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ORIGINAL ARTICLE
Year : 2014  |  Volume : 2  |  Issue : 1  |  Page : 28-32

Evaluation of the protective effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats


Department of Pharmacology, Armed Forces Medical College, Pune, Maharashtra, India

Date of Web Publication1-Jul-2014

Correspondence Address:
Anjan Khadka
Department of Pharmacology, Armed Forces Medical College, Pune - 40, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2348-0149.135723

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  Abstract 

Background: Cataract is an age-related disorder. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in cataract formation is still unclear. Previous data have indicated a cataractogenic as well as a potential protective effect of NSAIDs against cataract formation. Anti-cataract efficacy of NSAIDs has been studied extensively in different experimental settings. Use of aspirin in the prevention of cataract came from its use in elderly patients with osteoarthritis, rheumatoid arthritis, cardiovascular diseases and diabetes. Subsequently, a number of NSAIDs with diverse chemical structures like paracetamol, Ibuprofen, naproxen were reported to have anti-cataract potential as they delayed the onset and progression of cataract development. In view of this, naproxen is used as standard and celecoxib, a (cyclooxygenase II) COX II inhibitor, is used as drug for comparison to evaluate the protective effects on naphthalene-induced cataract in albino rats. Objective: The objective of the present study was to evaluate the effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats. Materials and Methods: Thirty-six adult albino rats were divided into six groups containing six animals each. Group I (control) received normal saline orally. Group II (control) received normal saline eye drops. Group III received naproxen (4 mg/kg) orally. Group IV received naproxen eye drops (2%). Group V received celecoxib (3 mg/kg) orally. Group VI received celecoxib eye drops (2%). Oral dose and eye drops were given daily for 10 days prior to induction of cataract. Cataract was induced by oral administration of naphthalene 1 gm/kg in albino rats. Rats were examined daily for the appearance of lenticular capacity by indirect illumination, direct ophthalmoscopy, slit lamp examination, and observed for any mortality for period of 30 days. Results: Oral naproxen significantly retarded the appearance and progression of cataract, whereas less significant improvement was seen with oral celecoxib. Although, naproxen eye drops were just marginally effective, celecoxib eye drops was not at all effective in preventing cataract. Conclusion: Oral naproxen being a nonselective COX inhibitor was more efficacious than celecoxib, a COX II selective inhibitor, in retarding the progress of cataract induced by naphthalene. Similarly, naproxen eye drops also showed a marginal effect in prevention of progression of cataract, whereas celecoxib eye drops had no effect at all.

Keywords: Celecoxib, cataract, naphthalene, naproxen


How to cite this article:
Brashier DB, Khadka A, Mishra P, Sharma AK, Dahiya N, Gupta AK. Evaluation of the protective effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats. Niger J Exp Clin Biosci 2014;2:28-32

How to cite this URL:
Brashier DB, Khadka A, Mishra P, Sharma AK, Dahiya N, Gupta AK. Evaluation of the protective effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats. Niger J Exp Clin Biosci [serial online] 2014 [cited 2019 Jan 18];2:28-32. Available from: http://www.njecbonline.org/text.asp?2014/2/1/28/135723


  Introduction Top


Cataract is a major cause of blindness in India. The most recent estimates from WHO reveal that 47.8% of global blindness is due to cataract and in South Asia region, which includes India, 51% of blindness is due to cataract. [1],[2] Incidence of cataract increases after the age of 50 that leads to 4 million blindness per year in India. [1],[2] There are many causative factors for cataract formation other than age, like nutritional deficiencies, environmental changes, radiation, metabolic diseases like diabetes and oxidative stress. [2] Aging is a physiological process that leads to a gradual decline in antioxidant enzymes. Endogenous anti-oxidative enzymes constitute a tissue defense system against aging and stress, likely to be caused by free radicals. [3] These enzymes like glutathione reductase and peroxidase and super oxide dismutase are necessary for removing the free radicals from the system and the lens also. [4] For arresting cataract, a single drug is not effective. Many studies have shown that four group of drugs namely aldose reductase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), antioxidants and drugs acting on glutathione are effective in preventing the development of cataract. [5],[6] These drugs are aimed at blocking the metabolic pathways of glucose responsible for diabetic vascular dysfunctions. Their role in the prevention of diabetic cataract in animals is now well established. However, their involvement in human is a subject of controversy.

