Retatrutide preserves spatial memory and reduces hippocampal inflammation in diabetic rats

Cognitive impairment and neurodegenerative changes are significant complications of diabetes mellitus, driven partly by hyperglycemia-induced neuroinflammation and disrupted neuronal signaling. Current diabetes treatments primarily focus on metabolic control, often failing to address these debilitating neurological sequelae. Retatrutide, a novel triple GIP/GLP-1/glucagon receptor agonist, has demonstrated potent metabolic efficacy, making it a compelling candidate to investigate for its potential neuroprotective effects in diabetes-associated cognitive dysfunction.

Male Sprague-Dawley rats were divided into four groups: control (C), streptozotocin-induced diabetic (STZ), streptozotocin-induced diabetic treated with Retatrutide (STZR), and Retatrutide alone (R). Diabetes was induced via streptozotocin. Spatial learning and memory were rigorously assessed using the Morris Water Maze and Passive Avoidance tests. Metabolic parameters were monitored throughout the study. Hippocampal cytokine levels (IL-1β, TNF-α), BDNF, CREB, and AKT mRNA expression, and Tau protein levels were evaluated using biochemical and molecular methods, complemented by cortical and hippocampal histopathology. The abstract does not specify the dose or duration of Retatrutide treatment.

Streptozotocin-induced diabetes led to persistent hyperglycemia, significant body weight loss, and impaired behavioral performance. Specifically, diabetic rats exhibited prolonged escape latencies in the Morris Water Maze and a selective short-term Passive Avoidance deficit. Retatrutide treatment effectively reduced blood glucose levels, though it did not prevent diabetes-associated weight loss. In behavioral assessments, Retatrutide-treated diabetic rats demonstrated preserved overall Morris Water Maze performance compared to untreated diabetic rats. The compound also provided a limited, task-dependent attenuation of short-term avoidance deficits, rather than achieving complete normalization across all memory measures. These cognitive improvements were accompanied by a significant reduction in hippocampal TNF-α levels, alongside a non-significant trend toward lower IL-1β. Furthermore, Retatrutide partially preserved cortical and hippocampal cytoarchitecture in diabetic animals.

Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and a significant reduction in hippocampal TNF-α.