Scopolamine provocation-based pharmacological MRI model for testing procognitive agents

Abstract

There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials.

Deciphering the scopolamine challenge rat model by preclinical functional MRI

“…We used the preclinical MRI as a “task” fMRI, by measuring the whisker stimulation induced BOLD activation in a block design. With this approach, we could not see the dramatic reduction of perfusion or negative BOLD in the prefrontal cortex that would explain some behavioral effects [5,10,33].…”

“…In contrast on the basis of its peripheral vascular action as a primary mechanism, a SCO provocation-based pharmaco-MRI model was proposed as a test for procognitive agents [5,10]. Indeed, non-blood-brain barrier-penetrating anticholinergic drug, butylscopolamine (BSCO) also evoked learning deficit similarly to SCO and both compounds induced negative blood oxygen-level-dependent (BOLD) changes in the prefrontal cortex in a pharmaco-MRI study, in isoflurane anesthesia [10].…”

Кавинтон (Винпоцетин): Новые Возможности Клинического Применения

“…Âèíïîöåòèí ñíèaeàë òîðìîç-íîå äåéñòâèå ñêîïîëàìèíà íà ïîâåäåíèå êðûñ â óêà-çàííûõ ýêñïåðèìåíòàëüíûõ óñëîâèÿõ. Êðîìå òîãî, äëÿ ýòîãî ïðåïàðàòà õàðàêòåðíà ñïîñîáíîñòü îñëàáëÿòü âëèÿíèå ñêîïîëàìèíà íà êèñëîðîä-çàâèñèìûå ïðîöåñ-ñû â ïðåôðîíòàëüíîé êîðå ãîëîâíîãî ìîçãà, âûÿâëåí-íàÿ â óñëîâèÿõ ìàãíèòíî-ðåçîíàíñíîãî ñêàíèðîâàíèÿ aeèâîòíûõ [29]. Ñóùåñòâóþò òàêaeå ìíîãî÷èñëåííûå ìîðôîëîãè÷åñêèå ñâèäåòåëüñòâà ñïîñîáíîñòè âèíïî-öåòèíà óëó÷øàòü íåéðîïëàñòè÷íîñòü.…”

Indications of success: Strategies for utilizing neuroimaging biomarkers in CNS drug discovery and development

“…These approaches can distinguish neural network aberrancies induced by psychotomimetic drugs such as ketamine and scopolamine. These changes may represent translatable biomarkers, as these alterations frequently resemble abnormalities observed in certain pathological conditions ( Molchan et al, 1994 ; Jones et al, 2012 ; Hegedűs et al, 2015 ; Joules et al, 2015 ). However, the above-mentioned methods are not fully validated and standardized, introducing the potential for contradictory results.…”