The first indication regarding the probable use of NSAIDs as a prophylactic anti-cataract agent came from studies on aspirin use in patients with rheumatoid arthritis and diabetes. [7],[8],[9],[10] The anti-cataract activity of these drugs is explained by virtue of their effect on different biochemical pathways. Later, a number of NSAIDs with diverse chemical structures were reported to delay the phenomenon of cataract in experimental animals. [11],[12] Potential of drugs have been conducted by feeding the drugs by oral route. Keeping in view that cataract development is a slow process, for which drugs will have to be taken for many years and may result in unnecessary systemic side effects. Therefore, studies to test their anti-cataract activity after topical application in the form of eye drops are being evaluated. NSAIDs after topical application were found to have significant anti- cataract activity. They delay both the onset and progression of cataract. [10],[13] The anti-cataract activity of these drugs are explained by virtue of their effect on biochemical pathways. The mechanism associated with the protective effects of NSAIDs includes acetylation, inhibition of glycosylation and carbamylation of lens proteins. Recently, NSAIDs have also been reported to possess anti-oxidant properties. In the previous literature, it is shown that naproxen is effective both orally and topically in preventing cataract, whereas many other non-selective cyclooxygenase inhibitors like aspirin, sulindac and indomethacin have also been widely studied and showed good results. [14],[15] However, the anti-cataract effects of COX II inhibitor group of NSAIDs are not available in the literature. [16],[17] This group has minimal gastric side effects and is suitable for chronic use for disease like rheumatoid arthritis in elderly who are also likely to develop cataract. In view of this, it was felt worthwhile to undertake the present study to explore the possibility of celecoxib preventing the development of cataract with naproxen as a standard NSAID for comparison.

The objective of the present study was to evaluate the effects of naproxen and celecoxib on naphthalene-induced cataract in albino rats.


  Materials and methods Top


Animals: Healthy young adult (approx. 8 weeks old) wistar albino rats of either sex, weighing between 250 and 300 g were used as experimental animals in this study. They were housed in clean cages and were maintained on standard laboratory diet and water adlibitum. After a 5 day acclimatization period the rats were used for the study.

Drugs used for induction of cataract: Naphthalene crystals were crushed in mortar using pestle and dissolved in warm liquid paraffin to make suspension. Cataract was induced by oral administration of naphthalene 1 g/kg in albino rats. [11],[12],[13]

Drugs used for study: Naproxen is a white, odorless, hygroscopic crystalline powder. However, to maintain uniformity it was also prepared as suspension in gum acacia of 200mg per ml. A dose of 4 mg/kg/day was administered to the rats. A suspension of 2% naproxen powder in normal saline was prepared using 1 g of drug in 100 ml of normal saline to be used as eye drops. Celecoxib is a white odorless, hygroscopic crystalline powder. However, to maintain uniformity it was also prepared as a suspension in gum acacia of 300 mg per ml. A dose of 3 mg/kg/day was administered to the rats.

Control Drugs

A 5% suspension of gum acacia was prepared for administration to control rats, as all the drugs were prepared in 5% gum acacia suspension. A fixed volume of 1.5 ml with or without drugs was administered orally to the rats. Control group rats were applied normal saline (0.9%) topically on eyes.

Oral Administration of Drugs

The animals were held gently but firmly at the time of feeding. A suitable wooden mouth gag was placed between the teeth of the rat taking care not to cause any injury to the animal. A polythene feeding tube lubricated with liquid paraffin was passed through the hole in the mouth gag into the stomach of the rat. After ensuring that the tube was in the stomach and not in the airway (by looking for air bubbles coming out of the tube into a beaker filled with water), the required amount of the drug was injected into the feeding tube using a syringe. About 1 ml of normal saline (dead space of the tube) was injected after each drug so that any drug remaining in the tube was also delivered into the stomach. The tube was gently pulled out after the completion of drug administration.

