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Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer's Disease.

Kim HJ, Shin EJ, Lee BH, Choi SH, Jung SW, Cho IH, Hwang SH, Kim JY, Han JS, Chung C, Jang CG, Rhim H, Kim HC, Nah SY - Mol. Cells (2015)

Bottom Line: The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments.In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models.Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Aβ and could be utilized for AD prevention or therapy.

View Article: PubMed Central - PubMed

Affiliation: Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Korea.

ABSTRACT
Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced [Ca(2+)]i transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated [Ca(2+)]i transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 2 weeks) also significantly attenuated amyloid-β protein (Aβ)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Aβ and could be utilized for AD prevention or therapy.

No MeSH data available.


Related in: MedlinePlus

Effect of gintonin (GT; 25 or 50 mg/kg, p.o.) on the Aβ (1–40)-induced changes in cholinergic system. (A) Experimental schedule to evaluate acute gintonin effect in Aβ (1–40)-induced cholinergic system impairment. Donepezil (DPZ; 1 mg/kg, i.p.) was used as a reference drug. Gintonin or DPZ administration started 3 days before the Aβ i.c.v. injection, and the drug administration was continued once a day for consecutive 14 days. Mice were sacrificed at 1 day after the final treatment with gintonin or DPZ. (B) Acetylcholine level. (C) Acetylcholinesterase activity and choline acetyltransferase activity in the hippocampus of the mouse. Sal = saline. Each value is the mean ± S.E.M of eight mice. *P < 0.01 vs. Sal + Aβ (40-1), #P < 0.05, ##P < 0.01 vs. Sal + Aβ (1–40) (one-way ANOVA followed by Fisher’s PLSD test).
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f3-molce-38-9-796: Effect of gintonin (GT; 25 or 50 mg/kg, p.o.) on the Aβ (1–40)-induced changes in cholinergic system. (A) Experimental schedule to evaluate acute gintonin effect in Aβ (1–40)-induced cholinergic system impairment. Donepezil (DPZ; 1 mg/kg, i.p.) was used as a reference drug. Gintonin or DPZ administration started 3 days before the Aβ i.c.v. injection, and the drug administration was continued once a day for consecutive 14 days. Mice were sacrificed at 1 day after the final treatment with gintonin or DPZ. (B) Acetylcholine level. (C) Acetylcholinesterase activity and choline acetyltransferase activity in the hippocampus of the mouse. Sal = saline. Each value is the mean ± S.E.M of eight mice. *P < 0.01 vs. Sal + Aβ (40-1), #P < 0.05, ##P < 0.01 vs. Sal + Aβ (1–40) (one-way ANOVA followed by Fisher’s PLSD test).

Mentions: Aβ-induced cholinergic dysfunctions are considered the main causes of memory impairments in patients with AD or in AD animal models (Bales et al., 2006; Maurice et al., 1996). In our previous study, we showed that oral administration of gintonin ameliorated Aβ (1–40)-induced memory impairment (Hwang et al., 2012a). However, it remains unknown whether the ameliorating effects of gintonin against memory impairment caused by Aβ (1–40) are achieved via improvement of the cholinergic system. In this study, since we showed that gintonin stimulates acetylcholine release and attenuates scopolamine-induced memory impairment (Figs. 1 and 2), we further investigated whether gintonin also protects against Aβ-induced cholinergic system disturbances including acetylcholine concentration and AChE or ChAT activity. We first examined the effects of gintonin on Aβ-induced cholinergic system dysfunction according to the procedure described in Fig. 3A. We observed that the hippo-campal acetylcholine levels significantly decreased in the Aβ (1–40)-infused mice [*P < 0.01 vs. Sal + Aβ (40-1)] (Fig. 3B), and treatment with gintonin significantly attenuated this effect [25 or 50 mg/kg gintonin + Aβ (1–40) vs. Sal + Aβ (1–40), #P < 0.05 or ##P < 0.01] (Fig. 3B). In addition, Aβ (1–40) significantly increased AChE activity [*P < 0.01 vs. Sal + Aβ (40-1)], but significantly decreased ChAT activity [*P < 0.01 vs. Sal + Aβ (40-1)] in the mouse hippocampus; these results are consistent with previous reports of Aβ-induced cholinergic dysfunction (Bales et al., 2006; Maurice et al., 1996). However, oral administration of gintonin 3 days before Aβ (1–40) infusion significantly attenuated the changes in AChE and ChAT activities [both AChE and ChAT activity: 25 or 50 mg/kg gintonin + Aβ (1–40) vs. Sal + Aβ (1–40), #P < 0.05 or ##P < 0.01] (Fig. 3C). The effect of gintonin on Aβ (1–40)-induced cholinergic dysfunction was comparable to that of donepezil (1 mg/kg) (Figs. 3B and 3C). These results indicate that gintonin significantly protects the cholinergic system from Aβ-induced cholinergic dysfunction in the mouse hippocampus.


