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Overview

  • Akinori Akaike
  • Yasuhiko Izumi
Open Access
Chapter

Abstract

The nicotinic acetylcholine receptor (nAChR) is a typical ion channel type receptor. nAChR agonists such as nicotine evoke rapid excitatory responses in order of milliseconds. In addition to acute responses, sustained stimulation of nAChRs induces delayed cellular responses leading to neuroprotection via intracellular signal pathways probably triggered by Ca2+ influx. The most predominant subtypes of nAChRs expressed in the central nervous system (CNS) are α4 (known as α4β2) and α7 nAChRs. Long-term exposure to nicotine or acetylcholinesterase (AChE) inhibitors exerts protection against neurotoxicity induced by glutamate, β-amyloid, and other toxic insults. Nicotinic neuroprotection is mediated by α7 nAChR which shows high Ca2+ permeability, though contribution of α4 nAChR to nicotinic neuroprotection has also been suggested. Agonist stimulation of these receptors leads to activation of the phosphoinositide 3-kinase (PI3K)-Akt signaling pathway, downstream of neurotrophin receptors. AChE inhibitors including donepezil which is used for treatment of Alzheimer’s disease, also activate PI3K-Akt pathway via nAChRs. Neuroprotective effects induced by long-term nAChR stimulation indicate that CNS nAChRs play important roles in promotion of neuronal survival under pathophysiological conditions such as brain ischemia and neurodegenerative diseases. Elucidation of neuroprotective mechanisms of nAChRs may enable development of novel therapies for neurodegenerative diseases.

Keywords

Acetylcholine Acetylcholinesterase Neuroprotection Nicotine Nicotinic 

1.1 Introduction

Acetylcholine (ACh) is a small molecule with a simple chemical structure comprising an ester of choline and acetic acid. This molecule plays a crucial role in maintaining homeostasis and brain functions by acting as a neurotransmitter in the peripheral nervous system including motor nerves and the autonomic and the central nervous system (CNS). ACh is synthetized by choline acetyltransferase with choline and acetyl coenzyme A as substrates (Fig. 1.1). ACh released from nerve endings upon nerve excitation is rapidly degraded by acetylcholinesterase (AChE) into choline and acetic acid. ACh released in the synaptic cleft acts as an agonist to its specific receptors to evoke various cellular responses. ACh receptors are divided into two major classes, nicotinic ACh receptors (nAChRs) and muscarinic ACh receptors (mAChRs). The names of these receptors are derived from their specific agonists; nicotine contained in tobacco leaves and muscarine isolated from poisonous mushrooms, Amanita muscaria. nAChRs are ligand-gated ion channels, which evoke rapid depolarization responses to elicit neuronal excitation or skeletal muscle contraction. On the other hand, mAChRs are representative G-protein-coupled receptors classified as M1–M5 (Caulfield and Birdsall 1998). M1, M3, and M5 receptors interact with Gq-type G proteins and primarily cause excitatory responses, whereas M2 and M4 receptors interact with Gi/Go type G proteins and cause suppressive responses such as hyperpolarization. Responses mediated by mAChRs are relatively slow whereas opening of ligand-gated channels of nAChRs induces rapid cellular responses in the order of milliseconds.
Fig. 1.1

Synthesis and metabolism of acetylcholine (ACh). Choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) are involved in synthesis and metabolism of ACh. ACh is synthesized from Acetyl coenzyme A (Acetyl-CoA) and Choline, releasing Coenzyme A (HS-CoA)

nAChRs are highly expressed in skeletal muscle and the nervous system. Recently, expression of nAChRs in immune cells and glial cells has also attracted attention for potential therapeutic targeting in inflammation and neurodegenerative diseases (de Jonge and Ulloa 2007; Fujii et al. 2017; Jurado-Coronel et al. 2016). nAChRs are grouped into muscle-type (Nm), peripheral neuronal-type (Nn), and central neuronal-type (CNS) based on their distribution, subunit composition, and selective antagonists, as per the classification in Goodman & Gilman’s “The Pharmacological Basis of Therapeutics” (12th Edition, 2011). In their classification, CNS AChRs are further divided into two subtypes: (α4)2(β2)3 (α-bungarotoxin-insensitive) and (α7)5 (α-bungarotoxin-sensitive). Nn AChRs are widely expressed in autonomic ganglia and the adrenal medulla. CNS AChRs are expressed in neurons and glia of various brain areas. One of the typical antagonists of Nm AChRs is d-tubocurarine, a toxic alkaloid derived from an arrow poison and clinically used as a non-depolarizing blocking agent of the neuromuscular junction. Hexamethonium and mecamylamine are selective antagonists of Nn and CNS AChRs.

In all types of nAChRs, agonists such as ACh itself or nicotine-induced ion channel opening and evoke influx of Na+ and Ca2+. This triggers cell depolarization and turns on various functional switches (Albuquerque et al. 2009). Nicotinic cholinergic responses correlated with fast neurotransmission are easily detected in the endplate at the neuromuscular junction and ganglion cells of the sympathetic nerves. By contrast, it is relatively difficult to detect postsynaptic nicotinic responses of neurons in the CNS because most neuronal nAChRs quickly desensitized when exposed to nicotinic agonists (Albuquerque et al. 2009; Alkondon et al. 1998; Frazier et al. 1998). Development of drug-delivery devices that allow fast drug delivery and removal has made it possible to detect fast responses mediated by functional CNS nAChRs. While peripheral nAChRs are involved in rapid responses such as skeletal muscle contraction, nAChRs expressed in the CNS tend to be involved in relatively slow functional changes. For example, in the cerebral cortex, persistent nAChR stimulation triggers signals to the phosphoinositide 3-kinase (PI3K) cascade, which contributes to neuroprotection (Kihara et al. 2001; Dajas-Bailador and Wonnacott 2004). In the hippocampal neurons, nAChRs induce long-term potentiation of synaptic transmission (Kenney and Gould 2008). nAChRs regulate dopamine release in the striatum (Exley and Cragg 2008). Moreover, nAChRs are one of the important factors regulating memory and addiction (Molas et al. 2017; Nees 2015). Thus, in addition to rapid responses such as membrane depolarization induced by inward currents via ion channels, nAChR can generate longer-lasting effects in the CNS neurons, where rapid cation influx may trigger activation of complex intracellular signaling pathways.