Administration of Eye Drops

Rats were restrained manually, two drops were instilled on cornea of both eyes, and animal was restrained for 10 minutes for drug to have its effect.

Thirty-six adult albino rats were taken and divided into six groups containing six animals each. Group I (control) received normal saline orally. Group II (control) received normal saline eye drops. Group III received naproxen (4 mg/kg) orally. Group IV received naproxen eye drops (2%). Group V received celecoxib (3 mg/kg) orally. Group VI received celecoxib eye drops (2%). Oral dose and eye drops were given daily for 10 days prior to induction of cataract.

Rats were examined daily for appearance of lenticular capacity by indirect illumination, direct ophthalmoscopy, slit lamp examination, and observed for any mortality for period of 30 days. Initiation and measurement of lenticular opacity was graded into four stages [18] [Figure 1], [Figure 2], [Figure 3].
Figure 1: Normal rat eye

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Figure 2: Stage 3 cataract

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Figure 3: Stage 4 cataract

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  1. First stage was invasion of lens by vacuoles on periphery.
  2. Second stage was the presence of linear opacities cataract.
  3. Third stage was the presence of plaques and clouding of lens.
  4. Fourth stage was mature cataract.


Statistical analysis: The data were analyzed by two-way ANOVA and followed by post hoc Tukey's test. P <0.05 was considered to be statistically significant.


  Results Top


Oral naproxen significantly retarded appearance and progression of cataract, whereas less significant improvement was seen with oral celecoxib. Naproxen eye drops were just marginally effective and celecoxib eye drops were not at all effective in preventing cataract [Table 1], [Table 2], [Table 3], [Table 4].
Table 1: Effects of medications in development of grade 1 cataract in a naphthalene-induced cataract model

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Table 2: Effects of medications in development of grade 2 cataract in a naphthalene-induced cataract model

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Table 3: Effects of medications in development of grade 3 cataract in a naphthalene-induced cataract model

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Table 4: Effects of medications in development of grade 4 cataract in a naphthalene-induced cataract model

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Control

Saline-treated control rats subjected to naphthalene challenge with the selected dose of 1 gm/kg showed 100% response. Similarly, all rats subjected to naphthalene challenge developed cataract. There was no mortality till end of 30 days of observation.

Effect of Oral naproxen on naphthalene-induced cataract in albino rats:

Oral naproxen significantly delayed the appearance as well as its progression to various stages with a dose of 4 gm/kg (P < 0.001). Mature cataract was developed only in two rats at the end of 30 days. There was no mortality till the end of 30 days of observation.

Effect of naproxen eye drops on naphthalene-induced cataract in albino rats:

Naproxen eye drops (2%) did not significantly delay the appearance as well as its progression to various stages. Mature cataract developed in all rats at the end of 30 days. There was no mortality till the end of 30 days of observation.

Effect of oral celecoxib on naphthalene-induced cataract in albino rats:

Oral celecoxib significantly delayed the appearance as well as its progression to various stages with dose of 3 gm/kg (P <0.05). Mature cataract was developed in all rats at the end of 30 days. There was no mortality till the end of 30 days of observation.

Effect of celecoxib eye drops on naphthalene-induced cataract in albino rats:

Celecoxib eye drops (2%) did not significantly delay the appearance as well as its progression to various stages with dose of 2%. Mature cataract developed in all rats at the end of 30 days.


