Full text of DOI:10.1007/s00417-001-0379-1

Graefe’s Arch Clin Exp Ophthalmol
(2001) 239:840–844
L A B O R AT O RY I N V E S T I G AT I O N
DOI 10.1007/s00417-001-0379-1
Nava Naveh
John Marshall
Melanocortins are comparable
to corticosteroids as inhibitors
of traumatic ocular inflammation in rabbits
Abstract Background: Melanocyte- brought about by MSH was more
Received: 16 August 2000
Revised: 13 July 2001
Accepted: 29 August 2001
Published online: 23 October 2001
© Springer-Verlag 2001
stimulating hormone (MSH) is a
known anti-inflammatory agent and
we investigated whether it reduces
the inflammatory reaction following
ocular surgery. Methods: Rabbits
received a perforating corneo-
limbal cut. Treatment involved
topical (10–8M) or intramuscular
(50 mg/kg/day) MSH, topical ste-
roids or saline. The parameters
studied were hyperemia, edema,
aqueous protein levels and the num-
ber of inflammatory cells in the
pronounced than that produced by
steroids. Aqueous protein levels
were reduced by a similar degree in
the steroid- and MSH-treated eyes as
in the saline group (P<0.001 for each
treatment group); In MSH- and ste-
roid-treated eyes the number of in-
flammatory cells in the aqueous was
reduced by 80% and 50%, respec-
tively. Conclusion: We demonstrated
that MSH reduced the clinical signs
of ocular inflammation, curtailed
blood–aqueous barrier (BAB) dis-
N. Naveh (
)
✉
aqueous, as well as their number de- ruption, and reduced aqueous in-
termined histologically in the injured flammatory cell number. The effica-
cornea. Each parameter was assessed cy of MSH applied systemically or
15 Rav-Ashi Street, Tel Aviv 69395, Israel
e-mail: hnave@zahav.net.il
Tel.: +972-3-6421902
N. Naveh
Maurice and Gabriela Goldschleger
Eye Research Institute,
Chaim Sheba Medical Center,
Tel Aviv University, Tel Aviv, Israel
at 24 h post injury. Results: Topi-
cally and systematically applied
MSH reduced edema to levels 60%
and 76%, respectively, of those ob-
served in operated saline-treated
eyes (P<0.001), and their efficacy
was comparable to that of topical
steroids. The decrease in hyperemia
topically was similar to that of ste-
roids in reducing clinical signs of
trauma, but MSH efficacy in main-
taining BAB integrity surpassed
that of steroids. We suggest that the
melanocortins might be a useful
anti-inflammatory agents in ocular
trauma.
J. Marshall
Department of Ophthalmology,
St. Thomas’ Hospital, London University,
London, UK
inflammatory and antipyretic agent with greater potency
than paracetamol [4, 7, 18, 31, 32]. The peptide inhibits
Introduction
α-Melanocyte-stimulating hormone (MSH) is a basic chronic [12, 33] and acute inflammation mediated by
tricapeptide whose amino acid sequence is identical to various cytokines [7] and alleviates allergic reactions
the 1–13 (N-terminal) amino acid sequence of adreno- [4, 18, 29, 32].
corticotrophic hormone (ACTH). Pro-opio-melanocortin
The anti-inflammatory effect of MSH takes place
(POMC), found in the pituitary, brain, inflammatory through a central and peripheral mechanisms [7, 31] and
cells, skin, and at other sites, is the precursor of ACTH, is related to its ability to counteract the effects and the
MSH (α-, β- and γ-MSH), lipotrophins, and endorphins, production of pro inflammatory cytokines such as nitric
which constitute a family of biologically active peptides oxide [36], tumor necrosis factor-α (TNF-α), and inter-
termed melanocortins. MSH, named for its effect on pig- leukin-1 (IL-1) [9, 30]. In addition, the chemotactic ac-
mentation in amphibian skin, is widely known as an anti- tivity of macrophages and neutrophils is inhibited by

841
ciliary body. The tissue was fixated with glutaraldehyde 2%. After
a drying process the cornea was cut and stained with Giemsa.
