Cyclosporin A Increases Tear Fluid Secretion via Release of Sensory Neurotransmitters and Muscarinic Pathway in Mice

doi:10.1006/exer.1998.0619

Experimental Eye Research

Volume 68, Issue 5, May 1999, Pages 541-546

https://doi.org/10.1006/exer.1998.0619 Get rights and content

Abstract

Cyclosporin A, an immunosuppressant, has the potential to increase tear fluid secretion through mechanisms which are not yet well understood. To gain insight into this question, we investigated the effect of cyclosporin A containing eyedrops on lacrimation in normal mice. Topical application of 0.1% cyclosporin A eyedrops for 3 days significantly increased lacrimation. This response was completely blocked by pre-exposure to 1% capsaicin. Immunohistochemical analysis revealed that capsaicin treatment depleted substance P from the lacrimal gland. Furthermore, following 1% atropine treatment, which completely blocks pilocarpine-stimulated (500 μg kg⁻¹, i.p.) lacrimation, application of 0.1% cyclosporin A eyedrops significantly increased lacrimation. However, this increase was less than the response seen with 0.1% cyclosporin A in the absence of atropine. Interestingly, substance P-induced tear secretion was also partially inhibited in atropine treated mice. These results suggest that cyclosporin A accelerates tear secretion by releasing neurotransmitters from sensory nerve endings which interacts with the parasympathetic nerves.

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In vivo characterisation of a novel water-soluble Cyclosporine A prodrug for the treatment of dry eye disease
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CsA is also known to take part in the inhibition of the c-Jun N-terminal kinases (JNK) and p38 signalling pathways involved in the activation of T cells [9]. In addition, CsA participates in the stimulation of apoptosis of the T cells that are already in an activated state [10], and it contributes to the enhancement of the release of a neurotransmitter, substance P, from the sensory nerves directing a stimulating interaction with the parasympathetic nerves [11,12]. Once in contact with the eye, CsA leads to a decrease in inflammation and an increase of the lachrymal production, both effects being highly beneficial for the treatment of DED.
Cyclosporine A (CsA) has been demonstrated to be effective for the treatment of a variety of ophthalmological conditions, including ocular surface disorders such as the dry eye disease (DED). Since CsA is characterised by its low water solubility, the development of a topical ophthalmic formulation represents an interesting pharmaceutical question. In the present study, two different strategies to address this challenge were studied and compared: (i) a water-soluble CsA prodrug formulated within an aqueous solution and (ii) a CsA oil-in-water emulsion (Restasis®, Allergan Inc., Irvine, CA). First, the prodrug formulation was shown to have an excellent ocular tolerance as well as no influence on the basal tear production; maintaining the ocular surface properties remained unchanged. Then, in order to allow in vivo investigations, a specific analytical method based on ultra high pressure liquid chromatography coupled with triple quadrupole mass spectrometer (UHPLC–MS/MS) was developed and optimised to quantify CsA in ocular tissues and fluids. The CsA ocular kinetics in lachrymal fluid for both formulations were found to be similar between 15 min and 48 h. The CsA ocular distribution study evidenced the ability of the prodrug formulation to penetrate into the eye, achieving therapeutically active CsA levels in tissues of both the anterior and posterior segments. In addition, the detailed analysis of the in vivo data using a bicompartmental model pointed out a higher bioavailability and lower elimination rate for CsA when it is generated from the prodrug than after direct application as an emulsion. The interesting in vivo properties displayed by the prodrug solution make it a safe and suitable option for the treatment of DED.
Immunopathogenesis of Keratoconjunctivitis Sicca in the Dog
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It is at that stage that parotid duct transposition is the only effective therapeutic way forward [37]. The original hypothesis that the lacrimomimetic effect of cyclosporine is through a local immunosuppressant is called into question by its lacrimogenic effects in dogs without cKCS, in which tear production is increased [33], and by experimental studies on neuromodulatory effects [38], which are discussed further elsewhere in this article. Other work on dogs rendered lacrimally deficient by removal of the NMG and the MLG demonstrated that the drug has effects on mucus production and the ocular surface separate from those on aqueous secretion [39].
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The aim of this study was to present morphological and functional evidence to evaluate whether tear secretion is influenced by neuropeptides released from sensory nerve endings of the conjunctiva. Following unilateral electrical stimulation of the trigeminal ganglion, tears were collected at both sides and assessed for volume and protein concentration; as well as gel electrophoresis and luminol chemiluminescence with immunostaining to immunoglobulin A and lysozyme measurements. Goblet cell density (goblet cells/100 basal cells) was recorded during histopathological examination of removed lids. Rats were pretreated with atropine to block parasympathetic; guanethidine to block sympathetic neuronal pathways; or hexamethonium to block synaptic transmission in ganglia. Capsaicin was used to deplete neurotransmitters from sensory nerve endings or SR140333 to block substance P tachykinin NK1 receptor mediated responses. Effects of inadequate electrode position or incidental lesion of trigeminal ganglion were examined by placing the electrode in false position, or no stimulation at a correct position. Electrical stimulation resulted in 380% increase of tear secretion (p < 0.001) and 30% decrease of goblet cell density (p < 0.001) on the the stimulated side compared to the unstimulated side. Atropine, guanethidine and hexamethonium pretreatments had no effect (p > 0.05), but capsaicin and SR140333 inhibited the effect of stimulation (by 96% and 72%, respectively, p < 0.001). Inadequate stimulation did not increase the tear secretion (p < 0.05). Protein concentration decreased, whilst tear volume and total secreted protein increased (p < 0.005) after stimulation. Electrophoresis showed no difference in protein pattern between stimulated and control side and analysis of equivalent amount of tear protein with luminol chemiluminescence indicated no difference in immunoglobulin A and lysozyme ratio following stimulation (p > 0.05). We conclude that antidromic electrical activation of conjunctival sensory nerve endings significantly increases water, mucus and protein phases of tear. It is suggested that the sensory neuropeptide substance P plays a pivotal role in this neurogenic regulatory mechanism.
Current advances in dry eye disease diagnosis and treatment
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The Potential of Stem Cells as Treatment for Ocular Surface Diseases
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^f1: Corresponding author: Tsutomu Fujihara, 8916-16 Takayama-cho, Ikoma-shi, Nara, 630-0101, Japan.

