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Pharmacological Blockade of LPAR1 Does Not Provide Neuroprotection in a Rat Model of Ocular Hypertensive Glaucoma

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Title: Pharmacological Blockade of LPAR1 Does Not Provide Neuroprotection in a Rat Model of Ocular Hypertensive Glaucoma
Authors: Kocherlakota, Sai, Nicol, Alan, Locri, Filippo, Stebbins, Karin J, Lorrain, Daniel S, Tribble, James R, Williams, Pete A
Source: Kocherlakota, S, Nicol, A, Locri, F, Stebbins, K J, Lorrain, D S, Tribble, J R & Williams, P A 2026, 'Pharmacological Blockade of LPAR1 Does Not Provide Neuroprotection in a Rat Model of Ocular Hypertensive Glaucoma', Translational Vision Science and Technology, vol. 15, no. 1, 11. https://doi.org/10.1167/tvst.15.1.11
Publication Year: 2026
Collection: King's College, London: Research Portal
Subject Terms: Animals, Ocular Hypertension/drug therapy, Receptors, Lysophosphatidic Acid/antagonists & inhibitors, Rats, Disease Models, Animal, Intraocular Pressure/drug effects, Retinal Ganglion Cells/drug effects, Glaucoma/drug therapy, Male, Neuroprotective Agents/pharmacology, Neuroprotection/drug effects, Sprague-Dawley, Cell Survival/drug effects
Description: PURPOSE: Current treatment strategies for glaucoma, the leading cause of irreversible blindness, only target intraocular pressure (IOP) but not the underlying retinal ganglion cell degeneration. IOP management is not always effective, necessitating neuroprotective strategies. Lysophosphatidic acid (LPA) is an extracellular signaling molecule implicated in modulating inflammation. It exerts its signaling effects through its receptors (LPAR1-6). Here we test the efficacy of PIPE-791, an LPAR1-selective antagonist, in conferring neuroprotection and modulating neuroinflammation in glaucoma. METHODS: A bead-induced rat ocular hypertension (OHT) model of glaucoma was used to test PIPE-791 (administered intraperitoneally at 3 mg/kg dosing). We monitored IOP through tonometry and evaluated PIPE-791's neuroprotective capacity by studying retinal ganglion cell survival using cell counting and its effects on retinal vasculature, immune cell numbers and cytokine profile. RESULTS: PIPE-791 had no effect on IOP in normotensive (NT) or OHT rat eyes. It also did not have any neuroprotective effect on retinal ganglion cell survival, nor did it normalize the changes in retinal vasculature observed in OHT retinas. Although PIPE-791 treatment increased microglial numbers in NT retinas, there was no effect in OHT retinas. Cytokine array profiling also revealed no significant effects for PIPE-791 on the cytokine changes between the NT and OHT retinas. These lack of changes could potentially be explained by the fact that LPAR1 protein levels are decreased in OHT retinas. CONCLUSIONS: Our data suggests that targeting LPAR1 through pharmacological means does not provide neuroprotection or modulate neuroinflammation favorably in glaucoma. TRANSLATIONAL RELEVANCE: Our study provides evidence that pharmacological targeting of LPAR1 as a potential therapeutic avenue in glaucoma may not be beneficial.
Document Type: article in journal/newspaper
File Description: application/pdf
Language: English
Relation: info:eu-repo/semantics/altIdentifier/pmid/41533855
DOI: 10.1167/tvst.15.1.11
Availability: https://kclpure.kcl.ac.uk/portal/en/publications/d9b97cd7-ff9f-4bd5-85ea-2efd6da16a5b
https://doi.org/10.1167/tvst.15.1.11
https://kclpure.kcl.ac.uk/ws/files/363026969/Pharmacological_Blockade_of_LPAR1_Does_Not_Provide_Neuroprotection_Version_of_Record.pdf
https://www.scopus.com/pages/publications/105027617972
Rights: info:eu-repo/semantics/openAccess ; http://creativecommons.org/licenses/by-nc-nd/4.0/
Accession Number: edsbas.6A2AF93
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  Data: Pharmacological Blockade of LPAR1 Does Not Provide Neuroprotection in a Rat Model of Ocular Hypertensive Glaucoma
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  Data: <searchLink fieldCode="AR" term="%22Kocherlakota%2C+Sai%22">Kocherlakota, Sai</searchLink><br /><searchLink fieldCode="AR" term="%22Nicol%2C+Alan%22">Nicol, Alan</searchLink><br /><searchLink fieldCode="AR" term="%22Locri%2C+Filippo%22">Locri, Filippo</searchLink><br /><searchLink fieldCode="AR" term="%22Stebbins%2C+Karin+J%22">Stebbins, Karin J</searchLink><br /><searchLink fieldCode="AR" term="%22Lorrain%2C+Daniel+S%22">Lorrain, Daniel S</searchLink><br /><searchLink fieldCode="AR" term="%22Tribble%2C+James+R%22">Tribble, James R</searchLink><br /><searchLink fieldCode="AR" term="%22Williams%2C+Pete+A%22">Williams, Pete A</searchLink>
