The effects of topical aqueous sirolimus on tear production in normal dogs and dogs with refractory dry eye

Spatola, Ronald A.; Nadelstein, Brad; Berdoulay, Andrew; English, Robert V.

doi:10.1111/vop.12503

Cited by 10 publications

(6 citation statements)

References 65 publications

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“…In fact, topical formulations of RAP are currently used for the treatment of various ocular disorders in humans and other animals. In particular, it is effective in the treatment of keratoconjunctivitis sicca, a very common disease in dogs, by stimulating tear production (Spatola et al, 2018). In this study, tear production was also increased in control animals, suggesting that the drug has direct lacrimostimulant properties, independently of its anti-inflammatory and immunosuppressive activity.…”

Section: Discussionmentioning

confidence: 99%

“…Everolimus (RAD001), a derivative of rapamycin with improved water solubility, is an FDA approved drug for the treatment of various solid tumors, including neuroendocrine tumors, breast cancer, renal cell carcinoma and subependymal giant cell astrocytoma (reviewed by Li et al, 2014; Seto, 2012). Topical application of rapamycin is beneficial in ocular inflammatory disorders, including dry eye disease (Spatola et al, 2018). In addition, rapamycin has been used extensively as a research tool (reviewed by Kunz & Hall, 1993).…”

Section: Introductionmentioning

confidence: 99%

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The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

Arcas,

Oudaha,

González

et al. 2024

Preprint

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Background and Purpose The mechanistic target of rapamycin (mTOR) signaling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin (RAP), a specific inhibitor of mTOR, has immunosuppressive, anti-inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that RAP may also have agonist activity on TRPM8. Experimental approach Using calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or Trpm8 KO mouse DRG neurons, we characterized RAP effects on TRPM8. We also examined the effects of RAP on tearing in mice. Key Results Micromolar concentrations of RAP activate rat and mouse TRPM8 directly and potentiate cold-evoked responses. These effects were also observed in human TRPM8. In cultured mouse DRG neurons, RAP evoked an increase in intracellular calcium almost exclusively in cold-sensitive neurons. Responses were drastically blunted in Trpm8 KO mice or by TRPM8 antagonists. Cutaneous cold thermoreceptor endings were also activated by RAP. Topical application of RAP to the eye surface evokes tearing in mice by a TRPM8-dependent mechanism. Conclusion and implications These results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant RAP. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, RAP could be used as an experimental tool in the clinic to explore cold thermoreceptors.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

Arcas,

Oudaha,

González

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Everolimus (RAD001), a derivative of rapamycin with improved water solubility, is an FDA approved drug for the treatment of various solid tumours, including neuroendocrine tumours, breast cancer, renal cell carcinoma and sub‐ependymal giant cell astrocytoma (see Li et al, 2014; Seto, 2012). Topical application of rapamycin is beneficial in ocular inflammatory disorders, including dry eye disease (Spatola et al, 2018). In addition, rapamycin has been used extensively as a research tool (see Kunz & Hall, 1993).…”

Section: Introductionmentioning

confidence: 99%

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

Arcas,

Oudaha,

González

et al. 2024

British J Pharmacology

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Background and PurposeThe mechanistic target of rapamycin (mTOR) signalling pathway is a key regulator of cell growth and metabolism. Its deregulation is implicated in several diseases. The macrolide rapamycin, a specific inhibitor of mTOR, has immunosuppressive, anti‐inflammatory and antiproliferative properties. Recently, we identified tacrolimus, another macrolide immunosuppressant, as a novel activator of TRPM8 ion channels, involved in cold temperature sensing, thermoregulation, tearing and cold pain. We hypothesized that rapamycin may also have agonist activity on TRPM8 channels.Experimental ApproachUsing calcium imaging and electrophysiology in transfected HEK293 cells and wildtype or Trpm8 KO mouse DRG neurons, we characterized rapamycin’s effects on TRPM8 channels. We also examined the effects of rapamycin on tearing in mice.Key ResultsMicromolar concentrations of rapamycin activated rat and mouse TRPM8 channels directly and potentiated cold‐evoked responses, effects also observed in human TRPM8 channels. In cultured mouse DRG neurons, rapamycin increased intracellular calcium levels almost exclusively in cold‐sensitive neurons. Responses were markedly decreased in Trpm8 KO mice or by TRPM8 channel antagonists. Cutaneous cold thermoreceptor endings were also activated by rapamycin. Topical application of rapamycin to the eye surface evokes tearing in mice by a TRPM8‐dependent mechanism.Conclusion and ImplicationsThese results identify TRPM8 cationic channels in sensory neurons as novel molecular targets of the immunosuppressant rapamycin. These findings may help explain some of its therapeutic effects after topical application to the skin and the eye surface. Moreover, rapamycin could be used as an experimental tool in the clinic to explore cold thermoreceptors.

