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

A study in male rats with streptozotocin-induced diabetes found that Retatrutide partially lessened some learning and memory impairments and related brain inflammation, but the benefits were incomplete. It lowered blood glucose and hippocampal TNF-α, but did not reverse diabetes-induced weight loss and did not normalise all memory measures.

Journal article — controlled interventional animal study. Population: Male Sprague-Dawley rats, including streptozotocin-induced diabetic rats and non-diabetic controls. Interventions: Retatrutide.

In streptozotocin-induced diabetic rats, diabetes caused persistent hyperglycaemia, marked weight loss, prolonged Morris Water Maze escape latencies, and a selective short-term Passive Avoidance deficit. Retatrutide reduced blood glucose but did not prevent diabetes-associated weight loss. Treated diabetic rats preserved overall Morris Water Maze performance relative to untreated diabetic rats and showed only limited, task-dependent attenuation of short-term avoidance deficits rather than complete normalisation across all memory measures. These effects accompanied a significant reduction in hippocampal TNF-α, a non-significant trend toward lower IL-1β, and partial preservation of cortical and hippocampal cytoarchitecture. In non-diabetic rats, Retatrutide alone did not improve behaviour despite increased BDNF and CREB mRNA expression.

This paper offers evidence that Retatrutide, a triple GIP/GLP-1/glucagon receptor agonist, may affect diabetes-related cognitive impairment and neuroinflammation beyond its glycaemic effects in a preclinical model. It does not establish direct central nervous system action, a dose-response relationship, or translational relevance to type 2 diabetes or humans.

Key findings

Streptozotocin-induced diabetes produced persistent hyperglycaemia, marked body weight loss, 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.
Retatrutide-treated diabetic rats showed preserved overall Morris Water Maze performance relative to untreated diabetic rats and only limited, task-dependent attenuation of short-term avoidance deficits.
Retatrutide treatment significantly reduced hippocampal TNF-α and showed a non-significant trend toward lower IL-1β.
Retatrutide treatment was accompanied by partial preservation of cortical and hippocampal cytoarchitecture.
Retatrutide alone did not improve behavioural performance beyond control levels, although it increased BDNF and CREB mRNA expression in non-diabetic rats.

Limitations

Direct central exposure of Retatrutide was not established in the present study.
The study used only male Sprague-Dawley rats and a streptozotocin-induced insulin-deficient model, not insulin-resistant or type 2 diabetes-like models.
The abstract reports no sample size, dose, or treatment duration, limiting quantitative interpretation.

The record

Journal: Behavioural brain research 514: 116343
Published: 2026-07-01
PMID: 42385950 — DOI: 10.1016/j.bbr.2026.116343
MeSH terms: Animals, Male, Diabetes Mellitus, Experimental, Rats, Sprague-Dawley, Rats, Hippocampus, Maze Learning, Hypoglycemic Agents, Memory, Avoidance Learning, Cognitive Enhancement, Brain-Derived Neurotrophic Factor, Glucagon-Like Peptide-1 Receptor Agonists, Fatty Acids, Peptides

Peptide profiles: Retatrutide.

All indexed evidence: Retatrutide trials & papers.