1.2 Structural and Pharmacological Characterization of Nicotinic Acetylcholine Receptors

nAChRs are classified as members of the cysteine-loop (Cys-loop) family of ligand-gated ion channels (Sine and Eagle 2006; Tsetlin et al. 2011). The Cys-loop ligand-gated channels, also known as Cys-loop receptors, play prominent roles in generating excitatory and inhibitory postsynaptic potentials in the nervous system. nAChRs, γ-aminobutyric acid type A (GABAA) receptors, glycine receptors, and 5-hydroxytryptamine type-3 (5-HT3) receptors are classified as Cys-loop receptors. These receptors are composed of five subunits, forming a pentameric conformation around a central water-filled pore. The Cys-loop receptors have structurally common features with a characteristic loop formed by a disulfide bond between two cysteine residues. In nAChRs, the two cysteine residues separate 13 highly conserved amino acids located in the extracellular N-terminal domain of the α-subunit. The four hydrophobic transmembrane domains are estimated to form α-helices that make up the ion channel pore. The channel pore is lined with residues from the second transmembrane domain (TM2) from each of the five subunits of the receptors. The extracellular domain is largely composed of the N-terminus with binding sites for agonists.

The International Union of Basic and Clinical Pharmacology Committee on Receptor Nomenclature and Drug Classification (NC-IUPHAR, URL: http://www.guidetopharmacology.org/nciuphar.jsp) recommends a nomenclature and classification scheme for nAChRs based on subunit composition of known, naturally occurring and/or heterologously-expressed nAChR subtypes. A total of 17 subunits (α1–10, β1–4, γ, δ, and ε) have been identified in nAChRs. All subunits except α8, which is present in avian species, have been identified in mammals. ACh-binding sites are found at interfaces of the α subunit and the δ or γ subunit in Nm AChRs, and at interfaces of the α subunit and β subunit or two adjacent α subunits in Nn and CNS AChRs (Fig. 1.2). All α subunits possess two tandem cysteine residues near the ACh-binding site. By contrast, β, γ, δ, and ε subunits lack these cysteine residues. Nm AChRs of adult animals possess the stoichiometry (α1)2β1δε while Nm AChRs expressed in embryonic muscles and denervated adult muscles possess the stoichiometry (α1)2β1γδ (Lukas et al. 1999). Other types of nAChRs are predominantly expressed in neurons (Table 1.1). They are assembled as combinations of α2–α6 and β2–β4 subunits or α7, α8, and α9 subunits forming functional homo-oligomers. Nm AChRs and some subtypes of CNS AChRs (α7, α8, α9, and α10) are sensitive to α-bungarotoxin, a well-known neurotoxic protein derived from the venom of kraits. For α2, α3, α4, and β2 and β4 subunits, pairwise combinations of α and β (e.g., α3β4 and α4β2) are sufficient to form a functional receptor in vitro, but more complex isoforms may exist in vivo. Among those subunit combinations, the α3β4 subunit combination is dominant in nAChRs of autonomic ganglia neurons. The α5 and β3 subunits participate in formation of functional hetero-oligomeric receptors when they are expressed as a third subunit with another α and β pair such as α4α5αβ2, α4αβ2β3, and α5α6β2. The α6 subunit can form a functional receptor when co-expressed with β4 in vitro. The α7 subunit forms functional homo-oligomers. This subunit can also combine with a β subunit to form a hetero-oligomeric assembly such as α7β2. The α8 and α9 subunits show similar properties to the α7 subunit. For functional expression of the α10 subunit, co-assembly with α9 is necessary.
Fig. 1.2

Examples of subunit assembly and location of agonist-binding sites. Large circles indicate subunits of nicotinic acetylcholine receptor (nAChR). Small filled circles indicate binding sites of acetylcholine. Muscle-type AChR (Nm AChR), central nervous system AChR (CNS AChR)

Table 1.1

Characteristics of nAChR

Subtype

Primary subunit composition

Ca2+ permeability

Major location

α-Bungarotoxin sensitivity

α1

(α1)2β1γδ, (α1)2β1δε

Low

Neuromuscular junction

Sensitive

α2

α2β2, α2β4

Low

CNS

Insensitive

α3

α3β2, α3β4

Low

Autonomic ganglion, CNS

Insensitive

α4

(α4)3(β2)2, (α4)2(β2)3

Low

CNS

Insensitive

α5

α3β2α5, α3β4α5, (α4)2(β2)2α5

High

Autonomic ganglion, CNS

Insensitive

α6

α6β2β3, α6α4β2β3

High

CNS

Insensitive

α7

(α7)5

High

CNS, Non-neuronal cells

Sensitive

α8 (avian only)

