0000000000260921
AUTHOR
Shyam Sunder Chatterjee
Excitotoxic Hippocampal Membrane Breakdown and its Inhibition by Bilobalide: Role of Chloride Fluxes
We have previously shown that hypoxia and N-methyl-D-aspartate (NMDA) receptor activation induce breakdown of choline-containing phospholipids in rat hippocampus, a process which is mediated by calcium influx and phospholipase A (2) activation. Bilobalide, a constituent of Ginkgo biloba, inhibited this process in a potent manner (Weichel et al., Naunyn-Schmiedeberg's Arch. Pharmacol. 360, 609-615, 1999). In this study, we used fluorescence microscopy and radioactive flux measurements to show that bilobalide does not interfere with NMDA-induced calcium influx. Instead, bilobalide seems to inhibit NMDA-induced fluxes of chloride ions through ligand-operated chloride channels. In our experimen…
KA-672 inhibits rat brain acetylcholinesterase in vitro but not in vivo.
Abstract KA-672, a lipophilic benzopyranone derivative which is currently under development as a cognitive enhancer and antidementia drug, has previously been shown to have facilitatory effects on learning and memory in rats at doses of 0.1–1 mg/kg. We now report that KA-672 inhibited the activity of acetylcholinesterase (AChE), measured in vitro in rat brain cortical homogenate, with an IC 50 value of 0.36 μ M indicating that KA-672 may improve cognitive functions as a consequence of AChE inhibition. However, when we employed the microdialysis procedure to monitor acetylcholine (ACh) release from rat hippocampus, no effect of KA-672 (0.1–10 mg/kg) was found, indicating a lack of inhibition…
Bilobalide, a constituent of Ginkgo biloba , inhibits NMDA-induced phospholipase A 2 activation and phospholipid breakdown in rat hippocampus
In rat hippocampal slices superfused with magnesium-free buffer, glutamate (1 mM) caused the release of large amounts of choline due to phospholipid breakdown. This phenomenon was mimicked by N-methyl-D-aspartate (NMDA) in a calcium-sensitive manner and was blocked by NMDA receptor antagonists such as MK-801 and 7-chlorokynurenate. The NMDA-induced release of choline was not caused by activation of phospholipase D but was mediated by phospholipase A2 (PLA2) activation as the release of choline was accompanied by the formation of lyso-phosphatidylcholine (lyso-PC) and glycerophospho-choline (GPCh) and was blocked by 5-[2-(2-carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]pentano ic acid, …
Stimulation of hippocampal acetylcholine release by hyperforin, a constituent of St. John’s Wort
Abstract Extracts of the medicinal plant St. John’s Wort ( Hypericum perforatum ) are widely used in the therapy of affective disorders and have been reported to exert antidepressant, anxiolytic, and cognitive effects in experimental and clinical studies. We here report that hyperforin, the major active constituent of the extract, increases the release of acetylcholine from rat hippocampus in vivo as determined by microdialysis. Hippocampal acetylcholine levels were increased by 50–100% following the systemic administration of pure hyperforin at doses of 1 and 10 mg/kg. The effect was almost completely suppressed by local perfusion with calcium-free buffer or with tetrodotoxin (1 μM). We co…
Dual modulation of striatal acetylcholine release by hyperforin, a constituent of St. John's wort.
Extracts of the medicinal plant St. John's wort (Hypericum perforatum) are widely used for the treatment of mild to moderate depression. Hyperforin, a constituent of St. John's wort, is known to inhibit the sodium-dependent uptake of catecholamines and amino acids into synaptic nerve endings, probably by interference with mechanisms controlling the synaptic sodium concentration. Because de novo synthesis of acetylcholine (ACh) is dependent on sodium-dependent high-affinity choline uptake, we studied the effect of hyperforin on choline (Ch) uptake in vitro and on striatal ACh release in vivo using microdialysis. In rat brain synaptosomes, hyperforin inhibited high-affinity choline uptake wit…
Phospholipid breakdown and choline release under hypoxic conditions: inhibition by bilobalide, a constituent of Ginkgo biloba
A marked increase of choline release from rat hippocampal slices was observed when the slices were superfused with oxygen-free buffer, indicating hypoxia-induced hydrolysis of choline-containing phospholipids. This increase of choline release was suppressed by bilobalide, an ingredient of Ginkgo biloba, but not by a mixture of ginkgolides. The EC50 value for bilobalide was 0.38 microM. In ex vivo experiments, bilobalide also inhibited hypoxia-induced choline release when given p.o. in doses of 2-20 mg/kg 1 h prior to slice preparation. The half-maximum effect was observed with 6 mg/kg bilobalide. A similar effect was noted after p.o. administration of 200 mg/kg EGb 761, a ginkgo extract con…
Hypericum Extract and Hyperforin: Memory-Enhancing Properties in Rodents
Effects of a Hypericum extract in therapeutic use and hyperforin sodium salt were evaluated in rat and mouse avoidance tests. In a conditioned avoidance response (CAR) test on the rat, oral daily administration of hyperforin (1.25 mg/kg/day) or of the extract (50 mg/kg/day) before the training sessions considerably improved learning ability from the second day onwards until the day 7. In addition, the memory of the learned responses acquired during 7 consecutive days of administration and training was largely retained even after 9 days without further treatment or training. The observations made using different doses indicate that these learning-facilitating and/or memory-consolidating effe…