Preventive Effect of Chotosan, a Kampo Medicine, on Transient Ischemia-Induced Learning Deficit Is Mediated by Stimulation of Muscarinic M1 But Not Nicotinic Receptor

Abstract

We have previously shown using a water maze task that transient 2 vessel occlusion (T2VO) induced learning deficit in mice and that the deficit was prevented by pre-treatment of mice with chotosan, a Kampo prescription. In this study, we investigated the mechanism underlying the preventive effect of chotosan on T2VO-induced learning deficit. Chotosan administration 1 h before T2VO operation prevented learning impairment. The extract of Uncaria, a major constituent of chotosan, also had a protective effect on learning impairment in T2VO mice, whereas Uncaria-free chotosan had no beneficial effect on maze performance of T2VO mice. The ameliorative effect of chotosan was blocked by pirenzepine, a muscarinic M 1 antagonist, but not by mecamylamine, a nicotinic receptor antagonist. Acetylcholine (ACh) content in the hippocampus of T2VO mice was significantly lower than that in the hippocampus of sham-operated control mice. Chotosan and Uncaria administration attenuated T2VO-induced reduction of ACh levels in the brain. These results suggest that the preventive effect of chotosan on transient ischemia-induced learning impairment is mainly attributable to the effect of Uncaria and that the ameliorative effect is mediated by stimulation of muscarinic M 1 receptor.

Kampo Formulations, Chotosan, and Yokukansan, for Dementia Therapy: Existing Clinical and Preclinical Evidence

“…In our study using a mouse model of transient cerebral ischemia (T2VO), single administration of CTS extract, at doses (375 -750 mg/kg per day, p.o.) equivalent to about 10 to 30 times the daily dose used for human therapy, exhibited a preventive effect on T2VO-induced spatial cognitive deficits in a manner reversible by a muscarinic M 1 -receptor antagonist, pirenzepine, but not by a nicotinic receptor antagonist, mecamylamine (18). Moreover, in a mouse model of permanent occlusion of common carotid arteries (P2VO), we found that daily administration of CTS (750 mg/kg per day, p.o.)…”

Diabetes-Induced Central Cholinergic Neuronal Loss and Cognitive Deficit Are Attenuated by Tacrine and a Chinese Herbal Prescription, Kangen-Karyu: Elucidation in Type 2 Diabetes db/db Mice

“…This observation is supported by the findings reported by Sharma et al (23) that adult (10 -11-week-old) db/db mice are hypolocomotive as evident by a decrease of basic and fine movements. On the basis of this fact, we adopted a 120-s observation period instead of a conventional 60-s observation period (6,20) for O-db/db mice and age-matched control m/m mice, in the training and probe tests of the water maze task in order to reduce contribution of different swimming abilities to their cognitive performance. This protocol clearly indicated that vehicle-treated O-db/db mice exhibit spatial cognitive deficits compared with agematched m/m control strain mice.…”

“…The water maze test was performed by slightly modifying the protocol adopted in previous studies (6,20). Briefly, the water maze testing took place during the first half of the light phase.…”

“…Analysis of cholinergic neurons in the middle septal and basal forebrain was conducted by the immunohistochemical technique with slight modification of the method described previously (19,20). Mice were fixed by intracardiac perfusion with 4% paraformaldehyde in phosphate-buffered saline (PBS) under anesthesia.…”

Chotosan Enhances Macrophage Colony-Stimulating Factor mRNA Expression in the Ischemic Rat Brain and C6Bu-1 Glioma Cells

“…12,13) Moreover, pharmacological studies have suggested that the anti-dementia effects of CTS are due to its anti-hypertensive, 14,15) free radical scavenging, 16) anti-excitotoxic effects, [17][18][19][20] improvement of microcirculation, 14) protection of endothelial function, and enhancement of central cholinergic systems. [21][22][23] Recently, Tohda et al 24) have reported using DNA microarray analysis and RT-PCR that permanent occlusion of bilateral common carotid arteries (P2VO) of rats, an animal model of cerebral hypoperfusion, [25][26][27][28] significantly elevated the expression level of M-CSF mRNA in the cerebral cortex of rats. This finding led us to hypothesize that M-CSF in the brain may be involved in the beneficial effects of chotosan in the treatment of patients with vascular dementia.…”