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Regular articleCyclosporin A Increases Tear Fluid Secretion via Release of Sensory Neurotransmitters and Muscarinic Pathway in Mice

Abstract

J. Biol. Chem.

Eur. J. Pharmacol.

J. Biol. Chem.

Ophthalmol

Jap. J. Ophthalmol.

J. Auton. Nerv. Syst.

Secretory responses and peptidergic and aminergic innervation of the rat lacrimal gland

Biogenic Amines

Cyclosporine: a new immunosuppressive agent for organ transplantation

Ann. Intern. Med.

Role of cyclic AMP and Ca2+in potentiation of rat lacrimal gland protein secretion

Invest. Ophthalmol. Vis. Sci.

Modulation of cortical acetylcholine release by serotonin: the role of substance P interneurons

Naunyn-Schmiedeberg's Arch. Pharmacol.

Reduction of capsaicin-induced ocular pain and neurogenic inflammation by calcium antagonists

Invest. Ophthalmol. Vis. Sci.

Topical cyclosporin treatment of keratoconjunctivitis sicca in secondary Sjögren's syndrome

Acta Ophthalmol.

Ultrastructure of the corneal nerves in the rat

Cell Tiss.

Regular article
Cyclosporin A Increases Tear Fluid Secretion via Release of Sensory Neurotransmitters and Muscarinic Pathway in Mice

Role of cyclic AMP and Ca²⁺in potentiation of rat lacrimal gland protein secretion