Study of the single or combined action of three different neuroprotection strategies in an acute hypertension model in mice

Abstract

Aims/Purpose: To study the neuroprotective effects of a TrkB receptor activator (DHF), a calcium channel blocker that prevents Ca2+ toxic influx (ITH12657) and/or a P2X7 receptor blocker (ITH15004) administered alone or in combination in an animal model of acute ocular hypertension (AOHT).Methods: Pigmented adult mice (C57BL/6 strain) were separated into 9 experimental groups (n = 8 per group), 7 received intraperitoneal injections of the neuroprotective drugs alone or in combination, 1 received saline as the vehicle group and 1 was naïve. AOHT was performed by connecting the anterior chamber of the left eye to a bottle of saline at a height of 130 cm achieving an intraocular pressure of 97 mmHg for 60 min. Longitudinally in vivo analysis of the pSTR amplitude and the inner retinal thickness was measured by electroretinogram and SD‐OCT, respectively; and ex vivo analysis of the retinal ganglion cell population was identified immunohistochemically by Brn3a at 7 after AOHT in all experimental groups.Results: The neuroprotectant treatment administered alone had a beneficial effect on the pSTR wave response amplitude (50–60% amplitude response) compared to vehicles (⁓25% amplitude response), which increased in all treatment combinations (⁓75%) except for ITH12657+ ITH15004 at 7 days after AOHT. Similar results were obtained in the inner retinal thickness, with the combined treatments producing a better retinal response after 7 days of AOHT, particularly for DHF + ITH15004 and DHF + ITH12657 + ITH15004 which showed no difference compared to control thicknesses. Regarding the RGC population, all treatments had a neuroprotective effect (⁓70% population survival at 7 days) compared to vehicles (⁓40%) which was not increased by their combination.Conclusions: The single or combined action of three different neuroprotective strategies results in functional and morphological protection of the retina 7 days after AOHT.