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“…The treatment aims to reestablish tear production, avoiding the complications of KCS . Alternative and supporting treatments have been sought to achieve better overall results, for use in refractory cases, and to reduce costs and improve owner compliance with treatment …”

Section: Introductionmentioning

confidence: 99%

“…13,18,[24][25][26]33 Alternative and supporting treatments have been sought to achieve better overall results, for use in refractory cases, and to reduce costs and improve owner compliance with treatment. 37,38 Oclacitinib is a novel drug for the treatment of pruritus related to allergic skin diseases and atopic dermatitis in dogs. 43 It is a janus kinase (JAK) inhibitor, with JAK1 selectivity, and is well tolerated by dogs.…”

Section: Introductionmentioning

confidence: 99%

Comparative efficacy of topical oclacitinib 0.1% and tacrolimus 0.01% in canine keratoconjunctivitis sicca

Oliveira

Williams

Bollmann

et al. 2019

Veterinary Ophthalmology

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Objective To assess the efficacy of 0.1% oclacitinib as a single agent, and in combination with tacrolimus 0.01%, for the control of ophthalmic signs of keratoconjunctivitis sicca (KCS) in dogs. Animals studied Thirty‐two dogs (57 eyes) diagnosed with idiopathic KCS were included. Inclusion criteria were Schirmer Tear Test 1 (STT‐1) values <15 mm/min and concurrent clinical signs such as ocular hyperemia and discharge. Procedures The animals were submitted to a randomized, open‐label, 5‐week study and divided into 3 treatment groups treated with the following ophthalmic solutions: (a) 0.1% oclacitinib, (b) 0.1% oclacitinib +0.01% tacrolimus, and (c) 0.01% tacrolimus. Eye drops were instilled twice daily (12‐hour intervals). At each follow‐up examination, STT‐1, clinical signs, and potential drug side effects were assessed. Results Oclacitinib did not significantly improve STT‐1 values or clinical scores. Tacrolimus alone and in combination with oclacitinib increased mean STT‐1 values by 11.84 ± 5.2 and 12.46 ± 5.3 mm/min, respectively (P = 0.0001). Clinical scores of ocular discharge and hyperemia also improved significantly in both groups receiving treatment with tacrolimus (P < 0.05). However, addition of oclacitinib to tacrolimus provided no additional improvement over tacrolimus alone. Conclusions Topical 0.1% oclacitinib twice daily is not effective in controlling the ocular signs of KCS in dogs. 0.01% tacrolimus increased STT‐1 values significantly and could potentially be used as a treatment for mild‐to‐moderate cases of KCS. Synergism between drugs did not occur, and therefore the use of oclacitinib is not justified in cases of canine KCS.

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The effects of topical aqueous sirolimus on tear production in normal dogs and dogs with refractory dry eye

Abstract: Topical 0.02% sirolimus might be an alternative treatment for canine patients with keratoconjunctivits sicca. The drug appears safe when applied topically in an aqueous suspension for up to 6 weeks. While initial results are promising, further studies are warranted.

Cited by 10 publications

References 65 publications

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

The ion channel TRPM8 is a direct target of the immunosuppressant rapamycin in primary sensory neurons

Comparative efficacy of topical oclacitinib 0.1% and tacrolimus 0.01% in canine keratoconjunctivitis sicca

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