(α8)5

High

CNS

Sensitive

α9

(α9)5, α9α10

High

Mechanosensory hair cells

Sensitive

α10

α9α10

High

Mechanosensory hair cells

Sensitive

Subtypes of nAChRs can be classified based on the predominant α-subunits (α1–α10) because the α subunit plays a key role in agonist binding to trigger ion channel opening, and subtype-selective antagonists like α-bungarotoxin distinguish receptors based on the α subunit combination (see Table 1.1). As per this receptor classification, Nm AChRs can be defined as α1 nAChRs, because the α1 subunit is highly expressed only in skeletal muscle and other α subunits are not detected in this tissue. Nn and CNS AChRs can be broadly classified into two subgroups, α2–α6 nAChRs, formed from the combination of α- and β-subunits, and α7–α9 nAChRs, forming homo-oligomers. The former subgroup, α2–α6 nAChRs, is insensitive to α-bungarotoxin whereas the latter subgroup, α7–α9 nAChRs, is sensitive to the toxin. Ion channels of homo-oligomeric receptors α7–α9 show high Ca2+ permeability. The α5 and α6 hetero-oligomeric receptors also show high Ca2+ permeability. Among those neuronal receptors, α3 nAChR is highly expressed in autonomic ganglia though this subtype is also expressed in CNS. The most predominant subtypes of nAChRs expressed in CNS are α4, known as α4β2 and α7 nAChRs (Dani 2015). Expression of both subunits is detected across wide areas of the CNS (Table 1.2). In the cerebral cortex, α2 and α5 subunits are also detected. Accumulating evidence also suggests anti-inflammatory and neuroprotective roles of α7 nAChR expressed in immune cells and glial cells (Egea et al. 2015; Morioka et al. 2015).
Table 1.2

Distribution of nAChR in CNS

α2

α3

α4

α5

α6

α7

Cortex

 

Cortex

Cortex

 

Cortex

Hippocampus

Hippocampus

Hippocampus

Hippocampus

 

Hippocampus

  

Striatum

Striatum

Striatum

 

Amygdala

 

Amygdala

  

Amygdala

  

Thalamus

   

Hypothalamus

 

Hypothalamus

  

Hypothalamus

 

Substantia nigra

Substantia nigra

Substantia nigra

Substantia nigra

Substantia nigra

 

Cerebellum

Cerebellum

  

Cerebellum

 

Spinal cord

Spinal cord

  

Spinal cord

1.3 Neuroprotection Mediated by Nicotinic Acetylcholine Receptors

It is widely recognized that glutamate acts as an excitatory neurotransmitter but also exerts excitatory neurotoxicity in pathological conditions such as ischemia (Meldrum and Garthwaite 1990; Duggan and Choi 1994; Brassai et al. 2015). In addition to cerebral ischemia, glutamate neurotoxicity is also considered as one of the risk factors for neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. Involvement of the cholinergic system in glutamate neurotoxicity was first reported in Mattson’s study (1989), showing that glutamate neurotoxicity in the hippocampus was enhanced by mAChR stimulation. Olney et al. (1991) showed evidence suggesting that N-methyl-D-aspartate (NMDA) receptor blockade by MK801 induces disinhibition of the central cholinergic system and causes excessive stimulation of mAChRs. They hypothesized that MK801 occasionally induces neurotoxicity instead of neuroprotection due to such an indirect mAChR stimulation. Thus, it is likely that mAChRs facilitate neuronal death in pathological states where glutamate neurotoxicity causes neurodegeneration.

On the other hand, accumulating evidence has suggested that nAChRs play a protective role in glutamate neurotoxicity. Approximately two decades ago, Akaike et al. (1994) and Kaneko et al. (1997) reported that glutamate neurotoxicity in the cerebral cortex was suppressed by nicotine and other nAChR agonists. Because NMDA receptors are acknowledged as a predominant route of glutamate cytotoxicity in the cerebral cortex, nicotine was suggested to prevent glutamate neurotoxicity by exerting a protective action against NMDA receptor-mediated intracellular responses to induce neuronal death. The neuroprotective effect of nicotine was antagonized by hexamethonium and mecamylamine, which are Nn and CNS nAChR antagonists, respectively, indicating that nicotine induces neuroprotection by its selective action on nAChRs. To our knowledge, our study (Akaike et al. 1994) was the first evidence for the neuroprotective role of nAChRs in the CNS. In this study, nicotine markedly reversed glutamate cytotoxicity, whereas muscarine exacerbated it. Carbachol, which acts on both nicotinic and muscarinic receptors, reduced glutamate cytotoxicity although its effect was less potent than that of nicotine. These observations indicate that nAChRs and mAChRs exert opposing effects on glutamate cytotoxicity. Moreover, findings of nAChR-mediated neuroprotection suggested a role of nicotinic cholinergic system in promoting neuronal survival under pathological conditions such as brain ischemia. A characteristic feature of the neuroprotective action of nicotine was that long-term exposure of more than an hour was necessary to ameliorate glutamate neurotoxicity. Following our findings in the cerebral cortex, neuroprotective effects mediated by nAChRs have been detected in various areas of the brain, including the hippocampus (Dajas-Bailador et al. 2000; Liu and Zhao 2004), the striatum (Ohnishi et al. 2009), dopaminergic neurons in the substantia nigra (Takeuchi et al. 2009), and the spinal cord (Nakamizo et al. 2005; Toborek et al. 2007). Nicotinic neuroprotection detected in those studies is estimated to be mediated by nAChR expressed in neurons though contribution of microglia activation by α7 nAChR in nicotinic neuroprotection is also suggested (Morioka et al. 2015).

It is unlikely that nicotine-induced protection against glutamate neurotoxicity is due to its direct action on NMDA receptors though there are some reports indicating that nicotine partially inhibits NMDA receptors. Aizenman et al. (1991) have demonstrated that nicotinic agonists partially inhibit whole cell NMDA-induced responses in cultured cortical neurons. Akaike et al. (1991) also reported modulatory action of cholinergic drugs on NMDA responses in the nucleus basalis of Meynert neurons. These studies suggest that nicotinic agonists have properties to directly interact with NMDA receptors and modulate their function. In this case, concomitant application of nicotine and glutamate or short-term nicotine exposure should affect glutamate neurotoxicity by direct modification of NMDA receptors. However, as described above, long-term exposure for more than an hour is necessary to detect nicotinic neuroprotection (Akaike et al. 1994; Kaneko et al. 1997). Moreover, nicotine-induced protection against glutamate cytotoxicity was antagonized by CNS nAChR antagonists. Therefore, persistent stimulation of nAChRs, but not direct inhibition of NMDA receptors is estimated to be the major route of nicotine-induced neuroprotection though direct interaction of nicotine with NMDA receptors may potentiate nicotine-induced neuroprotection.