these peptides [5, 9, 34, 36]. Studies conducted two de-
cades ago showed that MSH mediated changes in the
blood–aqueous barrier (BAB) and in intraocular pressure
[8, 11, 17, 19, 27]. In these studies crude extracts of the
peptide were used in high nonphysiological doses. Re-
cently MSH was detected in the normal aqueous of hu-
mans, mice, and rabbits [26, 38] and was demonstrated
Morphometric evaluation
The inflammatory cellular infiltrate at the traumatized corneo-lim-
bal area was evaluated by checking 10 fields in each section. The
fields were magnified by 60. projected and the inflammatory cells
to play a role in activation of regulatory T cells in the were counted using a computerized digitizer. The image-process-
ing system includes a digitizing pad (Summer Graphics, Seymour,
aqueous [38]. It also modulates the melanocyte response
in the retina–choroid [15].
Despite the fact that MSH takes part in anterior seg-
ment immune reactions and BAB permeability changes,
its role in ocular inflammation has not been studied. In
the present study the anti-inflammatory activity of MSH
in trauma-induced ocular inflammation was investigated
Conn., USA.) a personal computer and custom-designed software.
A handle with a mirror tilted 45 deg was built to fit the projecting
microscope. This allowed images of the stained section to be pro-
jected onto the digitizing pad. Limbal thickness was calculated us-
ing the same computerized digitizer, measuring seven consecutive
points at the middle of each section.
using physiological doses [1, 20] administered topically Clinical assessment
or systemically, and their effect was compared to that of
Conjunctival hyperemia, edema, hemorrhages, and discharge, as
topical corticosteroids.
well as corneal changes 24 h following ocular trauma, were as-
sessed using the operating microscope (Wild Leica AG, Heebrugg,
Switzerland). Discharge and corneal changes were negligible and
therefore were not included in the clinical evaluation. Additional
evaluation of hyperemia was done morphometrically using colored
photos (Nikon F601 camera, Nikon, Tokyo, Japan) taken during
clinical examination. Slides were coded, projected, and hemorrhag-
es as well as congested blood vessels were quantified morphomet-
rically as described. Hyperemia was the most reproducible clinical
sign and therefore its analysis is depicted in Results.
Materials and methods
Animals
Pigmented rabbits of either sex, weighing 2.5–3 kg, were used.
The rabbits were maintained in standard cages with free access to
food and water, in a temperature controlled room, and were ex-
posed to 12-h light–dark cycles.
Animal treatment followed the Association for Research in
Vision in Ophthalmology resolution on the use of animals in re-
search.
Experimental design
The study involved five groups of rabbits (14 animals in each
group), divided according to protocol: Control group 1: untreated
intact rabbits; group 2: operated rabbits treated daily by topical ap-
plication of 0.45% saline q.i.d., group 3: operated animals treated
daily with dexamethasone 2% q.i.d.; groups 4 and 5: operated ani-
mals treated with α-MSH applied topically (MSH 10–8, q.i.d.) or
given systemically ( i.m.) (25 µg/kg).
MSH drug preparation
MSH (acetate salt; Sigma, St. Louis, Mo. USA), was dissolved
in sterile saline (0.9% NaCl).The stock solution containing
250 µg/ml (10–4 M) was stored at –20 °C. The stock solution was
diluted with phosphate-buffered saline (PBS) to achieve doses for
topical application (10–7 to 10–10 M). For intramuscular (i.m.) in-
jections, a solution containing 50 µg/0.2 ml was used.
Treatment in-groups 2–5 was started 1 h prior to trauma.
Experimental procedure
Fully anesthetized animals underwent the surgical procedure as
described. Within 1 h prior to surgery, treatment was started ac-
cording to protocol. Any particular topical treatment involved ap-
plication of a 50-µl drop in the lower cul de sac. Systemic treat-
ment was applied i.m. (as described). Clinical examination of
anesthetized animals, performed through an operating microscope
at 24 h after trauma, included assessment of the following parame-
ters: conjunctival hyperemia and edema, corneal damage, and
aqueous flare using a score from 0 to 4. Following clinical exami-
nation, photographs of the surgical site were taken for computer-
ized evaluation of hyperemia (as described). At the end of exami-
nation the animals were killed and secondary aqueous was with-
drawn for protein and inflammatory cell determination. In addi-
tion, corneo-limbal tissue sample at the trauma site was excised
for histology (as described).
