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Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat.

Lee KM, Bang JH, Han JS, Kim BY, Lee IS, Kang HW, Jeon WK - BMC Complement Altern Med (2013)

Bottom Line: The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases.Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days.These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: KM-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea. wkjeon@kiom.re.kr.

ABSTRACT

Background: The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases. The present experiment was conducted to examine the effects of CP on white matter and hippocampal damage induced by chronic cerebral hypoperfusion.

Methods: Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days. The levels of microglial activation and myelin basic protein (MBP) were measured in the white matter and hippocampus of rats with chronic BCCAo, and the expression levels of mitogen-activated protein kinases (MAPKs) and inflammatory markers such as cyclooxygenase-2, interleukin-1β, and interleukin-6 were examined.

Results: MBP expression was reduced in the white matter and hippocampal regions of rats that received BCCAo. In contrast, reduced levels of MBP were not observed in BCCAo rats given CP treatments. The administration of CP alleviated microglial activation, the alteration of ERK and p38 MAPK signaling, and inflammatory mediator expression in rats with chronic BCCAo.

Conclusion: These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

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Effects of CP on the chronic BCCAo-induced MBP reduction in the white matter and hippocampus. Immunohistological staining was performed to evaluate the expression levels of MBP in the medial septum, corpus callosum, fimbria, fornix, and hippocampus in the sham-control group (n = 4), BCCAo + Vehicle group (n = 5), and BCCAo + CP group (n = 5). (A) Representative photomicrograph of MBP-positive cells. (B) MBP levels were decreased in the corpus callosum, fimbria, fornix, and hippocampus of the chronic BCCAo rats compared to control rats (*). Relative to the chronic BCCAo rats given vehicle, the chronic BCCAo-induced reduction of MBP expression in the CP-treated chronic BCCAo rats was not observed (#). CC, corpus callosum; HC, hippocampus; LV, lateral ventricle; FI, fimbria; FX, fornix.
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Figure 1: Effects of CP on the chronic BCCAo-induced MBP reduction in the white matter and hippocampus. Immunohistological staining was performed to evaluate the expression levels of MBP in the medial septum, corpus callosum, fimbria, fornix, and hippocampus in the sham-control group (n = 4), BCCAo + Vehicle group (n = 5), and BCCAo + CP group (n = 5). (A) Representative photomicrograph of MBP-positive cells. (B) MBP levels were decreased in the corpus callosum, fimbria, fornix, and hippocampus of the chronic BCCAo rats compared to control rats (*). Relative to the chronic BCCAo rats given vehicle, the chronic BCCAo-induced reduction of MBP expression in the CP-treated chronic BCCAo rats was not observed (#). CC, corpus callosum; HC, hippocampus; LV, lateral ventricle; FI, fimbria; FX, fornix.

Mentions: Chronic cerebral hypoperfusion leads to lesions in the white matter through the disruption of myelin sheaths and a loss of oligodendrocytes [15]. MBP is a crucial component of the myelin sheath. We examined the effects of CP on chronic BCCAo-induced MBP breakdown in the medial septum, corpus callosum, fimbria, fornix of the white matter, and hippocampus. An ANOVA revealed significant group effects in the corpus callosum, fimbria, fornix, and hippocampus (F(2,11) ≥ 3.79, p < 0.05). Post-hoc analyses of the group effects revealed that, compared to the sham-operated control rats, the expression level of MBP in the BCCAo rats with vehicle treatment was significantly decreased in white matter regions and the hippocampus (Figure 1). Interestingly, the reduced level of MBP was not observed in the chronic BCCAo rats administered CP, implying that CP treatment could ameliorate the degradation of the myelin sheath induced by chronic cerebral hypoperfusion. An ANOVA for the medial septum showed no group effects. On the other hand, the grey matter such as cerebral cortex, which is located near CA1 region of hippocampus vulnerable to chronic cerebral hypoperfusion, did not show alteration on MBP expression (Additional file 2: Figure S2). In addition, neuronal cell death, determined by counting NeuN-positive cells (neuronal antibody), was observed in CA1, CA3, and DG subfields of the hippocampus of rats with chronic BCCAo compared to sham-operated control rats. Reversely, this neuronal cell death was declined in CP-treated chronic BCCAo rats. However, these findings did not show statistical significance (Additional file 3: Figure S3).


Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat.

