Effects of Retatrutide on Learning and Memory in Streptozotocin-Induced Diabetic Rats

Diabetes Mellitus (DM) is a rapidly increasing disease around the world. It is known that DM is associated with numerous complications which affect life quality by its debilitating nature. DM is associated with cognitive impairment and neurodegeneration, partly driven by neuroinflammation and disrupted neuronal signalling. Incretin-based treatments have recently been suggested to exert potential effects on the central nervous system in diabetic patients. However, the triple agonist of GIP/GLP-1/GCG Retatrutides effects on cognition under diabetic conditions remain unexplored. This study aims to reveal whether impaired cognitive performance, such as learning and memory, is ameliorated by Retatrutide treatment in diabetic rats, together with associated metabolic, inflammatory and histological changes. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic rats treated with Retatrutide (STZR), and sham rats treated with Retatrutide alone (R). DM was induced by streptozotocin injections. Spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while neuroinflammatory markers (IL-1{beta}, TNF-), neurotrophic-related gene expression (BDNF, CREB, AKT), Tau protein levels, and histopathological changes in the cortex and hippocampus were evaluated using molecular, biochemical, and histological analyses. Streptozotocin-induced diabetes resulted in persistent hyperglycaemia, total body weight loss, impaired learning and memory. Retatrutide treatment reduced blood glucose levels without achieving a full euglycaemia or preventing weight loss. Behavioural tests showed that Retatrutide treatment preserved spatial learning and short-term memory compared to untreated animals. These effects were accompanied by attenuation of neuroinflammatory responses, particularly reduced TNF- levels, trends toward preserved neurotrophic-related transcriptional profiles, and partial maintenance of cortical and hippocampal structural integrity. Retatrutide alone did not enhance cognitive performance beyond control levels. These findings support the hypothesis that triple agonists may exert beneficial effects on cognitive performance under diabetic conditions. Retatrutide alleviates DM-associated cognitive impairment in streptozotocin-induced diabetic rats and is associated with reduced neural inflammatory burden and protected neuroanatomical structure. The observed cognitive benefits appear to extend beyond metabolic regulation alone. Further studies in models more closely reflecting type 2 diabetes are warranted to clarify the underlying mechanisms and translational relevance.