Oral Administration of Gintonin Attenuates Cholinergic Impairments by Scopolamine, Amyloid-β Protein, and Mouse Model of Alzheimer's Disease.

Kim HJ, Shin EJ, Lee BH, Choi SH, Jung SW, Cho IH, Hwang SH, Kim JY, Han JS, Chung C, Jang CG, Rhim H, Kim HC, Nah SY - Mol. Cells (2015)

Effect of gintonin (GT; 25 or 50 mg/kg, p.o.) on the Aβ (1–40)-induced changes in cholinergic system. (A) Experimental schedule to evaluate acute gintonin effect in Aβ (1–40)-induced cholinergic system impairment. Donepezil (DPZ; 1 mg/kg, i.p.) was used as a reference drug. Gintonin or DPZ administration started 3 days before the Aβ i.c.v. injection, and the drug administration was continued once a day for consecutive 14 days. Mice were sacrificed at 1 day after the final treatment with gintonin or DPZ. (B) Acetylcholine level. (C) Acetylcholinesterase activity and choline acetyltransferase activity in the hippocampus of the mouse. Sal = saline. Each value is the mean ± S.E.M of eight mice. *P < 0.01 vs. Sal + Aβ (40-1), #P < 0.05, ##P < 0.01 vs. Sal + Aβ (1–40) (one-way ANOVA followed by Fisher’s PLSD test).
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4588723&req=5