Lee KM, Bang JH, Han JS, Kim BY, Lee IS, Kang HW, Jeon WK - BMC Complement Altern Med (2013)

Effects of CP on the chronic BCCAo-induced MBP reduction in the white matter and hippocampus. Immunohistological staining was performed to evaluate the expression levels of MBP in the medial septum, corpus callosum, fimbria, fornix, and hippocampus in the sham-control group (n = 4), BCCAo + Vehicle group (n = 5), and BCCAo + CP group (n = 5). (A) Representative photomicrograph of MBP-positive cells. (B) MBP levels were decreased in the corpus callosum, fimbria, fornix, and hippocampus of the chronic BCCAo rats compared to control rats (*). Relative to the chronic BCCAo rats given vehicle, the chronic BCCAo-induced reduction of MBP expression in the CP-treated chronic BCCAo rats was not observed (#). CC, corpus callosum; HC, hippocampus; LV, lateral ventricle; FI, fimbria; FX, fornix.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4222777&req=5

Figure 1: Effects of CP on the chronic BCCAo-induced MBP reduction in the white matter and hippocampus. Immunohistological staining was performed to evaluate the expression levels of MBP in the medial septum, corpus callosum, fimbria, fornix, and hippocampus in the sham-control group (n = 4), BCCAo + Vehicle group (n = 5), and BCCAo + CP group (n = 5). (A) Representative photomicrograph of MBP-positive cells. (B) MBP levels were decreased in the corpus callosum, fimbria, fornix, and hippocampus of the chronic BCCAo rats compared to control rats (*). Relative to the chronic BCCAo rats given vehicle, the chronic BCCAo-induced reduction of MBP expression in the CP-treated chronic BCCAo rats was not observed (#). CC, corpus callosum; HC, hippocampus; LV, lateral ventricle; FI, fimbria; FX, fornix.
Mentions: Chronic cerebral hypoperfusion leads to lesions in the white matter through the disruption of myelin sheaths and a loss of oligodendrocytes [15]. MBP is a crucial component of the myelin sheath. We examined the effects of CP on chronic BCCAo-induced MBP breakdown in the medial septum, corpus callosum, fimbria, fornix of the white matter, and hippocampus. An ANOVA revealed significant group effects in the corpus callosum, fimbria, fornix, and hippocampus (F(2,11) ≥ 3.79, p < 0.05). Post-hoc analyses of the group effects revealed that, compared to the sham-operated control rats, the expression level of MBP in the BCCAo rats with vehicle treatment was significantly decreased in white matter regions and the hippocampus (Figure 1). Interestingly, the reduced level of MBP was not observed in the chronic BCCAo rats administered CP, implying that CP treatment could ameliorate the degradation of the myelin sheath induced by chronic cerebral hypoperfusion. An ANOVA for the medial septum showed no group effects. On the other hand, the grey matter such as cerebral cortex, which is located near CA1 region of hippocampus vulnerable to chronic cerebral hypoperfusion, did not show alteration on MBP expression (Additional file 2: Figure S2). In addition, neuronal cell death, determined by counting NeuN-positive cells (neuronal antibody), was observed in CA1, CA3, and DG subfields of the hippocampus of rats with chronic BCCAo compared to sham-operated control rats. Reversely, this neuronal cell death was declined in CP-treated chronic BCCAo rats. However, these findings did not show statistical significance (Additional file 3: Figure S3).

Bottom Line: The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases.Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days.These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

View Article: PubMed Central - HTML - PubMed

Affiliation: KM-Based Herbal Drug Development Group, Korea Institute of Oriental Medicine, Daejeon 305-811, Republic of Korea. wkjeon@kiom.re.kr.

ABSTRACT

Background: The cardiotonic pill (CP) is a herbal medicine composed of Salvia miltiorrhiza (SM), Panax notoginseng (PN), and Dryobalanops aromatica Gaertner (DAG) that is widely used to treat cardiovascular diseases. The present experiment was conducted to examine the effects of CP on white matter and hippocampal damage induced by chronic cerebral hypoperfusion.

Methods: Chronic cerebral hypoperfusion was induced in male Wistar rats by permanent bilateral common carotid artery occlusion (BCCAo). Daily oral administration of CP (200 mg/kg) began 21 days after BCCAo and continued for 42 days. The levels of microglial activation and myelin basic protein (MBP) were measured in the white matter and hippocampus of rats with chronic BCCAo, and the expression levels of mitogen-activated protein kinases (MAPKs) and inflammatory markers such as cyclooxygenase-2, interleukin-1β, and interleukin-6 were examined.

Results: MBP expression was reduced in the white matter and hippocampal regions of rats that received BCCAo. In contrast, reduced levels of MBP were not observed in BCCAo rats given CP treatments. The administration of CP alleviated microglial activation, the alteration of ERK and p38 MAPK signaling, and inflammatory mediator expression in rats with chronic BCCAo.

Conclusion: These results suggest that CP may have protective effects against chronic BCCAo-induced white matter and hippocampal damage by inhibiting inflammatory processes including microglial activation and proinflammatory mediator expression, and downreguating the hyperphosphorylation of ERK and p38 MAPK signaling.

Show MeSH
Related in: MedlinePlus