  Discussion Top


Oral naproxen significantly retarded appearance and progression of cataract, whereas less significant improvement was seen with oral celecoxib. Naproxen eye drops were just marginally effective and celecoxib eye drops were not at all effective in preventing cataract. Comparative studies on anti-cataract activity of various NSAIDs revealed that, though inhibition of lens aldose reductase (AR) by NSAIDs could be a significant factor, but it doesn't seem to be the sole cause of it. [19] Possible mechanism in naphthalene-induced cataract was believed to be by the direct toxic effect reducing glutathione levels. [20],[21] In this model, only oral naproxen could give some protection and topical administration didn't show any protective effects. Both oral and topical administration of celecoxib provided no protective effects. Further biochemical studies may explain their effects. This study is an attempt at revealing the possibilities of prevention of age-related cataract by systemic administration as well as topical administration of NSAIDs like naproxen and celecoxib. While oral administration of these NSAIDs could prevent cataract formation, topical ocular administration failed to do so.

The probable mechanism producing anti-cataract effects by naproxen and other NSAIDs can be due to acetylation, inhibition of glycosylation and carbamylation of lens proteins, and possibly also due to antioxidant and inhibition of aldose reductase. [19],[21]

The concentration of glutathione, a tripeptide thiol, decreases with age in the lens and more markedly in cataracts. [22] An approach to glutathione level inside the lens by its increased synthesis or decreased breakdown was tried by some groups using agents acting against glutathione. The potential role of vitamins and anti-oxidants in preventing various diseases is well documented. [4],[23],[24] Attempts to produce cataract in animals deficient in various vitamins have been largely unsuccessful. However, there are reports suggesting the beneficial effects of vitamins like C and E in preventing cataract. Various substances with diverse chemical structures and properties have been reported to have protective effect against cataract in different experimental models, like derivatives of amino acids containing germanium compounds, pantethine, glutathione isopropyl ester, etc. some plant products and drugs are reported to have anti-cataract activity.


  Conclusion Top


Oral naproxen being a nonselective COX inhibitor was more efficacious than celecoxib, a COX II selective inhibitor, in retarding the progress of cataract induced by naphthalene. Similarly, naproxen eye drops also showed a marginal effect in prevention of progression of cataract, whereas celecoxib eye drops had no effect at all.

 
  References Top

1.World Health Organization. Global initiative for the elimination of avoidable blindness: An informal consultation. Geneva: WHO; 1997. Available from: http ://www.who.int/ncd/vision2020.../WHOPBDscanneddocuments.PDF [Last cited on 2013 Sep 07].  Back to cited text no. 1
    
2.Hodge WG, Whitcher JP, Satariano W. Risk factors for age-related cataracts. Epidemiol Rev 1995; 17:336-46.  Back to cited text no. 2
    
3.Vajpayee RB, Joshi S, Saxena R, Gupta SK. Epidemiology of cataract in India: Combating plans and strategies. Ophthalmic Res 1999; 31:86-92.  Back to cited text no. 3
    
4.Thiagarajan R, Manikandan R. Antioxidants and cataract. Free Radic Res 2013; 47:337-45.  Back to cited text no. 4
    
5.Gupta SK, Joshi S. Naproxen: An aldose reductase inhibitor and potential anti-cataract agent. Dev Ophthalmol 1991; 21:170-8.  Back to cited text no. 5
    
6.Gupta SK, Joshi S. Relationship between aldose reductase inhibiting activity and anti-cataract action of various non-steroidal anti-inflammatory drugs. Dev Ophthalmol 1991; 21:151-6.  Back to cited text no. 6
    
7.Maloney SC, Fernandes BF, Castiglione E, Antecka E, Martins C, Marshall JC, et al. Expression of cyclooxygenase-2 in choroidal neovascular membranes from age-related macular degeneration patients. Retina 2009; 29:176-80.  Back to cited text no. 7
    
8.Weber M, Kodjikian L, Kruse FE, Zagorski Z, Allaire CM. Efficacy and safety of indomethacin 0.1% eye drops compared with ketorolac 0.5% eye drops in the management of ocular inflammation after cataract surgery. Acta Ophthalmol 2013; 91:e15-21.  Back to cited text no. 8
    
