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Potential Use in Glaucoma. Evidence from Animal Studies

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Potential Use in Glaucoma. Evidence from Animal Studies 5-Hydroxytryptamine1A N.N. OSBORNE, J.P.M. WOOD, J. MELENA, H.M. CHAO, M.S. NASH, agonists: potential use A.J. BRON, G. CHIDLOW in glaucoma. Evidence from animal studies Abstract retinal ganglion cells with large somata and large-diameter axons, which correspond to the Various classes of compounds exist to lower magnocellular visual pathway, may show an intraocular pressure (lOP) in the treatment of increased vulnerability, although this has been glaucoma. None of them is ideal since some questioned.3 One pOSSible cause of the death of patients respond better than others and the ganglion cells is mechanical damage and/ or side effects vary between individuals. New ischaemic damage to their axons at the level of classes of compounds need to be introduced to the lamina cribrosa induced by either elevated allow the clinician greater scope for effective intraocular pressure (lOP) or altered blood flow. treatment of all patients. It is now generally Another possible cause may be related to the agreed that the cause of ganglion cell finding that glutamate levels in the vitreous dysfunction in glaucoma is likely to be humour of glaucoma patients are elevated.4 multifactorial and that concentrating solely on This glutamate could have originated from an reducing lOP is inadequate. Irrespective of the injured retina, such as one that had experienced reason for the dysfunction, the future goal an ischaemic-like insult (hypoxia/ anoxia) must be to attenuate cell death. This may be l . An achieved with drugs that interact with caused by reduced blood flow or raised OP components of the retina, and is termed insult of this nature, which leads to the release 'neuroprotection'. Thus, drugs that can both of glutamate, would make retinal neurone-types reduce lOP and act as neuroprotectants would (ganglion cells and a subset of amacrine cells) be ideal for the treatment of glaucoma. In this that contain ionotropic glutamate receptors article we summarise studies on animals particularly vulnerable. Anatomical studies on which show serotonergic 5-HTIA agonists to retinas of glaucoma patients support the both reduce lOP when topically applied to the opinion that both ganglion cells and certain rabbit eye and blunt the damaging effect to the amacrine cells are particularly affected (see N.N. Osborne rat retina and ganglion cells induced by review by Osborne et aI.5). In experimental l.P.M. Wood glutamate toxicity or ischaemia. Reduction of ischaemia, glutamate is released from the l. Melena 6 7 lOP occurs via stimulation of 5-HT1A receptors retina • and causes destruction of ganglion and H.-M. Chao some amacrine cells.s The released glutamate M.S. Nash associated with the ciliary processes. Al. Bron Neuroprotection of retinal neurones appears to may well accumulate in the vitreous humour. G. Chidlow involve the interaction of 5-HT lA agonists Chronic glaucoma, for which the model is Nuffield Laboratory of with membrane sodium channels and/or primary open-angle glaucoma (POAG), is Ophthalmology 5-HT1A or even possibly 5-HT7 receptors. perhaps best defined as a heterogeneous group University of Oxford Oxford, UK Various 5-HTIA agonists are used in patients of disorders with a distinctive type of optic to treat depression, so classes of these drugs nerve damage and characteristic form of field NN Osborne � have a proven safety profile for use in patients. loss. The major causes of glaucoma are likely to Nuffield Laboratory of The animal studies summarised in this article be hypoxia/anoxia (affected ocular blood Ophthalmology suggest that 5-HT lA agonists need to be lOP. University of Oxford supply to optic nerve head) and/ or raised Walton Street considered as a new class of drugs for the Therefore, the ideal drug for treatment of Oxford OX2 6AW, UK treatment of glaucoma. glaucoma is a substance which, when topically Tel: +44 (0)1865 248996 applied, reduces raised lOP, facilitates ocular Fax: +44 (0)1865 794508 Key words Glaucoma, 5-HydroxytryptaminelA blood flow in the optic nerve head and protects e-mail 9 agonists, Intraocular pressure, Neuroprotection the retina from destruction. Experimental neville. [email protected] studies on animals now give us good reason to Financial support British believe that certain members of two classes of Council for the Prevention In chronic glaucoma the ganglion cells of the substances - l3-blockers (e.g. betaxolol) and of Blindness and the retina appear to die at a slow and variable rate. serotonin (5-hydroxytryptamine; 5-HT) 5-HT1A National Eye Research Anatomical and physiological studies of receptor agonists (e.g. 8-hydroxy-2-(di-N­ Centre. l.M. supported by a 1 Marie Curie grant glaucoma in humans and experimental propylamino)tetralin or 8-0H-DPAT and 2 (European Commission) glaucoma induced in monkeys suggest that flesinoxan) - may fulfil