α7 Nicotinic acetylcholine receptor: a key receptor in the cholinergic anti-inflammatory pathway exerting an antidepressant effect

Abstract

Depression is a common mental illness, which is related to monoamine neurotransmitters and the dysfunction of the cholinergic, immune, glutamatergic, and neuroendocrine systems. The hypothesis of monoamine neurotransmitters is one of the commonly recognized pathogenic mechanisms of depression; however, the drugs designed based on this hypothesis have not achieved good clinical results. A recent study demonstrated that depression and inflammation were strongly correlated, and the activation of alpha7 nicotinic acetylcholine receptor (α7 nAChR)-mediated cholinergic anti-inflammatory pathway (CAP) in the cholinergic system exhibited good therapeutic effects against depression. Therefore, anti-inflammation might be a potential direction for the treatment of depression. Moreover, it is also necessary to further reveal the key role of inflammation and α7 nAChR in the pathogenesis of depression. This review focused on the correlations between inflammation and depression as well-discussed the crucial role of α7 nAChR in the CAP.

Keywords: Depression; Inflammation; α7 nAChR.

Fig. 1

Role of neuroinflammation in the pathogenesis of depression. Low levels of DA can promote the inflammatory reaction, and the produced inflammatory cytokines can increase the probability of depression by reducing the prominent availability of neurotransmitters, increasing neurotoxicity, inhibiting GRs activity, and destroying neurogenesis and synaptic plasticity. ↑: upregulate; ↓: downregulate; ROS reactive oxygen species, RNS reactive nitrogen species, BH4 tetrahydrobiopterin, TDO tryptophan 2,3-dioxygenase, Kyn kynurenine, 5-HT 5-hydroxytryptamine, VMAT2 vesicle monoamine transporter 2, DA dopamine, p38MAPK p38 mitogen-activated protein kinase, MAPK mitogen-activated protein kinase, MAO monoamine oxidase, DRD3 dopamine receptors 3, DRD4 dopamine receptors 4, DRD5 dopamine receptors 5, SystemXc− Cystine/Glu reverse transporter system, Glu glutamate, EAATS excitatory amino acid reuptake transporters, HPA hypothalamus pituitary adrenal, GC glucocorticoid, GRs glucocorticoid receptors, NF-κB nuclear factors-kappa B, STAT5 signal transducer and activator of transcription 5, NGF nerve growth factor, BDNF brain-derived neurotrophic factor, TrkB tropomyosin receptor kinase B, PFC prefrontal cortex

Fig. 2

Molecular mechanisms of activation of α7 nAChR-mediated CAP. The activation of α7 nAChR could inhibit the expression of NF-κB through TLR4/NF-κB/NLRP3, JAK2/STAT3/NF-κB and Ca²⁺-related signaling pathways, reduce the production of inflammatory cytokines, reduce neuroinflammation, and finally play an antidepressant role. ↑: upregulate, ↓: downregulate, TLR4 Toll-like receptors 4, MyD88 myeloid differentiation factor 88, IKK inhibitor of kappa B kinase, IκB inhibitor of NF-κB, JAK2 Janus Kinase 2, STAT3 signal transduction and transcription activator 3, SOCS3 suppressor of cytokine signaling 3, NF-κB nuclear factors-kappa B, PLC phospholipase C, IP3 inositol 1,4,5-triphosphate, PI3K phosphatidylinositol 3-kinase, Akt protein kinase B, GSK-3 glycogen synthase kinase 3, BDNF brain-derived neurotrophic factor, TrkB tropomyosin receptor kinase B, ERK extracellular signal-regulated kinase, CaMKII Ca²⁺/calmodulin-dependent protein kinase II, CaMKIV Ca²⁺/calmodulin-dependent protein kinase IV, JNK c-Jun N-terminal kinase, Nrf2 nuclear transcription factor E2-related factor, HO-1 heme oxygenase-1, ROS reactive oxygen species, CREB cAMP-response element binding protein, NLRP3 NOD-like receptor protein 3, IL-1β interleukin-1β, IL-6 interleukin-6, TNF-α tumor necrosis factor-α, NO nitric oxide