Effects of retatrutide on learning and memory in streptozotocin-induced male diabetic rats.

Retatrutide may partially improve cognitive function in diabetic rats, but its effects are limited and not fully understood. Further research is necessary to determine its relevance to human conditions.

Summary and findings

The study measured the effects of Retatrutide on learning and memory in streptozotocin-induced diabetic male rats. The treatment did not prevent weight loss but reduced blood glucose levels and showed some preservation of Morris Water Maze performance. The findings suggest a partial attenuation of cognitive impairments associated with diabetes.

Abstract

Diabetes mellitus is associated with cognitive impairment and neurodegenerative changes, partly through hyperglycaemia-driven neuroinflammation and disrupted neuronal signalling. Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, has shown strong metabolic efficacy, but its effects on diabetes-associated cognitive dysfunction remain unclear. The present study investigated whether Retatrutide attenuates learning- and memory-related impairments in a streptozotocin-induced, insulin-deficient diabetic rat model. Male Sprague-Dawley rats were allocated to four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic treated with Retatrutide (STZR), and Retatrutide alone (R). Diabetes was induced with streptozotocin, and spatial learning and memory were assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored, while hippocampal cytokine levels (IL-1β, TNF-α), BDNF, CREB, and AKT mRNA expression, Tau protein levels, and cortical and hippocampal histopathology were evaluated using biochemical, molecular, and histological methods. Streptozotocin-induced diabetes produced persistent hyperglycaemia, marked body weight loss, and impaired behavioural performance, particularly prolonged escape latencies in the Morris Water Maze and a selective short-term Passive Avoidance deficit. Retatrutide reduced blood glucose levels but did not prevent diabetes-associated weight loss. In behavioural testing, Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and a limited, task-dependent attenuation of short-term avoidance deficits rather than complete normalisation across all memory measures. These effects were accompanied by a significant reduction in hippocampal TNF-α, a non-significant trend toward lower IL-1β, and partial preservation of cortical and hippocampal cytoarchitecture. Retatrutide alone did not improve behavioural performance beyond control levels, although BDNF and CREB mRNA expression were increased in the non-diabetic Retatrutide group. These findings indicate that Retatrutide is associated with a partial attenuation of streptozotocin-induced behavioural and neuroinflammatory alterations in male rats. The observed effects are consistent with actions extending beyond glycaemic control alone, although direct central exposure of Retatrutide was not established in the present study. Further studies in insulin-resistant and type 2 diabetes-like models are needed to clarify the underlying mechanisms and translational relevance.

Limitations

Not reported in abstract.

Elsewhere in the Retatrutide (LY3437943) corpus