PT  - JOURNAL ARTICLE
AU  - FRANCISCO JAVIER NAVARRO GIL
AU  - FERNANDO HUETE-TORAL
AU  - ALMUDENA CROCKE
AU  - CARMEN OLALLA DOMINGUEZ GODINEZ
AU  - GONZALO CARRACEDO
AU  - JESUS PINTOR JUST
TI  - Effect of melatonin and its analogues in the tear secretion.
AID  - 10.1124/jpet.119.259192
DP  - 2019 Jan 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - jpet.119.259192
4099  - http://jpet.aspetjournals.org/content/early/2019/08/01/jpet.119.259192.short
4100  - http://jpet.aspetjournals.org/content/early/2019/08/01/jpet.119.259192.full
AB  - It has been shown that melatonin is an enhancer of tear secretion associated with the Ap4A. The present study has investigated the isolated action of melatonin and its analogues, agomelatine, IIK7 and 5MCA-NAT (10 µl at 100 µM) on the tear secretion applied topically in cornea, in New Zealand white rabbits, and its relationship with membrane receptors MT1, MT2 and putative MT3. The results show a significant increase of the tear secretion, with a maximal effect at 60 min for the agonist with values of 138.9 ± 6.5 %, 128.9 ± 3.9 % and 120.0 ± 5.2 % respectively (p < 0.05), but not so for melatonin (101.6 ± 7.9%) (p > 0.05). Agonist action was tested combined with the antagonists (10 µl at 100 µM) DH97 (MT2 selective), prazosin (MT3 selective) and luzindole (non-selective MT1, MT2 and MT3), showed a different way of acting. DH97 reverses the effect of agomelatine, IIK7 and 5-MCA-NAT, obtaining a decrease of 108.1 ± 7.1 %, 20.9 ± 5.5 %, and 33 ± 6.3 % respectively (p < 0.05). Luzindole antagonizes agomelatine (71.6 ± 6.7 %) (p < 0.05) and 5MCA-NAT (27.9 ± 4.5 %) (p < 0.05). Prazosin only reverses the 5MCA-NAT action (35.8 ± 6.3 %) (p < 0.05). These results suggest that IIK7 possibly acts mainly through receptors MT2. Agomelatine may have a dual way of acting through MT2 and MT1 receptors and 5MCA-NAT acts through the three MTr receptors. Therefore, it can be said that the agomelatine, IIK7 and 5MCA-NAT act as secretagogues of tear secretion, acting through the receptors MTr and they could be considered excellent therapeutic candidates for dry eye treatment.SIGNIFICANCE STATEMENT Currently dry eye with aqueous deficit is treated by adding artificial tears palliatively. The study shows that the topical installation in therapeutic doses in rabbit corneas of three melatonin analogues: agomelatine, IIK7 and 5MCA-NAT, increases significantly the tear production, but not melatonin, acting through different melatonin membrane receptors subtypes (MTr). Therefore, this study suggests melatoninergic compounds could be considered excellent therapeutic candidates for dry eye treatment and ocular surface diseases occurring with a reduction in tear production.