, Jiaoyue; Xie, Hui; Pan, Juxin; Dong, Nuo; Liu, Zuguo MD

doi: 10.1097/ICO.0b013e3182a8196f
Basic Investigation

Purpose: To investigate the effect of benzalkonium chloride (BAK) on corneal nerves.

Methods: Fifty-four adult New Zealand Albino rabbits were randomly divided into 3 groups. BAK at concentrations of 0.005%, 0.01%, or 0.02% was applied once daily to 1 eye of each rabbit for 9 days. The contralateral untreated eyes were used as controls. Corneal mechanical sensitivity, aqueous tear production, tear break-up time (BUT), fluorescein, and Rose Bengal staining scores were compared with those of control values on days 3, 6, and 9. Corneal whole mounts were immunostained with a specific antitubulin βIII antibody to label nerve fibers. Epithelial superficial nerve terminal, subbasal, and stromal nerve fiber densities were quantified. The structure of the central cornea was examined by means of in vivo confocal microscopy on day 9.

Results: The topical application of BAK resulted in lower corneal sensitivity and higher Rose Bengal staining scores on day 3, whereas there were no significant changes in the BUT, Schirmer, and corneal fluorescein scores. Decreased nerve densities in superficial and subbasal layers were observed in BAK-treated eyes on days 3 and 6, respectively. The eyes treated with 0.02% BAK exhibited significantly reduced Schirmer scores, BUT, and stromal nerve fiber density, and increased fluorescein staining scores on day 9. Corneal superficial epithelial cell size was significantly larger in all BAK-treated eyes compared with that in control eyes.

Conclusions: The topical application of BAK can quickly cause corneal hypoesthesia without tear deficiency. Changes in corneal innervation significantly correlate with BAK-induced ocular surface changes.

Eye Institute and Affiliated Xiamen Eye Center, Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Vision Science, Xiamen, Fujian, China.

Reprints: Zuguo Liu and Wensheng Chen, Eye Institute and affiliated Xiamen Eye Center, Xiamen University, Xiangan Rd, Xiamen, Fujian 361000, China (;

Supported by the National Natural Science Foundation of China (30973249, 81100638).

The authors have no conflicts of interest to disclose.

Received April 27, 2013

Accepted August 04, 2013

Copyright © 2013 Wolters Kluwer Health, Inc. All rights reserved.