these criteria. Betaxolol 454 Eye (2000) 14, 454-463 © 2000 Royal College of Ophthalmologists Table 1. The concentration of biogenic amines in the human aqueous Table 3. Effects of various antagonists (1 pM) on the 5-HT (1 mM) humour induced accumulation of inositol phosphates (InsPs) in the rabbit iris-ciliary body Amine Concentration (ng/ml) Dopamine 0.2 % increase in InsPs accumulation Noradrenaline Agent relative to the effect of 5-HT Serotonin 50 5-HT 100 IS 5-HT + ketanserin 38 ± 8* From Martin et al. 5-HT + methysergide 57 + 6* 5-HT + cyproheptadine 90 ± 3 is already used to treat glaucoma patients and as a 5-HT + mianserin 66 ± 5* consequence our studies on the neuroprotective 5-HT + MDL 72222 80 ± 9 properties of betaxolol are of particular importance (for 5-HT + prazosin 80 ± 7 details see Osborne et aI.lO,ll). However, in this article our Data are mean ± SEM value for three or four experiments. A *p < 0.05 by Student's t-test when compared with 5-HT. studies on 5-HT l agonists will be summarised as they represent a new class of compounds for possible use in glaucoma. 5-HTIA agonists, such as buspirone and 8-0H-DPAT was originally thought to be a very selective ipsapirone, are presently used in the treatment of 5-HT lA agonist23 but subsequently has been shown to 12 24 depression. 8-0H-DPAT and flesinoxan are two of the have some affinity for the 5-HT7 receptor. 8-0H-DPAT most potent and selective 5-HTIA receptor agonists and when applied topically to the rabbit eye reduces lOP in 25 2 these drugs have proved invaluable in the study of both the light and dark. , 6 The full 5-HT1A agonist 5-HTIA receptor function. (+)8-0H-DPAT is a more effective hypotensive agent than the partial agonist (-)8-0H-DPAT (Fig. 3), and this result when taken with the finding that the effect of Serotonin receptors in the anterior uvea (±)8-0H-DPAT on lOP was blocked by pretreatment Indirect evidence suggests that some serotonergic nerves with pindolol, a mixed 5-HTIA antagonist/j3-blocker, but may exist in the iris-ciliary body of rabbits.13 More not by the specific j3-blocker betaxolol, suggests that compelling data show that serotonin is present in the 8-0H-DPAT lowers lOP via activating 5-HT1A receptors human14 and rabbit13 iris-ciliary body as well as the (Fig. 4).26 Recent studies with a number of 5-HTIA aqueous humour, where the concentration of the amine is agonists / cx l-adrenoceptor antagonists (e.g. flesinoxan, greater than that of noradrenaline (Table 1).15,16 Moreover, WB 4101) provide support for the view that 5-HTIA binding (Table 2) and secondary messenger studies (Table agonists reduce lOP. Flesinoxan is not only highly potent 3) on iris-ciliary body tissue from the rabbit suggests that but also a full agonist at 5-HT1A receptors, yet is a 13 17 7 5-HTIA and 5-HT2 receptors are present. , We have relatively weak arblocker? When applied topically to recently shown that mRNAs encoding the 5-HT lA and 5- the rabbit, it causes a dramatic reduction in lOP (Fig. 5). HT7 receptors are associated with the iris-ciliary body Confirmation that the effect involves 5-HTIA receptors complex of the rabbit and that the 5-HTIA receptors are was obtained by use of 5-HTIA antagonists, which primarily associated with the epithelial cell bilayer of the partially nullify the lOP response of the rabbits to ciliary processes (Figs. 1, 2).18 Studies on the isolated flesinoxan (unpublished observations). human iris-dliary body complex also support the Studies with ketanserin also suggest that antagonists of 19 existence of 5-HT1-type receptors and our preliminary 5-HT2 receptors, when applied topically, can lower lOP. experiments indicate that the mRNA which encodes the 5- For example, topically applied ketanserin lowers lOP in the 21 2 29 HTIA receptor is present (unpublished data). rabbit and in man. 8, It should, however, be borne in mind that ketanserin is known to have an affinity for CXl­ adrenoceptors27 and for this reason the effects of ketanserin lOP Effect of serotonergic drugs on on lOP may not be entirely caused by its effect on 5-HT2 Topical application of 5-HT has been reported to both receptors. Additional studies need to be conducted with elevate2D and lower21 lOP in rabbits. In addition, specific 5-HT 2 ligands to clarify the situation. 5-methyl-urapidil (a combined 5-HT1A agonist/ 22 cxl-adrenoceptor antagonist) reduces rabbit IOP. Serotonin receptors in the retina The evidence for serotonin being a neurotransmitter in Table 2. Apparent affinity values (K) of various drugs for eHJ5-HT the mammalian retina (as opposed to the non­ binding to 5-HT1A receptor sites in rabbit iris-ci/iary body membranes mammalian retina) remains a matter of debate because Ki Ligand value (M) there is a lack of clear data showing the existence of 1 DP-5-CT 2.5 X 10- 0 serotonergic neurones?D,31 However, numerous studies MDL 73005EF 3.3 X 10-10 1 have shown serotonin receptors to be associated with 5-CT 4.9 X 10- 0 9 5-HT 2.5 X 10- mammalian retinas.
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