In the forebrain including the cerebral cortex, α7 nAChRs, homo-oligomers of α7 subunits and α4β2 nAChRs, hetero-oligomers of α4 and β2 subunits are the major subtypes among CNS nAChRs (Albuquerque et al. 2009; Zoli et al. 2015). It has been reported that nicotine-induced protection against glutamate neurotoxicity was antagonized by selective α7 nAChR antagonists α-bungarotoxin and methyllycaconitine, as well as by the selective α4β2 nAChR antagonist dihydro-β-erythroidine (Kaneko et al. 1997). The α7 nAChR has attracted more attention because its mechanisms are thought to be involved in Alzheimer’s disease and β-amyloid (Aβ), a well-known risk factor of Alzheimer’s disease, is bound to α7 nAChRs under several conditions including in post-mortem Alzheimer’s disease brains (Wang et al. 2000; Parri et al. 2011). A selective α7 nAChR agonist, 3-(2,4)-dimethoxybenzylidene anabaseine (DMXB), exhibits potent neuroprotective action on glutamate neurotoxicity in vitro and brain ischemia in vivo (Shimohama et al. 1998). Aβ-induced neurotoxicity was suppressed by nicotine and DMXB (Kihara et al. 1997). Protective effects of nicotine and DMXB against Aβ-induced toxicity were antagonized by α-bungarotoxin, indicating that stimulation of α7 nAChRs is essential in suppressing Aβ-induced neurotoxicity. It is widely accepted that the β sheet conformation of Aβ is necessary in eliciting its neurotoxicity (Fändrich et al. 2011). Nicotine might influence the β sheet conformation of Aβ to attenuate its toxicity or to modulate survival signals. However, it has been reported that neither nicotine nor DMXB influences the β sheet conformation (Kihara et al. 1999). Thus, signal transduction downstream of α7 nAChRs is likely to be involved in the protective effect of nicotine against Aβ neurotoxicity.

1.4 Intracellular Signal Transduction Triggered by Nicotinic Acetylcholine Receptors

On exposure to agonists, nAChR exists in an active, open state, and elicits rapid depolarization in order of milliseconds. Thus, nAChR is classified as an excitatory receptor that evokes rapid excitation in neuronal, muscular, and secreting cells. Progressive decline of agonist-evoked current indicates closure of the channel. Upon further exposure to agonists, nAChRs exist in desensitized, non-functional states. Besides such short-term response, it is also recognized that nAChRs mediate long-term modification of cell functions via specific signaling pathways (Dajas-Bailador and Wonnacott 2004). nAChRs, especially α7 nAChRs, generate specific and complex Ca2+ signals that include adenylyl cyclase, protein kinase A, protein kinase C, Ca2+-calmodulin-dependent kinase, and phosphatidylinositol 3-kinase (PI3K) (Fig. 1.3). These phosphorylated downstream targets activate cellular signaling related to exocytosis and extracellular signal-regulated mitogen-activated protein kinase (ERK)-linked neuronal functions. Kihara et al. (2001) showed that α7 nAChR stimulation promoted PI3K-Akt signal transduction and inhibited Aβ neurotoxicity. PI3K phosphorylates Akt (or known as protein kinase B), a serine/threonine kinase. Activation of PI3-Akt cascade stimulates B-cell lymphoma 2 (Bcl-2) family members, which act as anti-apoptotic factors. It has been shown that Fyn, a member of the non-receptor type Src tyrosine kinase family, is associated with α7 nAChRs, though it is not clear whether other Src family members are involved in the cascade downstream of nAChRs. A relationship between nAChRs and Fyn was also implicated in a study, showing that catecholamine release induced by nicotine was dependent on the presence of Fyn and extracellular Ca2+ (Allen et al. 1996). In the study by Kihara et al. (2001), an inhibitor of Src tyrosine kinase reduced Akt phosphorylation. In addition, PI3K and Fyn were physically associated with α7 nAChRs. These findings suggest that nAChR stimulation causes Akt phosphorylation via signal transduction through Fyn to PI3K. Ca2+ influx through the α7 nAChR ion channels might contribute to this process. It has been proposed that PI3K-Akt activation leads to up-regulation of Bcl-2 to promote neuronal survival (Matsuzaki et al. 1999; Kihara et al. 2001).
Fig. 1.3

Nicotinic acetylcholine receptor (nAChR)-mediated signaling pathway in the brain. Adenylate cyclase (AC), acetylcholine (ACh), nAChR, AKT8 virus oncogene cellular homolog (Akt), B-cell lymphoma 2 (Bcl-2), calcium/calmodulin-dependent protein kinase (CaMK), calcium/calmodulin-dependent protein kinase kinase (CaMKK), cAMP-responsive element binding protein (CREB), extracellular signal-regulated kinase (ERK), Fgr/Yes-related novel protein (Fyn), Janus-activated kinase (JAK), MAPK/ERK kinase (MEK), nicotinic acetylcholine receptor (nAChR), phosphoinositide 3-kinase (PI3K), protein kinase A (PKA), SH2-containing collagen-related proteins (Shc), tropomyosin receptor kinase (Trk)