f3-molce-38-9-796: Effect of gintonin (GT; 25 or 50 mg/kg, p.o.) on the Aβ (1–40)-induced changes in cholinergic system. (A) Experimental schedule to evaluate acute gintonin effect in Aβ (1–40)-induced cholinergic system impairment. Donepezil (DPZ; 1 mg/kg, i.p.) was used as a reference drug. Gintonin or DPZ administration started 3 days before the Aβ i.c.v. injection, and the drug administration was continued once a day for consecutive 14 days. Mice were sacrificed at 1 day after the final treatment with gintonin or DPZ. (B) Acetylcholine level. (C) Acetylcholinesterase activity and choline acetyltransferase activity in the hippocampus of the mouse. Sal = saline. Each value is the mean ± S.E.M of eight mice. *P < 0.01 vs. Sal + Aβ (40-1), #P < 0.05, ##P < 0.01 vs. Sal + Aβ (1–40) (one-way ANOVA followed by Fisher’s PLSD test).
Mentions: Aβ-induced cholinergic dysfunctions are considered the main causes of memory impairments in patients with AD or in AD animal models (Bales et al., 2006; Maurice et al., 1996). In our previous study, we showed that oral administration of gintonin ameliorated Aβ (1–40)-induced memory impairment (Hwang et al., 2012a). However, it remains unknown whether the ameliorating effects of gintonin against memory impairment caused by Aβ (1–40) are achieved via improvement of the cholinergic system. In this study, since we showed that gintonin stimulates acetylcholine release and attenuates scopolamine-induced memory impairment (Figs. 1 and 2), we further investigated whether gintonin also protects against Aβ-induced cholinergic system disturbances including acetylcholine concentration and AChE or ChAT activity. We first examined the effects of gintonin on Aβ-induced cholinergic system dysfunction according to the procedure described in Fig. 3A. We observed that the hippo-campal acetylcholine levels significantly decreased in the Aβ (1–40)-infused mice [*P < 0.01 vs. Sal + Aβ (40-1)] (Fig. 3B), and treatment with gintonin significantly attenuated this effect [25 or 50 mg/kg gintonin + Aβ (1–40) vs. Sal + Aβ (1–40), #P < 0.05 or ##P < 0.01] (Fig. 3B). In addition, Aβ (1–40) significantly increased AChE activity [*P < 0.01 vs. Sal + Aβ (40-1)], but significantly decreased ChAT activity [*P < 0.01 vs. Sal + Aβ (40-1)] in the mouse hippocampus; these results are consistent with previous reports of Aβ-induced cholinergic dysfunction (Bales et al., 2006; Maurice et al., 1996). However, oral administration of gintonin 3 days before Aβ (1–40) infusion significantly attenuated the changes in AChE and ChAT activities [both AChE and ChAT activity: 25 or 50 mg/kg gintonin + Aβ (1–40) vs. Sal + Aβ (1–40), #P < 0.05 or ##P < 0.01] (Fig. 3C). The effect of gintonin on Aβ (1–40)-induced cholinergic dysfunction was comparable to that of donepezil (1 mg/kg) (Figs. 3B and 3C). These results indicate that gintonin significantly protects the cholinergic system from Aβ-induced cholinergic dysfunction in the mouse hippocampus.

Bottom Line: The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments.In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models.Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Aβ and could be utilized for AD prevention or therapy.

View Article: PubMed Central - PubMed

Affiliation: Ginsentology Research Laboratory and Department of Physiology, College of Veterinary Medicine, Konkuk University, Seoul 143-701, Korea.

ABSTRACT
Gintonin is a novel ginseng-derived lysophosphatidic acid (LPA) receptor ligand. Oral administration of gintonin ameliorates learning and memory dysfunctions in Alzheimer's disease (AD) animal models. The brain cholinergic system plays a key role in cognitive functions. The brains of AD patients show a reduction in acetylcholine concentration caused by cholinergic system impairments. However, little is known about the role of LPA in the cholinergic system. In this study, we used gintonin to investigate the effect of LPA receptor activation on the cholinergic system in vitro and in vivo using wild-type and AD animal models. Gintonin induced [Ca(2+)]i transient in cultured mouse hippocampal neural progenitor cells (NPCs). Gintonin-mediated [Ca(2+)]i transients were linked to stimulation of acetylcholine release through LPA receptor activation. Oral administration of gintonin-enriched fraction (25, 50, or 100 mg/kg, 3 weeks) significantly attenuated scopolamine-induced memory impairment. Oral administration of gintonin (25 or 50 mg/kg, 2 weeks) also significantly attenuated amyloid-β protein (Aβ)-induced cholinergic dysfunctions, such as decreased acetylcholine concentration, decreased choline acetyltransferase (ChAT) activity and immunoreactivity, and increased acetylcholine esterase (AChE) activity. In a transgenic AD mouse model, long-term oral administration of gintonin (25 or 50 mg/kg, 3 months) also attenuated AD-related cholinergic impairments. In this study, we showed that activation of G protein-coupled LPA receptors by gintonin is coupled to the regulation of cholinergic functions. Furthermore, this study showed that gintonin could be a novel agent for the restoration of cholinergic system damages due to Aβ and could be utilized for AD prevention or therapy.

No MeSH data available.


Related in: MedlinePlus