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Beneficial effects of anisodamine in shock involved cholinergic anti-inflammatory pathway.

Zhao T, Li DJ, Liu C, Su DF, Shen FM - Front Pharmacol (2011)

Bottom Line: The main mechanism of anisodamine for anti-shock proposed in Pharmacology for Chinese medical students is to improve blood flow in the microcirculation.Here, we suggest a new mechanism for its anti-shock effect.That is, anisodamine, by blocking muscarinic receptor, results in rerouting of acetylcholine to α7 nicotinic acetylcholine receptor (α7nAChR) bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.

ABSTRACT
Anisodamine, an antagonist of muscarinic receptor, has been used therapeutically to improve blood flow in circulatory disorders such as septic shock in China since 1965. The main mechanism of anisodamine for anti-shock proposed in Pharmacology for Chinese medical students is to improve blood flow in the microcirculation. Here, we suggest a new mechanism for its anti-shock effect. That is, anisodamine, by blocking muscarinic receptor, results in rerouting of acetylcholine to α7 nicotinic acetylcholine receptor (α7nAChR) bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway.

No MeSH data available.


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Action mode of anisodamine in cholinergic anti-inflammatory pathway.
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Figure 3: Action mode of anisodamine in cholinergic anti-inflammatory pathway.

Mentions: The cholinergic anti-inflammatory pathway was a recently proposed pathway, which links the vagus nerve and immune system through α7 nicotinic acetylcholine receptor (α7nAChR). That is, the vagus nerve can modulate the immune response and inhibit inflammation through a physiological mechanism, which can be translated into a pharmacological strategy. Acetylcholine, the principal neurotransmitter of the vagus nerve, signaling through α7nAChR, can inhibit the production of pro-inflammatory cytokines from macrophages (Libert, 2003; Wang et al., 2003; Figure 3). Our previous study evaluated the effect of anisodamine, the muscarinic receptor antagonist, in rodent models of endotoxic shock. We hypothesized that blocking muscarinic receptor with anisodamine resulted in rerouting of acetylcholine to α7nAChR bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway. It was found that methyllycaconitine (an selective α7nAChR antagonist) significantly antagonized the beneficial effect of anisodamine on mean arterial pressure and TNF-α, interleukin-1β expression in response to lipopolysaccharide; the anti-shock effects of anisodamine were markedly attenuated in vagotomized mice and α7nAChR−/− mice; in vitro, anisodamine significantly augmented the effect of acetylcholine on fluorescence intensity stained with fluorescein isothiocyanate-labeled-α-bungarotoxin and TNF-α production stimulated with lipopolysaccharide. Our results suggest that activation of the vagal immune reflex can not only be pursued by stimulation of the vagus nerve or α7nAChR but also by inhibition of muscarinic receptors, which results in secondary activation of the cholinergic anti-inflammatory pathway (Liu et al., 2009; van Westerloo, 2009; Figure 3). We also found that α7nAChR played an important role in the organ damage in spontaneously hypertensive rats (SHRs), and chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved end organ damage and inhibited tissue levels of pro-inflammatory cytokines involved the NF-κB pathway (Li et al., 2011). These suggest that the cholinergic anti-inflammatory pathway might act, at least partly, through the NF-κB pathway, and anisodamine can indirectly activate the cholinergic anti-inflammatory pathway by blocking muscarinic receptor.


Beneficial effects of anisodamine in shock involved cholinergic anti-inflammatory pathway.

Zhao T, Li DJ, Liu C, Su DF, Shen FM - Front Pharmacol (2011)

Action mode of anisodamine in cholinergic anti-inflammatory pathway.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3108475&req=5

Figure 3: Action mode of anisodamine in cholinergic anti-inflammatory pathway.
Mentions: The cholinergic anti-inflammatory pathway was a recently proposed pathway, which links the vagus nerve and immune system through α7 nicotinic acetylcholine receptor (α7nAChR). That is, the vagus nerve can modulate the immune response and inhibit inflammation through a physiological mechanism, which can be translated into a pharmacological strategy. Acetylcholine, the principal neurotransmitter of the vagus nerve, signaling through α7nAChR, can inhibit the production of pro-inflammatory cytokines from macrophages (Libert, 2003; Wang et al., 2003; Figure 3). Our previous study evaluated the effect of anisodamine, the muscarinic receptor antagonist, in rodent models of endotoxic shock. We hypothesized that blocking muscarinic receptor with anisodamine resulted in rerouting of acetylcholine to α7nAChR bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway. It was found that methyllycaconitine (an selective α7nAChR antagonist) significantly antagonized the beneficial effect of anisodamine on mean arterial pressure and TNF-α, interleukin-1β expression in response to lipopolysaccharide; the anti-shock effects of anisodamine were markedly attenuated in vagotomized mice and α7nAChR−/− mice; in vitro, anisodamine significantly augmented the effect of acetylcholine on fluorescence intensity stained with fluorescein isothiocyanate-labeled-α-bungarotoxin and TNF-α production stimulated with lipopolysaccharide. Our results suggest that activation of the vagal immune reflex can not only be pursued by stimulation of the vagus nerve or α7nAChR but also by inhibition of muscarinic receptors, which results in secondary activation of the cholinergic anti-inflammatory pathway (Liu et al., 2009; van Westerloo, 2009; Figure 3). We also found that α7nAChR played an important role in the organ damage in spontaneously hypertensive rats (SHRs), and chronic treatment of SHRs with the α7nAChR agonist PNU-282987 relieved end organ damage and inhibited tissue levels of pro-inflammatory cytokines involved the NF-κB pathway (Li et al., 2011). These suggest that the cholinergic anti-inflammatory pathway might act, at least partly, through the NF-κB pathway, and anisodamine can indirectly activate the cholinergic anti-inflammatory pathway by blocking muscarinic receptor.

Bottom Line: The main mechanism of anisodamine for anti-shock proposed in Pharmacology for Chinese medical students is to improve blood flow in the microcirculation.Here, we suggest a new mechanism for its anti-shock effect.That is, anisodamine, by blocking muscarinic receptor, results in rerouting of acetylcholine to α7 nicotinic acetylcholine receptor (α7nAChR) bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmacology, School of Pharmacy, Second Military Medical University Shanghai, China.

ABSTRACT
Anisodamine, an antagonist of muscarinic receptor, has been used therapeutically to improve blood flow in circulatory disorders such as septic shock in China since 1965. The main mechanism of anisodamine for anti-shock proposed in Pharmacology for Chinese medical students is to improve blood flow in the microcirculation. Here, we suggest a new mechanism for its anti-shock effect. That is, anisodamine, by blocking muscarinic receptor, results in rerouting of acetylcholine to α7 nicotinic acetylcholine receptor (α7nAChR) bringing about increased acetylcholine-mediated activation of α7nAChR and the cholinergic anti-inflammatory pathway.

No MeSH data available.


Related in: MedlinePlus