The intracellular signal pathway downstream of CNS nAChRs is known as a major pathway of neuroprotective action of neurotrophins including nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) (Dajas-Bailador and Wonnacott 2004; Lim et al. 2008). NGF and BDNF are known to affect survival and differentiation of central and peripheral neurons. The PI3K/Akt signaling cascades play a key role in neuronal survival due to neurotrophins (Chan et al. 2014). It has been reported that NGF and BDNF prevent glutamate neurotoxicity in a time-dependent manner, exhibiting significant neuroprotection in a period >1 h (Shimohama et al. 1993a, b; Kume et al. 1997, 2000). Each neurotrophin interacts with specific tropomyosin receptor kinase (Trk) receptors. Trk receptors show selectivity to members of the neurotrophin family. TrkA, TrkB, and TrkC serve as preferential receptors for NGF, BDNF, and neurotrophin-3, respectively (Kalb 2005). In contrast to these high-affinity receptors, the low-affinity neurotrophin receptor, p75, interacts with all neurotrophin members. BDNF promotes survival of neurons via TrkB in several brain regions including the cerebral cortex. Moreover, nAChRs appear to transduce survival signals similar to signals downstream of the Trk receptors of neurotrophins (Dajas-Bailador and Wonnacott 2004). Thus, nicotine and neurotrophins show similar properties in terms of time-course and signal pathways of neuroprotection.

1.5 Acetylcholinesterase Inhibitors Used for Treatment of Alzheimer’ Disease

The finding that glutamate neurotoxicity is suppressed by continuous stimulation of nAChRs suggests a possible function of the nicotinic cholinergic system as a factor promoting neuron survival in the CNS. AChE inhibitors including donepezil, which easily permeates the blood–brain barrier, are used for Alzheimer’s disease. Takada et al. (2003) reported that in cultured cortical neurons, AChE inhibitors including donepezil, galantamine, and tacrine inhibited glutamate neurotoxicity, though concomitant addition of AChE inhibitors and glutamate did not exhibit neuroprotection. Neuroprotective effects of AChE inhibitors were antagonized by Nn and CNS AChR antagonists including mecamylamine and methyllycaconitine, but not by a mAChR antagonist, scopolamine. Thus, AChE inhibitors appeared to possess neuroprotective effects similar to properties of nicotinic neuroprotection. AChE inhibitors such as donepezil remarkably suppress apoptosis of neurons induced by long-term administration of low concentrations of glutamate. Investigation of the involvement of PI3K on the protective action of AChE inhibitors revealed that the neuroprotective action of donepezil and galantamine is associated with Fyn, Janus Activating Kinase 2 (JAK2), and PI3K (Takada-Takatori et al. 2006; Akaike et al. 2010). In addition, these central AChE inhibitors promoted phosphorylation of Akt and increased the expression level of Bcl-2 protein. These results indicate that the PI3K-Akt signaling pathway is important for protection mechanisms of AChE inhibitors.

nAChRs are also recognized as major functional molecules mediating pharmacological action of tobacco smoking. Nicotine is a major ingredient of tobacco and stimulates all subtypes of nAChRs, though nicotine induces more rapid desensitization of nAChRs than ACh (Albuquerque et al. 2009). Several clinical studies have shown a negative correlation between prevalence of sporadic Parkinson’s disease and smoking history in relation to nAChR and neurodegenerative diseases, although no clear conclusion can be reached as to the relationship between Alzheimer’s disease and smoking (Godwin-Austen et al. 1982; Tanner et al. 2002; Ulrich et al. 1997). Moreover, galantamine, possessing allosteric potentiating action on α7 nAChR, is used as a treatment for Alzheimer’s disease (Albuquerque et al. 2001; Santos et al. 2002). Interestingly, long-term tobacco smoking or nicotine application induces up-regulation of nAChRs and, in most cases, facilitates their functions (Brody et al. 2013; Govind et al. 2009). This phenomenon is quite unique because, in most neuronal receptors including mAChRs, long-term receptor stimulation by specific agonists usually induces down-regulation of receptors and reduction of receptor functions. Moreover, AChE inhibitors including donepezil induce significant up-regulation of nAChRs (Kume et al. 2005; Takada-Takatori et al. 2010). Activation of the PI3-Akt pathway is necessary for nAChR up-regulation following long-term donepezil exposure. Receptor up-regulation following long-term exposure to nicotine and AChE inhibitors may be linked to diverse properties of nAChRs, from enhancement of learning and memory to addiction and neuroprotection, although precise mechanisms of up-regulation are not fully understood.

1.6 Conclusion

Nicotine induces fast nAChR currents of the order of milliseconds, while sustained nicotine exposure induces delayed intracellular responses. Neuroprotection is one of the dominant delayed responses mediated by CNS nAChRs. Mechanisms of neuroprotective effects exerted by persistent nAChR stimulation cannot be described only by simple excitatory reactions following depolarization induced by ion channel openings, but rather by activation of the intracellular PI3K-Akt signaling pathway leading to up-regulation of the anti-apoptotic protein Bcl-2. α7 nAChR, which shows high Ca2+ permeability, plays a crucial role in nicotinic neuroprotection. The metabolic change with Ca2+ as the second messenger may play an important role in triggering signals downstream of nAChRs. Therefore, it can be proposed that nAChRs are apparently implicated in two types of cellular functions; one for fast depolarization and the other for slow intracellular responses leading to neuroprotection (Fig. 1.4). Nicotine and other nAChR agonists evoke both acute and delayed responses; the former involves receptor desensitization and the latter involves receptor up-regulation. On the other hand, AChE inhibitors directly or indirectly stimulate nAChRs without evoking apparent acute responses (Akaike et al. 2010; Takada-Takatori et al. 2010). Neuroprotection and nAChR up-regulation by long-term exposure to AChE inhibitors, used in treatment of Alzheimer’s disease, suggest that CNS nAChRs are an important component of defense mechanisms of neurons against risk factors of neurodegeneration in pathophysiological conditions. Manipulation of neuroprotective properties of nAChRs may be a novel therapeutic approach for treatment of neurodegenerative diseases including Alzheimer’s disease.
Fig. 1.4

