Development of aldose reductase inhibitors for the treatment of inflammatory disorders

Introduction: Accumulating evidence attributes a significant role to aldose reductase (ALR2) in the pathogenesis of several inflammatory pathologies. Aldose reductase inhibitors (ARIs) were found to attenuate reactive oxygen species (ROS) production both in vitro and in vivo. Thus, they disrupt signaling cascades that lead to the production of cytokines/chemokines, which induce and exacerbate inflammation. As a result, ARIs might hold a significant therapeutic potential as alternate anti-inflammatory drugs. Areas covered: The authors present a comprehensive review of the current data that support the central role of ALR2 in several inflammatory pathologies (i.e., diabetes, cancer, sepsis, asthma and ocular inflammation). Further, the authors describe the potential underlying molecular mechanisms and provide a commentary on the status of ARIs in this field. Expert opinion: It is important that future efforts focus on delineating all the steps of the molecular mechanism that implicates ALR2 in inflammatory pathologies. At the same time, utilizing the previous efforts in the field of ARIs, several candidates that have been proven safe in the clinic may be evaluated for their clinical significance as anti-inflammatory medication. Finally, structurally novel ARIs, designed to target specifically the proinflammatory subpocket of ALR2, should be pursued.