Cardiovascular toxin-induced hyperglycemic and hypoarousal pathology-associated cognitive impairment: an in silico and in vivo validation

Background and purpose: Medication-induced cardiotoxicity is a significant factor in the attrition of drugs during preclinical and clinical development processes. Patients with diabetes mellitus (hyperglycemic) are more than twice as likely to experience cardiac failure. Additionally, type 2 diabetes mellitus (T2D) patients often display significant hyperarousal-related clinical anomalies such as fear, panic, nervousness, pain, and seizures. Consequently, hyperarousal in patients with inadequate metabolic outcomes (hyperglycemic conditions) is usually treated with drugs that block sodium/calcium channels, augment inhibitory (gamma-aminobutyric acid [GABA]) neurotransmission, and reduce excitatory (glutamatergic) neurotransmission. These perilous combined clinical-pathological conditions of hyperglycemia and hypoarousal may result in severe learning disabilities and cognitive impairment. Unfortunately, only a few studies have investigated the synergistic effects of hypoarousal and hyperglycemia on cognition. Methods: General behavioral assessment, plus maze, Y-maze spontaneous alternation, Hebb-Williams maze and Passive avoidance paradigm were evaluated in this study. The current study assessed the in silico structural properties attributed to its pharmacodynamic actions and interaction with Gamma-aminobutyric acid (GABA) and insulin receptors using Schrodinger and LigPrep software. Results: The administration of alloxan and phenytoin induced significant learning and cognitive deficiencies. Based on the in silico studies, alloxan is a better drug to induce hyperglycemia as compared to the well-established hyperglycemic agent, streptozotocin (STZ). Conclusions: The current study indicated that administering alloxan and phenytoin to rodents can serve as a valid animal model to understand the pathophysiology associated with hypoarousal and hyperglycemia-mediated cognitive impairment and to identify novel therapeutic interventions for hyperglycemic and hypoarousal-related learning and cognitive deficiency.