Challenges in Developing a Rat Model of Pharmacologically Induced Neurovascular Uncoupling
Varga Bence Tamás
János Szentágothai Neurosciences Division
Dr. Bereczki Dániel
NET Farmakológiai és Farmakoterápiás Intézet, Knoll (Issekutz) terem
2026-11-04 10:00:00
Functional neurosciences
Dr. Sperlágh Beáta
Gyertyán István
Dr. Farkas Eszter
Dr. Kovács Péter
Dr. Tábi Tamás
Dr. Gáll Zsolt
Dr. Krizbai István
Dr. Farkas Sándor
The neurovascular unit regulates cerebral blood flow in response to neuronal activity, a process impaired in disorders like Alzheimer’s disease but also in normal aging. Despite its clinical relevance, no reliable pharmacological models of NVU exist for preclinical drug development. This doctoral work aimed to establish such a model in rats by simultaneously blocking three vasodilatory pathways with a single “cocktail” of inhibitors: MS-PPOH for EETs, L-NAME for nitric oxide, and indomethacin for prostaglandins, a strategy based on prior mouse studies.
Initial experiments in young rats confirmed NVU induction (54 % reduced cerebral blood flow response) but revealed dose-limiting toxicity (hypertension, intestinal damage). Dose reduction improved tolerability but abolished NVU effects, highlighting a narrow therapeutic window. A key innovation was testing aged, cognitively experienced rats, a translationally more relevant population. Here, intermediate dosing caused transient attentional deficits and mild cerebral blood flow disruption (28 %), but severe weight loss due to decreased food intake. Conditioned taste aversion assay revealed gastrointestinal toxicity in aged animals. Stand-alone MS-PPOH treatment failed to alter brain EET levels, suggesting poor target engagement.
While partial NVU induction was achieved, the model’s utility is limited by toxicity, particularly in aged rats. Future work should explore alternative dosing strategies, icv. delivery, and non-invasive cerebral blood flow monitoring (e.g., fMRI or fUS) to improve translational validity. This research provides a foundation for refining NVU models, essential for developing therapies targeting cerebrovascular dysfunction in cognitive decline.