Schematic representation of presumed roles of the nicotinic acetylcholine receptor (nAChR) in the central nervous system (CNS). Acetylcholine (ACh) and nicotine act on CNS nAChR to exert both neuroexcitation via ionic channel function and neuroprotection via intracellular signal transduction. Acetylcholinesterase (AChE) inhibitors such as donepezil exert neuroprotection without exhibiting neuroexcitation

References

  1. Aizenman E, Tang LH, Reynolds IJ (1991) Effects of nicotinic agonists on the NMDA receptor. Brain Res 551:355–357CrossRefGoogle Scholar
  2. Akaike N, Harata N, Tateishi N (1991) Modulatory action of cholinergic drugs on N-methyl-D-aspartate response in dissociated rat nucleus basalis of Meynert neurons. Neurosci Lett 130:243–247CrossRefGoogle Scholar
  3. Akaike A, Tamura Y, Yokota T et al (1994) Nicotine-induced protection of cultured cortical neurons against N-methyl-D-aspartate receptor-mediated glutamate cytotoxicity. Brain Res 644:181–187CrossRefGoogle Scholar
  4. Akaike A, Takada-Takatori Y, Kume T et al (2010) Mechanisms of neuroprotective effects of nicotine and acetylcholinesterase inhibitors: role of α4 and α7 receptors in neuroprotection. J Mol Neurosci 40:211–216.  https://doi.org/10.1007/s12031-009-9236-1 CrossRefPubMedGoogle Scholar
  5. Albuquerque EX, Santos MD, Alkondon M (2001) Modulation of nicotinic receptor activity in the central nervous system: a novel approach to the treatment of Alzheimer disease. Alzheimer Dis Assoc Disord 5(Suppl 1):S19–S25CrossRefGoogle Scholar
  6. Albuquerque EX, Pereira FR, Alkondon M et al (2009) Mammalian acetylcholine receptors: from structure to function. Physiol Rev 89:73–120CrossRefGoogle Scholar
  7. Alkondon M, Pereira EF, Albuquerque EX (1998) α-bungarotoxin- and methyllycaconitine-sensitive nicotinic receptors mediate fast synaptic transmission in interneurons of rat hippocampal slices. Brain Res 810:257–263CrossRefGoogle Scholar
  8. Allen CM, Ely CM, Juaneza MA et al (1996) Activation of Fyn tyrosine kinase upon secretagogue stimulation of bovine chromaffin cells. J Neurosci Res 44:421–429CrossRefGoogle Scholar
  9. Brassai A, Suvanjeiev RG, Bán E et al (2015) Role of synaptic and nonsynaptic glutamate receptors in ischemia induced neurotoxicity. Brain Res Bull 112:1–6.  https://doi.org/10.1016/j.brainresbull.2014.12.007 CrossRefPubMedGoogle Scholar
  10. Brody AL, Mukhin AG, La Charite J et al (2013) Up-regulation of nicotinic acetylcholine receptors in menthol cigarette smokers. Int J Neuropsychopharmacol 16:957–966.  https://doi.org/10.1017/S1461145712001022 CrossRefPubMedGoogle Scholar
  11. Caulfield MP, Birdsall NJ (1998) International Union of Pharmacology. XVII. Classification of muscarinic acetylcholine receptors. Pharmacol Rev 50:279–290PubMedGoogle Scholar
  12. Chan KM, Gordon T, Zochodne DW et al (2014) Improving peripheral nerve regeneration: from molecular mechanisms to potential therapeutic targets. Exp Neurol 261:826–835.  https://doi.org/10.1016/j.expneurol.2014.09.006 CrossRefPubMedGoogle Scholar
  13. Dajas-Bailador F, Wonnacott S (2004) Nicotinic acetylcholine receptors and the regulation of neuronal signaling. Trends Pharmacol Sci 25:317–324CrossRefGoogle Scholar
  14. Dajas-Bailador FA, Lima PA, Wonnacott S (2000) The α7 nicotinic acetylcholine receptor subtype mediates nicotine protection against NMDA excitotoxicity in primary hippocampal cultures through a Ca2+ dependent mechanism. Neuropharmacology 39:2799–2807CrossRefGoogle Scholar
  15. Dani JA (2015) Neuronal nicotinic acetylcholine receptor structure and function and response to nicotine. Int Rev Neurobiol 124:3–19.  https://doi.org/10.1016/bs.irn.2015.07.001 CrossRefPubMedPubMedCentralGoogle Scholar
  16. de Jonge WJ, Ulloa L (2007) The α7 nicotinic acetylcholine receptor as a pharmacological target for inflammation. Br J Pharmacol 151:915–929CrossRefGoogle Scholar
  17. Duggan LL, Choi DW (1994) Excitotoxicity, free radicals, and cell membrane changes. Ann Neurol 35(Suppl):S17–S21CrossRefGoogle Scholar
  18. Egea J, Buendia I, Parada E et al (2015) Anti-inflammatory role of microglial α7 nAChRs and its role in neuroprotection. Biochem Pharmacol 97:463–472.  https://doi.org/10.1016/j.bcp.2015.07.032 CrossRefPubMedGoogle Scholar
  19. Exley R, Cragg SJ (2008) Presynaptic nicotinic receptors: a dynamic and diverse cholinergic filter of striatal dopamine neurotransmission. Br J Pharmacol 153(Suppl 1):S283–S297PubMedGoogle Scholar
  20. Fändrich M, Schmidt M, Grigorieff N (2011) Recent progress in understanding Alzheimer’s β-amyloid structures. Trends Biochem Sci 36:338–345.  https://doi.org/10.1016/j.tibs.2011.02.002 CrossRefPubMedPubMedCentralGoogle Scholar