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  Data: Kocherlakota, S, Nicol, A, Locri, F, Stebbins, K J, Lorrain, D S, Tribble, J R & Williams, P A 2026, 'Pharmacological Blockade of LPAR1 Does Not Provide Neuroprotection in a Rat Model of Ocular Hypertensive Glaucoma', Translational Vision Science and Technology, vol. 15, no. 1, 11. https://doi.org/10.1167/tvst.15.1.11
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  Data: 2026
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  Data: <searchLink fieldCode="DE" term="%22Animals%22">Animals</searchLink><br /><searchLink fieldCode="DE" term="%22Ocular+Hypertension%2Fdrug+therapy%22">Ocular Hypertension/drug therapy</searchLink><br /><searchLink fieldCode="DE" term="%22Receptors%22">Receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Lysophosphatidic+Acid%2Fantagonists+%26+inhibitors%22">Lysophosphatidic Acid/antagonists & inhibitors</searchLink><br /><searchLink fieldCode="DE" term="%22Rats%22">Rats</searchLink><br /><searchLink fieldCode="DE" term="%22Disease+Models%22">Disease Models</searchLink><br /><searchLink fieldCode="DE" term="%22Animal%22">Animal</searchLink><br /><searchLink fieldCode="DE" term="%22Intraocular+Pressure%2Fdrug+effects%22">Intraocular Pressure/drug effects</searchLink><br /><searchLink fieldCode="DE" term="%22Retinal+Ganglion+Cells%2Fdrug+effects%22">Retinal Ganglion Cells/drug effects</searchLink><br /><searchLink fieldCode="DE" term="%22Glaucoma%2Fdrug+therapy%22">Glaucoma/drug therapy</searchLink><br /><searchLink fieldCode="DE" term="%22Male%22">Male</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroprotective+Agents%2Fpharmacology%22">Neuroprotective Agents/pharmacology</searchLink><br /><searchLink fieldCode="DE" term="%22Neuroprotection%2Fdrug+effects%22">Neuroprotection/drug effects</searchLink><br /><searchLink fieldCode="DE" term="%22Sprague-Dawley%22">Sprague-Dawley</searchLink><br /><searchLink fieldCode="DE" term="%22Cell+Survival%2Fdrug+effects%22">Cell Survival/drug effects</searchLink>
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  Data: PURPOSE: Current treatment strategies for glaucoma, the leading cause of irreversible blindness, only target intraocular pressure (IOP) but not the underlying retinal ganglion cell degeneration. IOP management is not always effective, necessitating neuroprotective strategies. Lysophosphatidic acid (LPA) is an extracellular signaling molecule implicated in modulating inflammation. It exerts its signaling effects through its receptors (LPAR1-6). Here we test the efficacy of PIPE-791, an LPAR1-selective antagonist, in conferring neuroprotection and modulating neuroinflammation in glaucoma. METHODS: A bead-induced rat ocular hypertension (OHT) model of glaucoma was used to test PIPE-791 (administered intraperitoneally at 3 mg/kg dosing). We monitored IOP through tonometry and evaluated PIPE-791's neuroprotective capacity by studying retinal ganglion cell survival using cell counting and its effects on retinal vasculature, immune cell numbers and cytokine profile. RESULTS: PIPE-791 had no effect on IOP in normotensive (NT) or OHT rat eyes. It also did not have any neuroprotective effect on retinal ganglion cell survival, nor did it normalize the changes in retinal vasculature observed in OHT retinas. Although PIPE-791 treatment increased microglial numbers in NT retinas, there was no effect in OHT retinas. Cytokine array profiling also revealed no significant effects for PIPE-791 on the cytokine changes between the NT and OHT retinas. These lack of changes could potentially be explained by the fact that LPAR1 protein levels are decreased in OHT retinas. CONCLUSIONS: Our data suggests that targeting LPAR1 through pharmacological means does not provide neuroprotection or modulate neuroinflammation favorably in glaucoma. TRANSLATIONAL RELEVANCE: Our study provides evidence that pharmacological targeting of LPAR1 as a potential therapeutic avenue in glaucoma may not be beneficial.
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  Data: 10.1167/tvst.15.1.11
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  Data: https://kclpure.kcl.ac.uk/portal/en/publications/d9b97cd7-ff9f-4bd5-85ea-2efd6da16a5b<br />https://doi.org/10.1167/tvst.15.1.11<br />https://kclpure.kcl.ac.uk/ws/files/363026969/Pharmacological_Blockade_of_LPAR1_Does_Not_Provide_Neuroprotection_Version_of_Record.pdf<br />https://www.scopus.com/pages/publications/105027617972
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        Value: 10.1167/tvst.15.1.11
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