PhD Scientific Days 2022

Pharmaceutical Sciences II. (Poster discussion will take place in the Aula during the Coffee Break)

Attempt to Establish a Neurovascular Uncoupling Model in Rats

Text of the abstract

The objective of the present study was to establish a pharmacologically induced neurovascular uncoupling (NVU) method in rats as a translationally valid animal model of human cognitive decline.
Diminished neurovascular coupling (NVC) has been shown during aging and in various brain disorders. Pharmacologically induced NVU with subsequent neurological and cognitive defects was described in mice (Tarantini, 2015), however, no similar procedure has been reported so far in rats.
In this study, we used 28 male Hannover Wistar rats. NVU was induced by intraperitoneal administration of a pharmacological “cocktail” consisting of N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MSPPOH, a specific inhibitor of epoxyeicosatrienoic acid)-producing epoxidases, 5 mg/kg), L-NG-nitroarginine methyl ester (L-NAME, a nitric oxide synthase inhibitor, 10 mg/kg) and indomethacin (a nonselective inhibitor of cyclooxygenases, 1 mg/kg) and injected twice daily for 8 consecutive days.
Animals were tested in Morris water-maze and fear-conditioning assays on days 5-7 and 4 and 8 of the treatment period, respectively. Blood pressure of the animals was monitored on days -1, 2, 5 and 7. NVC was measured in the barrel cortex in a non-recovery operation. A laser Doppler probe was used to detect changes in cerebral blood-flow (CBF), while the contralateral whisker pad was stimulated. Brain and small intestine tissue samples were collected post mortem and processed for prostaglandin E2 (PGE2) level measurements.
When contrasted with the control group, the animals treated with the “cocktail” showed no impairment in their performance in any of the cognitive tasks. However, we observed an overall higher blood pressure in these rats. They also showed about 50 % less increase in CBF, while their whiskers were stimulated. Intestinal bleeding and ulcers were found in some of the treated animals and ELISA assays of the tissue samples revealed significantly decreased levels of PGE2 both in the brain and small intestine.
Although we could evoke NVU by the applied mixture of pharmacons, it also induced adverse side effects such as hypertension and intestinal alterations. Furthermore, the treatment did not cause cognitive impairment. Thus, further refinements are still required for the development of an applicable model, mostly with regard to finding the appropriate dosages and learning assays.