  21. Frazier CJ, Buhler AV, Weiner JL et al (1998) Synaptic potentials mediated via α-bungarotoxin-sensitive nicotinic acetylcholine receptors in rat hippocampal interneurons. J Neurosci 18:8228–8235CrossRefGoogle Scholar
  22. Fujii T, Mashimo M, Moriwaki Y et al (2017) Expression and function of the cholinergic system in immune cells. Front Immunol 8:1085.  https://doi.org/10.3389/fimmu.2017.01085 CrossRefPubMedPubMedCentralGoogle Scholar
  23. Godwin-Austen RB, Lee PN, Marmot MG, Stern GM (1982) Smoking and Parkinson’s disease. J Neurol Neurosurg Psychiatry 45:577–581CrossRefGoogle Scholar
  24. Govind AP, Vezina P, Green WN (2009) Nicotine-induced upregulation of nicotinic receptors: underlying mechanisms and relevance to nicotine addiction. Biochem Pharmacol 78:756–765.  https://doi.org/10.1016/j.bcp.2009.06.011 CrossRefPubMedPubMedCentralGoogle Scholar
  25. Jurado-Coronel JC, Avila-Rodriguez M, Capani F et al (2016) Targeting the nicotinic acetylcholine receptors (nAChRs) in astrocytes as a potential therapeutic target in Parkinson’s disease. Curr Pharm Des 22:1305–1311CrossRefGoogle Scholar
  26. Kalb R (2005) The protean actions of neurotrophins and their receptors on the life and death of neurons. Trends Neurosci 28:5–11CrossRefGoogle Scholar
  27. Kaneko S, Maeda T, Kume T et al (1997) Nicotine protects cultured cortical neurons against glutamate-induced cytotoxicity via α7-neuronal receptors and neuronal CNS receptors. Brain Res 765:135–140CrossRefGoogle Scholar
  28. Kenney JW, Gould TJ (2008) Modulation of hippocampus-dependent learning and synaptic plasticity by nicotine. Mol Neurobiol 38:101–121.  https://doi.org/10.1007/s12035-008-8037-9 CrossRefPubMedPubMedCentralGoogle Scholar
  29. Kihara T, Shimohama S, Sawada H et al (1997) Nicotinic receptor stimulation protects neurons against β-amyloid toxicity. Ann Neurol 42:159–163CrossRefGoogle Scholar
  30. Kihara T, Shimohama S, Akaike A (1999) Effects of nicotinic receptor agonists on β -amyloid beta-sheet formation. Jpn J Pharmacol 79:393–396CrossRefGoogle Scholar
  31. Kihara T, Shimohama S, Sawada H et al (2001) α7 nicotinic receptor transduces signals to phosphatidylinositol 3-kinase to block A β-amyloid-induced neurotoxicity. J Biol Chem 276:13541–13546CrossRefGoogle Scholar
  32. Kume T, Kouchiyama H, Kaneko S et al (1997) BDNF prevents NO mediated glutamate cytotoxicity in cultured cortical neurons. Brain Res 765:200–204CrossRefGoogle Scholar
  33. Kume T, Nishikawa H, Tomioka H et al (2000) p75-mediated neuroprotection by NGF against glutamate cytotoxicity in cortical cultures. Brain Res 852:279–289CrossRefGoogle Scholar
  34. Kume T, Sugimoto M, Takada Y et al (2005) Up-regulation of nicotinic acetylcholine receptors by central-type acetylcholinesterase inhibitors in rat cortical neurons. Eur J Pharmacol 527:77–85CrossRefGoogle Scholar
  35. Lim JY, Park SI, Oh JH (2008) Brain-derived neurotrophic factor stimulates the neural differentiation of human umbilical cord blood-derived mesenchymal stem cells and survival of differentiated cells through MAPK/ERK and PI3K/Akt-dependent signaling pathways. J Neurosci Res 86:2168–2178.  https://doi.org/10.1002/jnr.21669 CrossRefPubMedGoogle Scholar
  36. Liu Q, Zhao B (2004) Nicotine attenuates beta-amyloid peptide-induced neurotoxicity, free radical and calcium accumulation in hippocampal neuronal cultures. Br J Pharmacol 141:746–754CrossRefGoogle Scholar
  37. Lukas RJ, Changeux J-P, Novere NL (1999) International Union of Pharmacology. XX. Current status of the nomenclature for nicotinic acetylcholine receptors and their subunits. Pharmacol Rev 51:397–401PubMedGoogle Scholar
  38. Matsuzaki H, Tamatani M, Mitsuda N (1999) Activation of Akt kinase inhibits apoptosis and changes in Bcl-2 and Bax expression induced by nitric oxide in primary hippocampal neurons. J Neurochem 73:2037–2046PubMedGoogle Scholar
  39. Mattson MP (1989) Acetylcholine potentiates glutamate-induced neurodegeneration in cultured hippocampal neurons. Brain Res 497:402–406CrossRefGoogle Scholar
  40. Meldrum B, Garthwaite J (1990) Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol Sci 11:379–387CrossRefGoogle Scholar
  41. Molas S, DeGroot SR, Zhao-Shea R et al (2017) Anxiety and nicotine dependence: emerging role of the habenulo-interpeduncular axis. Trends Pharmacol Sci 38:169–180.  https://doi.org/10.1016/j.tips.2016.11.001 CrossRefPubMedGoogle Scholar
  42. Morioka N, Harano S, Tokuhara M et al (2015) Stimulation of α7 nicotinic acetylcholine receptor regulates glutamate transporter GLAST via basic fibroblast growth factor production in cultured cortical microglia. Brain Res 1625:111–120.  https://doi.org/10.1016/j.brainres.2015.08.029 CrossRefPubMedGoogle Scholar
