Muscone

Int J Pharm. 2013 Nov 1;456(1):73-9.

Influence of borneol and muscone on geniposide transport through MDCK and MDCK-MDR1 cells as blood-brain barrier in vitro model.[Pubmed: 23973509]

METHODS AND RESULTS:
The objective of this study was (1) to characterize geniposide transport through MDCK and MDCK-MDR1 cell lines to confirm its transport mechanism and (2) to evaluate the effect of borneol and Muscone as enhancers of geniposide transport in the BBB models so as to explore the enhancement mechanism. Transport studies of geniposide were performed in both directions, from apical to basolateral and from basolateral to apical sides. Drug concentrations were analyzed by HPLC. Geniposide showed relatively poor absorption in MDCK and MDCK-MDR1 cells, apparent permeability coefficients ranging from 0.323×10(-6) to 0.422×10(-6) cm/s. The in vitro experiments showed that geniposide transport in both directions was not concentration dependent and saturable, indicating purely passive diffusion. The efflux ratio of geniposide was less than 2 in the two cell models, which suggested that geniposide was not P-gp substrates. Geniposide transport in both directions significantly increased when co-administrated with increasing concentrations of borneol and Muscone.
CONCLUSIONS:
Actin staining results indicated that borneol and Muscone increased geniposide transport in the BBB models may attribute to disassembly effect on tight junction integrity.

Cell Mol Neurobiol. 2015 May 15.

Effects of Muscone on the Expression of P-gp, MMP-9 on Blood-Brain Barrier Model In Vitro.[Pubmed: 25976179]

Muscone is the main chemical ingredient in Musk which is main crude drug in Tongqiaohuoxue decoction (TQHXD), and TQHXD has a protective effect on damaged neurons, so we hypothesize that Muscone can alter blood-brain barrier (BBB) permeability via the modulation of P-glycoprotein (P-gp) and matrix metalloproteinase-9 (MMP-9) expression.
METHODS AND RESULTS:
In this study, astrocytes (AC) and human umbilical vein endothelial cells (ECV304) were co-cultured to simulate the BBB model in vitro. Leak testing, transmembrane resistance experiments, and BBB-specific enzyme testing were used to test whether the model was successful. Different concentrations of Muscone permeating the BBB were detected by gas chromatography (GC). The change of the transendothelial electrical resistance (TEER) on the BBB in vitro after treating with Muscone was detected by Millicell-ERS. The protein expression of P-gp, MMP-9 in normal, and oxygen/glucose deprivation (OGD) BBB model was determined by western blotting to inquire that the mechanism of Muscone penetrates the BBB model in vitro. The results show that Muscone was detected in the lower medium of the BBB model by GC; the values of TEER were no significant difference before and after Muscone (8 μM) was added to the BBB model; the expression of P-gp significantly decreased after the BBB model treatment with Muscone (4, 8, and 16 μM) for 24 h; the expression of P-gp and MMP-9 in different concentrations of Muscone groups had different degrees of reduction compared with the BBB in the state of OGD.
CONCLUSIONS:
In conclusion, Muscone could permeate the BBB model, and it was associated with the inhibition of P-gp and MMP-9 expression. An understanding of the mechanisms of Muscone across the BBB is crucial to the development of therapeutic modalities for cerebral vascular diseases.

Am J Transl Res . 2018 Dec 15;10(12):4235-4246. eCollection 2018.

Muscone improves cardiac function in mice after myocardial infarction by alleviating cardiac macrophage-mediated chronic inflammation through inhibition of NF-κB and NLRP3 inflammasome[Pubmed: 30662666]

