Mattio_1986_Neuropharmacol_25_1167

The effects of various doses of physostigmine (Phy) on the activity of acetylcholinesterase (AChE) in plasma, cerebrospinal fluid (CSF) and brain were studied in beagle dogs. Two routes of administration were compared: intravenous (i.v.) and intracerebroventricular (i.c.v.). With intracerebroventricular administration, over 90% inhibition of the activity of AChE in CSF was reached within 5 min of injection at all doses (10-120 micrograms). Even at the smallest dose (10 micrograms), 50% inhibition of activity of the enzyme in CSF was still present at 90 min. The activity of AChE in plasma was only minimally inhibited by intraventricular administration of physostigmine. A different response was obtained following intravenous administration of physostigmine (250-1000 micrograms). The activity of AChE in plasma was inhibited but the activity of AChE in CSF was increased (36-80% at 180 min). This increase was dose-dependent and was blocked by pretreatment with atropine (1.5 mg i.v.) which suggests the involvement of a muscarinic receptor mechanism. The time course of the accumulation and regional distribution of [3H]physostigmine in brain also varied with the route of administration. At 5 min, with intravenous administration, physostigmine (1000 micrograms) reached greater concentrations and caused greater inhibition of AChE in the cortex. With intraventricular administration, physostigmine (80 micrograms) reached greater concentrations in two regions adjacent to the ventricular surface: the striatum and hippocampus. These regions also showed greater inhibition of the activity of AChE. Moderate to severe symptoms of cholinergic hyperactivity were seen only with the largest intraventricular dose (120 micrograms). This study suggests that intraventricular administration of physostigmine, a reversible inhibitor of cholinesterase (ChE), may offer distinct advantages over intravenous administration. Inhibition of acetylcholinesterase in CSF was more pronounced and persisted longer when physostigmine was administered directly into the CSF than when given intravenously. The implications of this study for a cholinergic therapy of Alzheimer's disease are discussed.