In examining the enduring consequences of diabetes, recent research has focused on the anticipated outcomes of the condition. Specifically, cognitive impairment has been linked to diabetes mellitus dating back to the discovery of insulin. This study delves into the neuroprotective effects of TZP, i.e. tirzepatide a dual GIP and GLP-1 receptor agonist that works by mimicking these two gut hormones, against cognitive impairment associated with type 2 diabetes mellitus (T2DM). T2DM-like zebrafish model of varying age groups was created through a 6-week administration of a high-fat diet (HFD). Parameters such as body weight, body mass index, and blood glucose levels were monitored, and behavioural assessments (T-maze, novel tank diving test, and inhibitory avoidance test) were conducted at the conclusion of the protocol to assess learning and memory. Additionally, lipid profile biochemical parameters (MDA, AChEs, and GSH), molecular markers (IL-1β, IL-10, TNF-α, Bcl-2, Bax, GSK-3β, and AMPK), and histopathological examinations were performed. Treatment with the novel GLP-1 and GIP dual agonist TZP (10 nM/kg, i.p.) significantly ameliorated cognitive impairment, as evidenced by behavioural parameters, and restored antioxidant like GSH (p < 0.05) and catalase (p < 0.05) and anti-inflammatory marker levels, i.e. IL-10 (p < 0.05) compared to the HFD group. TZP also mitigated abnormal glucose (73.2 ± 5.889) and lipid profiles (TG 0.159 ± 0.0075 and TC 0.100 ± 0.0020) in hyperglycaemic zebrafish. This study suggests that the positive effects of TZP on cognition and memory may stem from its neuroprotective capabilities, potentially attributed to its antioxidant, anti-inflammatory, and anti-apoptotic properties, as well as its ability to enhance AMPK levels as GLP-1 agonist has the potential to increase the level of AMPK.