Abstract Muscone is the main active monomer of traditional Chinese medicine musk. Previous studies have reported a variety of beneficial effects of Muscone. However, the effects of Muscone on chronic inflammation after myocardial infarction (MI) are rarely reported. This study evaluated the anti-inflammatory effects of Muscone on myocardial infarction by establishing a MI model in mice. We found that Muscone remarkably decreased the levels of inflammatory cytokines (IL-1β, TNF-α and IL-6), and ultimately improved cardiac function and survival rate. Furthermore, the main anti-inflammatory effect of Muscone was alleviating cardiac macrophage-mediated inflammatory response in heart tissues after MI. Bone marrow-derived macrophages (BMDMs) induced with lipopolysaccharide (LPS) were used as an in vitro inflammation model to further clarify anti-inflammatory mechanisms of Muscone. Muscone significantly downregulated the levels of LPS-induced inflammatory cytokines and inhibited NF-κB and NLRP3 inflammasome activation in BMDMs. Moreover, ROS and antioxidant indices in LPS-induced BMDMs were also ameliorated after Muscone treatment. To sum up, our study found that Muscone alleviated cardiac macrophage-mediated chronic inflammation by inhibiting NF-κB and NLRP3 inflammasome activation, thereby improving cardiac function in MI mice. Besides, the inhibitory effect of Muscone on inflammation may be related to the scavenging of ROS. It is suggested that Muscone may serve as a promising and effective drug for post-MI treatment. Keywords: Muscone; NF-κB; NLRP3 inflammasome; anti-inflammation; macrophage; myocardial

Int J Mol Med. 2014 Jul;34(1):103-11.

Beneficial effects of muscone on cardiac remodeling in a mouse model of myocardial infarction.[Pubmed: 24807380]

Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether Muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether Muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice.
METHODS AND RESULTS:
Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with Muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with Muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with Muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)‑β1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and nuclear factor (NF)-κB. Treatment with Muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS).
CONCLUSIONS:
Our results demonstrate that Muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti-inflammatory and anti-apoptotic effects in the ischemic myocardium.

Nat Prod Commun. 2012 Aug;7(8):1069-74.

Muscone exerts neuroprotection in an experimental model of stroke via inhibition of the fas pathway.[Pubmed: 22978231]

Identifying small molecules that are neuroprotective against stroke injury will be highly beneficial for treatment therapies. A cell viability assay and gas chromatography-mass spectrometry were used to identify active small molecules in XingNaoJing, which is a well known Chinese medicine prescribed for the effective treatment of stroke.
METHODS AND RESULTS:
Studies have found that Muscone is the active compound that prevents PC12 cell and cortical neuron damage following various injuries. Analysis of apoptosis indicated that Muscone inhibited glutamate-induced apoptotic cell death of PC12 cells and cortical neurons. Fas and caspase-8 expression were upregulated following glutamate treatment in cortical neurons, and was markedly attenuated in the presence of Muscone. Furthermore, Muscone significantly reduced cerebral infarct volume, neurological dysfunction and inhibited cortical neuron apoptosis in middle cerebral artery occluded (MCAO) rats in a dose-dependent manner. Moreover, a significant decrease in Fas and caspase-8 expression in the rat cortex was observed in MCAO rats treated with Muscone. Our results demonstrate that Muscone may be a small active molecule with neuroprotective properties, and that inhibition of apoptosis and Fas is an important mechanism of neuroprotection by Muscone.
CONCLUSIONS:
These findings suggest a potential therapeutic role for Muscone in the treatment of stroke.

Neurochem Int. 2014 May;70:10-21.

Neuroprotective effect of muscone on glutamate-induced apoptosis in PC12 cells via antioxidant and Ca(2+) antagonism.[Pubmed: 24636892 ]

In the pathogenesis of cerebral ischemia, glutamate excitotoxicity activates N-methyl-d-aspartate (NMDA) receptors which induce calcium influx and oxidative stress. Muscone exerts potent neuroprotective activities on cerebral ischemia. However, its underlying mechanism is yet to be elucidated.
METHODS AND RESULTS:
In this study, we demonstrated that pretreatment with Muscone in PC12 cells markedly ameliorated the loss of cell viability, mitochondrial membrane potential (MMP) collapse, the release of lactate dehydrogenase (LDH), Ca(2+) overload, reactive oxygen species (ROS) generation, and cell apoptosis induced by glutamate. Furthermore, Muscone also decreased NR1 (NMDA receptor subunit 1) protein expression, the ratio of Bax/Bcl-2 protein expression and prevented activitation of Ca(2+)/calmodulin-dependent protein kinase type II (CaMKII) and ASK1/JNK/p38 signaling pathways elicited by glutamate in PC12 cells.
CONCLUSIONS:
In conclusion, our results provided novel evidence that Muscone protected PC12 cells against glutamate-induced apoptosis by attenuating ROS generation and Ca(2+) influx, via NR1 and CaMKII-depended ASK-1/JNK/p38 signaling pathways.