  43. Nakamizo T, Kawamata J, Yamashita H et al (2005) Stimulation of nicotinic acetylcholine receptors protects motor neurons. Biochem Biophys Res Commun 330:1285–1289CrossRefGoogle Scholar
  44. Nees F (2015) The nicotinic cholinergic system function. Neuropharmacology 96(Pt B):289–301.  https://doi.org/10.1016/j.neuropharm.2014.10.021 CrossRefPubMedGoogle Scholar
  45. Ohnishi M, Katsuki H, Takagi M et al (2009) Long-term treatment with nicotine suppresses neurotoxicity of, and microglial activation by, thrombin in cortico-striatal slice cultures. Eur J Pharmacol 602:288–293.  https://doi.org/10.1016/j.ejphar CrossRefPubMedGoogle Scholar
  46. Olney JW, Labruyere J, Wang G et al (1991) NMDA antagonist neurotoxicity: mechanism and prevention. Science 254:1515–1518CrossRefGoogle Scholar
  47. Parri HR, Hernandez CM, Dineley KT (2011) Research update: α7 nicotinic acetylcholine receptor mechanisms in Alzheimer’s disease. Biochem Pharmacol 82:931–942.  https://doi.org/10.1016/j.bcp.2011.06.039 CrossRefPubMedGoogle Scholar
  48. Santos MD, Alkondon M, Pereira EF et al (2002) The nicotinic allosteric potentiating ligand galantamine facilitates synaptic transmission in the mammalian central nervous system. Mol Pharmacol 61:1222–1234CrossRefGoogle Scholar
  49. Shimohama S, Ogawa N, Tamura Y et al (1993a) Protective effect of nerve growth factor against glutamate-induced neurotoxicity in cultured cortical neurons. Brain Res 632:269–302CrossRefGoogle Scholar
  50. Shimohama S, Tamura Y, Akaike A et al (1993b) Brain-derived neurotrophic factor pretreatment exerts a partially protective effect against glutamate-induced neurotoxicity in cultured rat cortical neurons. Neurosci Lett 164:55–58CrossRefGoogle Scholar
  51. Shimohama S, Greenwald DL, Shafron DH et al (1998) Nicotinic α7 receptors protect against glutamate neurotoxicity and neuronal ischemic damage. Brain Res 779:359–363CrossRefGoogle Scholar
  52. Sine SM, Eagle AG (2006) Recent advances in Cys-loop receptor structure and function. Nature 440:448–455.  https://doi.org/10.1038/nature04708 CrossRefPubMedGoogle Scholar
  53. Takada Y, Yonezawa A, Kume T et al (2003) Nicotinic acetylcholine receptor-mediated neuroprotection by donepezil against glutamate neurotoxicity in rat cortical neurons. J Pharmacol Exp Ther 306:722–727CrossRefGoogle Scholar
  54. Takada-Takatori Y, Kume T, Sugimoto M et al (2006) Acetylcholinesterase inhibitors used in treatment of Alzheimer’s disease prevent glutamate neurotoxicity via nicotinic acetylcholine receptors and phosphatidylinositol 3-kinase cascade. Neuropharmacology 51:474–486CrossRefGoogle Scholar
  55. Takada-Takatori Y, Kume T, Izumi Y et al (2010) Mechanisms of chronic nicotine treatment-induced enhancement of the sensitivity of cortical neurons to the neuroprotective effect of donepezil in cortical neurons. J Pharmacol Sci 112:265–272CrossRefGoogle Scholar
  56. Takeuchi H, Yanagida T, Inden M et al (2009) Nicotinic receptor stimulation protects nigral dopaminergic neurons in rotenone-induced Parkinson's disease models. J Neurosci Res 87:576–585.  https://doi.org/10.1002/jnr.21869 CrossRefPubMedGoogle Scholar
  57. Tanner CM, Goldman SM, Aston DA et al (2002) Smoking and Parkinson’s disease in twins. Neurology 58:581–588CrossRefGoogle Scholar
  58. Toborek M, Son KW, Pudelko A et al (2007) ERK 1/2 signaling pathway is involved in nicotine-mediated neuroprotection in spinal cord neurons. J Cell Biochem 100:279–292CrossRefGoogle Scholar
  59. Tsetlin V, Kuzmin D, Kasheverov I (2011) Assembly of nicotinic and other Cys-loop receptors. J Neurochem 116:734–741.  https://doi.org/10.1111/j.1471-4159.2010.07060 CrossRefPubMedGoogle Scholar
  60. Ulrich J, Johannson-Locher G, Seiler WO et al (1997) Does smoking protect from Alzheimer’s disease? Alzheimer-type changes in 301 unselected brains from patients with known smoking history. Acta Neuropathol 94:450–454CrossRefGoogle Scholar
  61. Wang HY, Lee DH, D'Andrea MR et al (2000) β-Amyloid1-42 binds to α7 nicotinic acetylcholine receptor with high affinity. Implications for Alzheimer’s disease pathology. J Biol Chem 275:5626–5632CrossRefGoogle Scholar
  62. Zoli M, Pistillo F, Gotti C (2015) Diversity of native nicotinic receptor subtypes in mammalian brain. Neuropharmacology 96(Pt B):302–311.  https://doi.org/10.1016/j.neuropharm.2014.11.003 CrossRefPubMedGoogle Scholar

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Authors and Affiliations

  1. 1.Department of Pharmacology, Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
  2. 2.Wakayama Medical UniversityWakayamaJapan
  3. 3.Department of PharmacologyKobe Pharmaceutical UniversityKobeJapan

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