Role of SERCA and AQP-5 in Diabetes Mellitus-Induced Xerostomia in Adult Male Albino Rat and The Potential Therapeutic Effect of Aldose Reductase Inhibitors: Histological Study.

Background: Saliva plays essential roles in different biological processes. Autonomic receptors stimulation is the main regulator of its secretion. Ca2+ acts as a 2nd messenger via increasing its cytoplasmic-level (i-Ca2+) &decreasing its endoplasmic reticulum-level (ER-Ca2+) with subsequent protein synthesis as a-amylase and water flow through aquaporin-5 channels (AQP-5). Sarco-ER Ca2+-ATPase (SERCA) pumps i-Ca2+ back to ER-Ca2+ maintaining low i-Ca2+ during rest and allowing its increase during salivary activation. Polyol-pathway overactivity with biological molecules glycation and oxidative-stress is the main mechanism of diabetic complications as xerostomia. As aldose-reductase (AR) is its key-enzyme, multiple ARinhibitors (ARIs) were newly explored to cure diabetic complications. Aim of work: Investigating SERCA &AQP-5 roles in diabetes-induced xerostomia molecular mechanism in adult male albino rats &the potential ARIs therapeutic effect. Materials &Methods: 32 rats were divided into 2 groups: control &experimental [received 55mg/kg streptozotocin to induce diabetes]. 18 hyperglycemic rats were divided into 3 subgroups: diabetic, diabetic/recovery &diabetic/ARIs [received daily oral 57 mg/kg Epalrestat for 4 weeks]. Serum glucose measurement, saliva collection &biochemical, histological, immunohistochemical [for active SERCA, AQP-5, inactive SERCA &caspase-3] and morphometric studies were done. Results: All serological, biochemical &histological manifestations of diabetes &xerostomia deteriorated from diabetic subgroup to diabetic/recovery subgroup. However, Epalrestat use evidently improved xerostomia manifestations but not diabetic manifestations. Conclusion: The main molecular mechanism of diabetesinduced xerostomia is polyol-pathway overactivity and consequent SERCA inactivation, i-Ca2+ overload, ER-stress, AQP-5 reduction, &a-amylase improper folding. Epalrestat, an ARI, ameliorates such xerostomia by blocking this pathway and preventing these changes with no effect on diabetes itself. [ABSTRACT FROM AUTHOR]