Abstract
Purpose :
Adiponectin (ADPN) receptor agonists have been shown to have a therapeutic effect on dry eye disease (DED) due to their anti-inflammatory and wound healing properties. ADPN was recently reported to suppress sensory hypersensitivity and peripheral neuropathic pain. SL100 was developed as a small synthetic molecule agonist of the ADPN receptor 1/2. The effects of SL100 on neurogenesis and electrophysiology in ex vivo neuronal settings, as well as its therapeutic effect in DED animal models, were investigated.
Methods :
Animal models of DED were induced by desiccating-stress or corneal alkali (NaOH) burn to compare the efficacy of topical SL100 (0.3% & 1% solution) with cyclosporin A (0.05% solution), and corneal staining and immune cell infiltration were analyzed. The effect of SL100 (10 μM) on neurite outgrowth in the neuroblastoma cell line SH-SY5Y was studied. In primary cultured mouse neurons, the effect of SL100 (10 M) on patch clamp recordings and calcium imaging was investigated (DIV 14 days).
Results :
Topical SL100 (1 %) effectively improved the ocular staining and inflammation markers in the DED (p<0.001) or alkali burn (p<0.001) models compared with vehicle, with efficacy compable to cyclosporin A (0.05 %). SL100 significantly improved neurite outgrowth of SH-SY5Y (length of neurite, n=400, p<0.001), whereas cyclosporin A turned out to suppress the neurite outgrowth (p<0.001). The anayses of neuronal action potential and calcium influx are under progress and the final data will be presented later on.
Conclusions :
In the DED animal models, SL100 demonstrated significant efficacy, most likely due to its anti-inflammatory and wound healing properties. However, recent clinical trials of DED drug candidates revealed that there is little correlation between clinical signs and subjective symptoms, implying that a new DED drug is required to improve both corneal surface markers and discomfort. According to preliminary data, SL100 appears to have neuromodulatory effects in addition to its homeostatic effects, such as promoting neurogenesis and suppressing hypersensitivity. Although it needs to be validated in an appropriate animal model. If confirmed, SL100 has a potential as a new DED treatment that could address both corneal signs and subjective symptoms.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.