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 (
alpha7nAChR). 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
alpha7nAChR knockout mice failed to suppress TNF levels, indicating that the alpha7nAChR-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 alpha7nAChR-dependent mechanism. Our data also indicate that a clinically used centrally-acting
acetylcholinesterase inhibitor can be utilized to suppress abnormal
inflammation to therapeutic advantage.