phenanthrenes and Amnesia

Alzheimer's disease (AD) is a common form of dementia which is characterized by the deposition of amyloids in affected neurons and a cholinergic neurotransmission deficit in the brain. The current therapeutic intervention for AD is primarily based on the inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) is a diterpene extracted from the root of Salvia miltiorrhiza, a herb that is commonly prescribed in Chinese medicine to treat cardiovascular disease. In the present study, we demonstrated that CT is an inhibitor of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC(50) values of 4.09 and 6.38 microM, respectively. The IC(50) ratio of CT for BuChE:AChE was 1.56. CT inhibited human AChE in a reversible manner, and the inhibition showed the characteristics of mixed-type as both the KM and V(max) were affected by CT. The effect of CT on learning impairment in scopolamine-treated rats was also evaluated by the acquisition protocol of the Morris water maze. The task learning ability of scopolamine-treated rats was significantly reversed by CT (5 mg/kg), and the CT-fed rats were able to develop a spatial searching strategy comparable to that of the control animals. In addition, chronic CT treatment did not cause hepatotoxicity as measured by blood alanine transferase (ALT) level. Our findings demonstrate the ability of CT to improve task learning in rats with scopolamine-induced cognitive impairment. These results suggest that CT has the potential as a therapeutic drug for treating AD.

Topics: Acetylcholinesterase; Alzheimer Disease; Amnesia; Animals; Butyrylcholinesterase; Cholinesterase Inhibitors; Humans; Male; Maze Learning; Phenanthrenes; Phytotherapy; Plant Extracts; Plant Roots; Rats; Rats, Sprague-Dawley; Salvia miltiorrhiza; Scopolamine

The effects of blocking phospholipase A2 (PLA2), a key enzyme in arachidonic acid (ArA) release, on memory retention have been studied in a one-trial passive avoidance task in the day-old chick. Bilateral intracerebral injections of the PLA2 and lipoxygenase inhibitor nordihydroguaiaretic acid (NDGA) (15 microliters of 4 mM NDGA/hemisphere, calculated to give an equivalent intracerebral concentration of 120 microM) or the PLA2 inhibitor aristolochic acid (AST) (5 microliters of a 4 mM AST/hemisphere, calculated to give an equivalent intracerebral concentration of approximately 40 microM) were made into the intermediate medial hyperstriatum ventrale (IMHV), an area that is of crucial importance for memory formation in the chick in this task. Pretraining injections of either inhibitor resulted in the chicks showing lasting amnesia for the avoidance response. The onset of amnesia with both inhibitors NDGA and AST was at 1.25 h post-training. Injection of drugs post-training had no effect on retention. Time and dose dependencies of both drugs were evaluated. Additional tests showed that the amnestic effect is not due to state-dependent learning nor to interference of the drugs with general motor ability or motivation. The results support the theory that arachidonic acid release is a necessary step in the early, although not immediate, events mediating the synaptic plasticity associated with memory formation. This is compatible with the hypothesis that ArA may serve as a late retrograde messenger between post- and presynaptic sites of plasticity, although it is not proof of such a role.

Topics: Amnesia; Animals; Aristolochic Acids; Avoidance Learning; Behavior, Animal; Brain; Chickens; Female; Male; Masoprocol; Phenanthrenes; Phospholipases A; Phospholipases A2; Synaptic Transmission