Translational difficulties in establishing a pharmacologically induced neurovascular uncoupling model in rats

Neurovascular uncoupling (NVU) contributes to neurological disorders like Alzheimer's disease. While a mouse NVU model exists, a reliable rat model critical for cognitive research remains underdeveloped. To address this methodological gap, we investigated a pharmacological approach in rats using the same drugs (N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH), L-NG-nitroarginine methyl ester (L-NAME), indomethacin) that proved to be efficacious in mice. The compounds were formulated as a cocktail solution and administered intraperitoneally for 13 days to aged, cognitively experienced Long-Evans rats. Our goal was to induce NVU while minimizing adverse systemic effects seen previously (e.g., hypertension, intestinal ulceration). The treatment induced only a modest (28%, non-significant) reduction in cerebral hyperaemia, with decreased prostaglandin E2 levels but unchanged 11,12-epoxyeicosatrienoic acid concentration in the brain. Cognitive effects were limited-transient impairment in the 5-choice task but no changes in spontaneous alternation, visual discrimination, cooperation, or motor learning. Significant adverse effects emerged: reduced food intake, weight loss, gastrointestinal malaise, and moderate renal toxicity. Our findings specifically highlight the challenges of achieving sufficient and symptomatically apparent NVU while minimizing systemic toxicity. While partial NVU occurred, this polypharmacy approach had major limitations. A reliable, industrially applicable rat NVU model remains urgently needed to accelerate antidementia drug development.