Surgical procedure
The right eye of each animal received a 6-mm-long nonperforating
corneo-limbal cut, followed by paracentesis, and aspiration of
150 µl of aqueous using a 25-gauge needle. Twenty-four hours la-
ter, when the anterior chamber was reformed, the aqueous was as-
pirated again and protein and cells were determined.
Protein and inflammatory cell count
These parameters were determined in the secondary aqueous. Pro-
tein was measured using the Lowry technique, while inflammatory
cells were counted using a Coulter cell counter.
Histopathology
Statistical analysis
At 24 h post trauma, after secondary aqueous had been withdrawn, Statistical analysis of the clinical observations was carried out
a triangle-shaped piece of tissue was excised at the middle of the using two-way analysis of variance (ANOVA). Other results were
corneo-limbal cut. The sample contained sclera, cornea, and the iris analyzed using Student’s t-test.

842
Table 3 Inflammatory cells and protein levels in the aqueous
Results
Group
Number of cells
Protein levels
(µg/ml)
Eyes subjected to trauma developed edema and hyper-
emia, but no corneal damage. Discharge from the operat-
ed eyes was watery and mild and its amount varied, and
therefore discharge was not included in the analysis.
Eyes treated with topical MSH (Table 1) experienced
a significant reduction in edema compared with the sa-
line-treated group (P<0.05). Steroids and systemically
administered MSH curtailed edema similarly, (P<0.05
for each medication vs saline) but were less effective
than the topical hormone (Table 1). Hyperemia was
reduced significantly in both MSH-treated groups
(P<0.001 for each medication vs saline), and to a lesser
degree by steroids.
in 0.1 ml aqueous
Control
Undetectable
30,000±2,500
6,000±750*
5,700±650*
15,000±1200*
88±10
250±9
120±10*
128±20*
150±11*
Saline i.m 50 µg/kg/day
MSH i.m. 50 µg/kg/day
MSH topically 10–8
M
Steroid topically 2%
* P=0001 using two-way analysis, performed for each parameter
separately
Computerized evaluation (Table 2) showed that MSH
applied topically reduced hyperemia to levels 53% of those
in operated saline-treated eyes (P<0.001 vs saline) being
more efficacious than systemic MSH or steroids (a reduc-
tion to 62% and 75% of baseline, respectively, P<0.05, vs
saline). Hyperemia was not influenced by the length of the
surgical cut, which was similar for each group.
Protein levels were 2.8 times greater in the operated
saline-treated group than in intact eyes (Table 3). In the
three treated groups, protein levels (Table 3) were simi-
larly reduced (approximately by 50%) when compared to
the saline group (P<0.001 for each of the drugs).
Fig. 1 MSH inhibits cellular infiltration at the injury site
The number of inflammatory cells in the aqueous
(Table 3) was reduced by 80% in the two MSH groups,
while a 50% decrease was noted in the steroid-treated
eyes (P<0.001 for each drug vs saline).
Neither MSH nor steroids significantly affected the
number of inflammatory cells found at the injury site
Table 1 MSH anti-inflammatory activity: clinical assessment
Treatment group
Edemaa
Hyperemiaa
Saline i.m. 50 µg/kg/day
MSH i.m. 50 µg/kg/day
100±28
76*±18
60*±15
79*±14
100
78*±15
77*±13
87**±20
MSH topically 10–8
M
Steroid topically 2%
a Data given as the percentage of the ratio between the mean of
each treated MSH group/ mean of saline control
* P<0.001; **P<0.05
Fig. 2 MSH inhibits edema at the injury site
(Fig. 1). However, edema at the trauma site, as manifest-
ed by limbal thickness, was significantly reduced by top-
ical and systemic MSH, (P<0.001 for both vs saline)
(Fig. 2), while steroids were less effective. (P<0.05 vs.
saline).
