Modulation of α‐adrenoceptor signalling protects photoreceptors after retinal detachment by inhibiting oxidative stress and inflammation

Abstract

Background and Purpose Currently available treatments do not halt progression of photoreceptor death and subsequent visual impairment related to retinal detachment (RD) which is observed in various retinal disorders. This study investigated the neuroprotective effects of two adrenoceptor ligands, the α1‐adrenoceptor antagonist doxazosin and the α2‐adrenoceptor agonist guanabenz, against photoreceptor cell death in RD. Experimental Approach We used a model of experimental RD in Brown‐Norway rats induced by subretinal injection of sodium hyaluronate. Oxidative stress biomarkers and cytokine production were quantified with elisa. Protein expression levels and immunofluorescent labelling were determined in rats with RD and controls for mechanistic elucidation. The effects of systemic (i.p.) administration of doxazosin or guanabenz on photoreceptor apoptosis, retinal histology and electroretinography were evaluated in rats with RD and compared to the effects in vehicle controls. Key Results Photoreceptors were the major source of RD‐induced ROS overproduction in the rat retina through the regulation of NADPH oxidase. Systemic administration of doxazosin or guanabenz decreased the RD‐induced production of ROS and proinflammatory cytokines, including IL‐1β and the chemokine CCL2, and suppressed retinal gliosis, resulting in attenuation of photoreceptor death and preservation of retinal structures and functions in RD. Conclusions and Implications Our findings point to α‐adrenoceptors as novel therapeutic targets to provide photoreceptor protection and suggest that both doxazosin and guanabenz, two FDA‐approved drugs, could be further explored to treat retinal diseases.

Blockade of Adenosine A2A Receptor Protects Photoreceptors after Retinal Detachment by Inhibiting Inflammation and Oxidative Stress

“…Recent studies have shown that RIP kinase-mediated necrotic signaling [ 69 ] and FAS-mediated apoptosis pathway [ 70 ] contribute to photoreceptor death after RD. However, accumulating evidence suggests that the rapid increase of oxidative stress is currently considered to be a critical event for irreversible cellular damage in RD [ 14 ]. Previous studies have demonstrated an increased generation of ROS after RD, whereas photoreceptor cell death can be prevented after RD by suppressing ROS [ 71 , 72 ].…”

“…Concurrent with this, previous studies have demonstrated that microglia A 2A R blockade suppresses elevated pressure-induced oxidative stress in retina [ 32 ]. Furthermore, modulation of α -adrenoceptor signaling protects photoreceptors from apoptosis after RD by inhibiting ROS production [ 14 ]. In our work, we showed that ZM241385 was able to prevent photoreceptor loss from ROS overproduction triggered after RD, further reinforcing its role in controlling retinal neuroinflammation.…”

“…Müller cells are central to the pathophysiology of RD, being involved in gliosis, initiation of inflammatory cascades, and proliferative responses [ 11 ]. Increased levels of proinflammatory mediator, IL-1 β , are found in the retina and aqueous humor of RD patients and experimental RD [ 8 , 12 – 14 ]. Excessive generation of ROS and the consequent induction of oxidative stress are one of the critical factors that trigger cellular response to RD [ 15 ] and are also a major cytotoxic factor for photoreceptor apoptosis [ 9 , 16 ].…”

Neuroprotective Potential of Ginkgo biloba in Retinal Diseases

“…Similarly, Murakami et al [86] conducted a study on photoreceptor cell death and RD, and considered that a better understanding of the molecular mechanisms related to the death of these cells would allow new therapies to be developed to prevent vision deficits due to loss of photoreceptor cells. According to Li et al [87], currently, no effective therapy is clinically available to protect photoreceptor cells. Therefore, the development of neuroprotective reagents for photoreceptors could contribute to long-term visual stability for postoperative RD patients.…”

TRPML1 Inhibited Photoreceptor Apoptosis and Protected the Retina by Activation of Autophagy in Experimental Retinal Detachment

“…Reactive oxygen species (ROS) are mainly derived from the respiration of mitochondria [25]. Recent studies in the ophthalmology field found that photoreceptors were the main source of ROS production in an experimental RD rat model [26] and that excess ROS led to photoreceptor cell death [11]. Coincidentally, TRPML1 was demonstrated to remove excess ROS and ROS accumulated in both a TRPML1 knockdown (KD) cell line and a skin fibroblast cell line from an MLIV patient [21, 27].…”