title: Vascular action as the primary mechanism of cognitive effects of cholinergic, CNS-acting drugs, a rat phMRI BOLD study.
abstract: Concordant results of functional magnetic resonance imaging (fMRI) and behavioral tests prove that some non-blood-brain barrier-penetrating drugs produce robust central nervous system (CNS) effects. The anticholinergic scopolamine interferes with learning when tested in rats, which coincides with a negative blood-oxygen-level-dependent (BOLD) change in the prefrontal cortex (PFC) as demonstrated by fMRI. The peripherally acting butylscopolamine also evokes a learning deficit in a water-labyrinth test and provokes a negative BOLD signal in the PFC. Donepezil-a highly CNS-penetrating cholinesterase inhibitor-prevents the negative BOLD and cognitive deficits regardless whether the provoking agent is scopolamine or butylscopolamine. Interestingly, the non-BBB-penetrating cholinesterase inhibitor neostigmine also prevents or substantially inhibits those cognitive and fMRI changes. Intact cerebral blood flow and optimal metabolism are crucial for the normal functioning of neurons and other cells in the brain. Drugs that are not BBB penetrating yet act on the CNS highlight the importance of unimpaired circulation, and point to the cerebral vasculature as a primary target for drug action in diseases where impaired circulation and consequently suboptimal energy metabolism are followed by upstream pathologic events.
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Pál
authors.initials: P
authors.lastname: Kocsis
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.affiliation: Discovery Chemistry, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: János
authors.initials: J
authors.lastname: Éles
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Judit
authors.initials: J
authors.lastname: Laszy
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Nikolett
authors.initials: N
authors.lastname: Hegedűs
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Dávid
authors.initials: D
authors.lastname: Gajári
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Levente
authors.initials: L
authors.lastname: Deli
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Zsófia
authors.initials: Z
authors.lastname: Pozsgay
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Dávid
authors.affiliation: Pharmacology and Drug Safety Research, Gedeon Richter Ltd. H-1475, Budapest, Hungary.
authors.forename: Károly
authors.initials: K
authors.lastname: Tihanyi
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000000981:diagnostic imaging / Q000378:metabolism; D002800:Cholinesterase Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D003071:Cognition / Q000187:drug effects*; D008279:Magnetic Resonance Imaging; D009388:Neostigmine / Q000493:pharmacokinetics / Q000494:pharmacology*; D011859:Radiography; D051381:Rats
chemical_list: D002800:Cholinesterase Inhibitors; D009388:Neostigmine