Table 2 Hyperemia evaluated by morphometry
Group
Corneal cut
(mm)a
Hyperemia (% of
saline group)
Saline i.m. 50 µg/kg/day
MSH i.m. 50 µg/kg/day
97±17
102±20
95±15
100
62**
53**
75**
MSH topically 10–8
M
Steroid topically 2%
93±18
Discussion
a A 6-mm corneal cut was considered as 100%; measurements
were made under the operating microscope
** P<0.05 compared to saline group
Our study demonstrated for the first time that MSH, ap-
plied either topically or systemically, alleviated hyper-

843
emia and edema, clinical signs associated with surgical not inhibit LTB4-induced aqueous inflammatory cell in-
induced inflammation of the eyes. In addition, the pep- filtration [35].
tide reduced BAB failure in operated eyes and the infil-
Our demonstration of an MSH-related anti-inflamma-
tration of inflammatory cells into the aqueous following tory activity following ocular surgery is in agreement
the surgical trauma. The efficacy of topically applied with the melanocortins’ well-established inhibitory ef-
MSH in reducing edema was slightly greater than that of fect on inflammation in many organs [4, 19] The mecha-
systemic MSH or topical steroids. MSH treatment (topi- nism underlying the anti-inflammatory action of MSH is
cal and systemic) caused a significantly more pro- attributable to its ability to counteract the pro-inflamma-
nounced reduction of hyperemia than was found with tory effects of the cytokines TNF-α, IL-1, IL-6 and nitric
steroid therapy.
oxide [8, 31, 32]. In addition, chemotaxis of macro-
In our study, inflammatory (polymorphonuclear, phages and neutrophils is inhibited by MSH through re-
PMN) cells infiltrated the aqueous of the operated eyes. ceptor-specific mechanisms [8, 22, 28, 31].
PMN cell number at the corneal surgery site was also in-
creased, and a failure of the BAB was manifested by ous might possibly be exerted through down regulation
leakage of protein into the aqueous. of TNF and IL-6 [2, 16] and trough inhibition of prostag-
Steroid-related reduction of PMN number in the aque-
Our findings in eyes subjected to corneo-limbal cut landins and a reduced expression of mRNA cyclooxyge-
and perforation (paracentesis) are in agreement with nase 2(COX-2) [23, 25].
well-established data on paracentesis-induced BAB fail-
MSH in our study was used in a physiological dose,
ure in primates [3, 24] and with other experimental in contrast to the studies carried out two decades ago [11,
models in which inflammation was induced by intraocu- 12, 17, 20, 21, 26]. At that time MSH was known for its
lar injection of leukotriene B4 (LTB4) [37], combined role in disrupting the BAB because crude MSH prepara-
injection of TNF-αand IL-6 [9, 13], or TNF alone [10, tions in high nonphysiological doses were used [11, 12,
16].
20] It was also given in amounts exceeding normal val-
In our study, the reduction in the number of PMN in ues by a factor one thousand to one million times greater
the aqueous by MSH administered either topically or than the doses used by us. Therefore these data are irrel-
systemically was 2 times greater than that observed in evant to our study [17, 26].
the steroid-treated group.
Recent data on melanocortins showed that MSH de-
Protein levels in the aqueous of operated eyes in our rivatives applied systemically to humans [14, 18, 30, 36]
study were reduced by 50% in all treated groups, and no or rats [6, 19] caused no ocular side effects.
statistically significant difference existed between ste-
In summary, we have demonstrated for the first time
roid-treated and or MSH-treated eyes. Steroids are that MSH, applied topically or given systemically, reduc-
known to reduce aqueous protein levels in traumatized es ocular inflammation, curtails BAB disruption and re-
eyes: protein levels were diminished by steroids treat- duces PMN infiltration into the aqueous in rabbits’ eyes
ment following perforating corneal injury [37], or cata- subjected to perforating surgery. The peptide’s efficacy
ract surgery [27].
in curtailing the inflammatory-related clinical signs and
In our study, PMN cell number in the cornea at the in- BAB failure was comparable to that of steroids. MSH
jury site was unaffected by either drug. This is in accor- was more effective than steroids in reducing hyperemia
dance with a report that the number of PMN cells in iris and the number of inflammatory cells in the aqueous. We
and ciliary bodies in the aqueous of uveitic eyes was not suggest that the melanocortins might be considered as
reduced by steroids [38]. In another report steroids did future novel anti-inflammatory agents.
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