Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway

Abstract

The excessive release of cytokines by the immune system contributes importantly to the pathogenesis of inflammatory diseases. Recent advances in understanding the biology of cytokine toxicity led to the discovery of the "cholinergic anti-inflammatory pathway," defined as neural signals transmitted via the vagus nerve that inhibit cytokine release through a mechanism that requires the alpha7 subunit-containing nicotinic acetylcholine receptor (α7nAChR). Vagus nerve regulation of peripheral functions is controlled by brain nuclei and neural networks, but despite considerable importance, little is known about the molecular basis for central regulation of the vagus nerve-based cholinergic anti-inflammatory pathway. Here we report that brain acetylcholinesterase activity controls systemic and organ specific TNF production during endotoxemia. Peripheral administration of the acetylcholinesterase inhibitor galantamine significantly reduced serum TNF levels through vagus nerve signaling, and protected against lethality during murine endotoxemia. Administration of a centrally-acting muscarinic receptor antagonist abolished the suppression of TNF by galantamine, indicating that suppressing acetylcholinesterase activity, coupled with central muscarinic receptors, controls peripheral cytokine responses. Administration of galantamine to α7nAChR knockout mice failed to suppress TNF levels, indicating that the α7nAChR-mediated cholinergic anti-inflammatory pathway is required for the anti-inflammatory effect of galantamine. These findings show that inhibition of brain acetylcholinesterase suppresses systemic inflammation through a central muscarinic receptor-mediated and vagal-and α7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting acetylcholinesterase inhibitor can be utilized to suppress abnormal inflammation to therapeutic advantage.

Combined administration of anisodamine and neostigmine produces anti-shock effects: involvement of α7 nicotinic acetylcholine receptors

“…Activation of this anti-inflammatory pathway can be achieved by the following: 1) direct stimulation of the vagus nerve [16,17] , 2) the use of nicotine or nicotinic agonists (GTS-21, CAP55) to activate the α7nAChR [18][19][20] , and 3) the use of cholinesterase inhibitors (physostigmine, galantamine) [21][22][23] .…”

Nicotinic acetylcholine receptor-mediated calcium signaling in the nervous system

“…However evidence suggests that astrocytic nAChRs may be involved in neuroprotection. Furthermore there may be a role for nAChRs in inflammatory responses in the brain as in the periphery [93][94][95] . The identification of novel gene targets regulated by neuronal nAChR function remains a big challenge, requiring the continued elucidation of the signaling pathways through which nAChRs regulate their expression.…”

Cholinergic deficiency involved in vascular dementia: possible mechanism and strategy of treatment

“…Indeed, galantamine was able to reverse the learning impairment induced by mecamylamine [122] , and the activation of nicotinic receptors makes anti-inflammation of galantamine possible. In addition to nAChR, central muscarinic receptors may also be involved in the anti-inflammatory process of galantamine [123] .…”