Alzheimer’s disease (AD), a prevalent neurodegenerative disorder, is characterized by amyloid beta and tau protein aggregation, oxidative stress, and neuroinflammation. Urolithin A (Uro A) and Urolithin B (Uro B), known for their anti-inflammatory, antioxidant, and neuroprotective properties, are promising therapeutic candidates for AD. This study evaluated the effects of Uro A and Uro B on memory, anxiety-like behaviors, brain oxidative stress markers, and histopathological changes in male rats subjected to streptozotocin (STZ)-induced AD. Wistar rats were divided into eight groups (n = 7) and treated with Uro A or Uro B (10 or 20 mg/kg), memantine (positive control), or vehicle control for 14 days following intracerebroventricular STZ injection. Behavioral tests, biochemical analyses, and histological evaluations were conducted after six weeks. Modest improvements in memory performance were observed (p < 0.05) in the shuttle box test and reduced anxiety-like behaviors in the elevated plus-maze test. Biochemical analyses revealed decreased oxidative stress markers (malondialdehyde and hydroperoxides) and increased total antioxidant capacity (p < 0.05). Also, it seems that both compounds can reduce necrotic neurons and amyloid-like depositions in the hippocampus and cerebral cortex, and no adverse effects on the histology of the liver, kidney, pancreas, and testis were observed. These findings demonstrate the therapeutic potential of Uro A and Uro B in ameliorating cognitive deficits, oxidative stress, and neuronal damage in AD. Further studies are needed to explore the mechanisms underlying these effects and their applicability in clinical contexts. Significance statement This study demonstrates that Urolithin A and B appeared to improve memory, reduce anxiety-like behaviors, and alleviate oxidative stress and neuronal damage in Alzheimer’s-Like Model in rats. Notably, Urolithin B’s neuroprotective effects are reported for the first time in this model. It seems that both compounds can also reduce amyloid-like deposition in the hippocampus and cortex without causing toxicity in vital organs, highlighting their strong therapeutic potential and safety profile for treating Alzheimer’s disease.

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