9.Moschos MM, Chatziralli IP, Pantazis P, Rouvas AA, Sergentanis TN. Is topical diclofenac essential before and after uneventful phacoemulsification cataract surgery? J Ocul Pharmacol Ther 2012; 28:335-9.  Back to cited text no. 9
    
10.Russo P, Papa V, Russo S, Di Bella A, Pabst G, Milazzo G, et al. A Topical nonsteroidal anti-inflammatory drugs in uncomplicated cataract surgery: Effect of sodium naproxen. Eur J Ophthalmol 2005; 15:598-606.  Back to cited text no. 10
    
11.Holmen JB, Ekesten B, Lundgren B. Naphthalene-induced cataract model in rats: A comparative study between slit and retroillumination images, biochemical changes and naphthalene dose and duration. Curr Eye Res 1999; 19:418-25.  Back to cited text no. 11
    
12.Lou MF, Xu GT, Zigler S Jr, York B Jr. Inhibition of naphthalene cataract in rats by aldose reductase inhibitors. Curr Eye Res 1996; 15:423-3.  Back to cited text no. 12
    
13.Rathbun WB, Holleschau AM, Cohen JF, Nagasawa HT. Prevention of acetaminophen- and naphthalene-induced cataract and glutathione loss by CySSME. Invest Ophthalmol Vis Sci 1996; 37:923-9.  Back to cited text no. 13
    
14.Papa V, Milazzo G, Santocono M, Servolle V, Sourdille P, Santiago PY, et al. Naproxen ophthalmic solution to manage inflammation after phacoemulsification. J Cataract Refract Surg 2002; 2:321-7.  Back to cited text no. 14
    
15.Papa V, Russo S, Russo P, Di Bella A, Santocono M, Milazzo G. Topical naproxen sodium for inhibition of miosis during cataract surgery. Prospective, randomized clinical trials; Naproxen Study Group. Eye (Lond) 2002; 16:292-6.  Back to cited text no. 15
    
16.Reis A, Birnbaum F, Hansen LL, Reinhard T. Cyclooxygenase-2 inhibitors: A new therapeutic option in the treatment of macular edema after cataract surgery. J Cataract Refract Surg 2005; 31:1437-40.  Back to cited text no. 16
    
17.Joshi RS. Pre-operative use of the topical steroidal and non-steroidal anti-inflammatory agents to maintain intra-operative mydriasis during cataract surgery. Indian J Ophthalmol 2013; 61:246-7.  Back to cited text no. 17
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18.Taylor HR, West SK. The clinical grading of lens opacities. Aust N Z J Ophthalmol 1989; 17:81-6.  Back to cited text no. 18
    
19.Gupta SK, Joshi S. Role of naproxen as anti-oxidant in selenite cataract. Ophthalmic Res 1994; 26:226-31.  Back to cited text no. 19
    
20.Xu GT, Zigler JS Jr, Lou MF. The possible mechanism of naphthalene cataract in rat and its prevention by an aldose reductase inhibitor (ALO1576). Exp Eye Res 1992; 54:63-72.  Back to cited text no. 20
    
21.Korte I, Hockwin O, Bours J, Wegener A. Alterations of lens metabolism with experimentally induced cataract in rats. Ophthalmic Res 1988; 20:174-8.  Back to cited text no. 21
    
22.Petersen A, Zetterberg M, Sjostrand J, Palsson AZ, Karlsson JO. Potential protective effects of NSAIDs /ASA in oxidatively stressed human lens epithelial cells and intact mouse lenses in culture. Ophthalmic Res 2005; 37:318-27.  Back to cited text no. 22
    
23.Suresha BS, Srinivasan K. Antioxidant potential of fungal metabolite nigerloxin during eye lens abnormalities in galactose-fed rats. Curr Eye Res 2013; 38:1064-71.  Back to cited text no. 23
    
24.Holmén JB, Ekesten B, Lundgren B. Naphthalene-induced cataract model in rats: A comparative study between slit and retroillumination images, biochemical changes and naphthalene dose and duration. Curr Eye Res 1999; 19:418-25.  Back to cited text no. 24
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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