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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 Ca 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 Ca 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.

Nicotinic acetylcholine receptors (nAChRs) in the central nervous system are involved in higher brain function, i.e., memory, cognition, learning, among others. These receptors also exert various pharmacological effects, such as neuroprotection and antinociception. Therefore, elucidating the localization and/or expression level of nAChRs in the brain is useful to clarify functions regulated by nAChRs, under physiological and pathological conditions. “Molecular imaging” is a powerful tool that enables one to noninvasively obtain information from living subjects. Many signal types, such as, radiation, nuclear magnetic resonance, fluorescence, bioluminescence, and ultrasound, are commonly used for molecular imaging. Among them, nuclear medical molecular imaging, which uses radioactive imaging probes, has a great advantage due to its high sensitivity and the fact that it is a quantitative approach. Many nuclear medical imaging probes targeting nAChRs have been developed and some of them have successfully visualized nAChRs in the animal and human brain. Moreover, changes in nAChR density under pathological conditions have been detected in patients. This chapter summarizes the history and recent advance of nAChR imaging.

In the central nervous system, acetylcholine (ACh) is an important neurotransmitter related to higher brain functions and some neurodegenerative diseases. It is released from cholinergic nerve terminals and acts on presynaptic and postsynaptic ACh receptors (AChRs). Following release, ACh is rapidly hydrolyzed and the resultant choline is recycled as a substrate for new ACh synthesis. However, this classical concept of cholinergic transmission is currently reevaluated due to new evidence. In the cholinergic synapse, ACh may be itself taken up into postsynaptic neurons by a specific transport system and may act on AChRs at intracellular organelles (Golgi apparatus and mitochondria). Choline for ACh synthesis in cholinergic nerve terminals may be mainly supplied from choline at relevant concentration levels present in the extracellular space, rather than recycled from ACh-derived choline. Recent evidence has reopened the issue of classical cholinergic transmission and cognition, and may provide a novel approach to rational drug development for the treatment of neurodegenerative disorders such as Alzheimer’s disease.

Glutamate neurotoxicity is involved in various neurodegenerative disorders including brain ischemic stroke, trauma, and Alzheimer’s and Parkinson’s diseases. In addition to excitatory neuronal death, neuroinflammation accompanied by the activation of glial cells has been shown to be induced by these disorders. We previously reported the roles of nicotinic acetylcholine receptors (nAChRs) in the survival of central nervous system neurons during excitotoxic events and neuroinflammation. Nicotine and other nAChR agonists protected cortical neurons against glutamate neurotoxicity via α4- and α7-nAChRs in cultures of neurons obtained from the cerebral cortex of fetal rats. In addition, donepezil, a therapeutic acetylcholinesterase inhibitor currently being used for the treatment of Alzheimer’s disease, protected neuronal cells from glutamate neurotoxicity. Moreover, nicotine and donepezil induced the upregulation of nAChRs. Thus, we propose that nicotine as well as donepezil prevents glutamate neurotoxicity through Α4- and α7-nAChRs and the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. In addition to the beneficial effect on neuronal cells, we have reported the responses of astrocytes to bradykinin, an inflammatory mediator, and the effect of nAChR stimulation on these responses using cultured cortical astrocytes. Bradykinin induced a transient increase of intracellular calcium concentration ([Ca]) in cultured astrocytes. Both nicotine and donepezil reduced this bradykinin-induced [Ca] increase. This reduction was inhibited not only by mecamylamine, an nAChR antagonist, but also by PI3K and Akt inhibitors. These results suggest that nAChR stimulation suppresses the inflammatory response induced by bradykinin via the PI3K-Akt pathway in astrocytes.

Accumulated evidence shows that activation of microglia is associated with a change in morphology, from ramified to globular, which also represents a transition to M1 microglia. M1 microglia contribute to the induction and development of various neuroinflammatory disorders, including stroke, spinal cord injury, multiple sclerosis, Parkinson’s disease, Alzheimer’s disease psychiatric disorders, neuropathic pain and epilepsy. Thus, inhibition of microglial activation would be crucial in treating neurological disorders. Recent studies suggest a number of attractive molecular targets for blocking microglial activation. Among them, the nicotinic ACh receptor (nAChR), which especially contains the α7 subunit, contributes to the regulation of microglial activity through the inhibition of the synthesis of proinflammatory molecules. In addition, the glutamate transporter GLAST expressed in microglia is upregulated by α7 nAChR stimulation, which is mediated through both inositol triphosphate-Ca/calmodulin-dependent protein kinase II and fibroblast growth factor-2 pathways. It is possible, then, that activation of microglial α7 nAChR could be neuroprotective through inhibition of the production of proinflammatory molecules and enhancement of glutamate clearance from the synapse. This chapter will give an overview of the role of the α7 nAChR in microglial functioning and its potential as a therapeutic target for neurological disorders.

Shati/Nat8l was originally isolated as a methamphetamine-related-molecule from the nucleus accumbens of mice. Since then, Shati/Nat8l has been characterized as an -acetyltransferase-8-like protein (Nat8l) that catalyzes -acetylaspartate (NAA) synthesis from aspartate and acetyl-coenzyme A. It has been shown that elevated NAA levels detected by proton magnetic resonance spectroscopy (H-MRS) brain imaging indicates increased neuronal activity. Our group produced Shati/Nat8l knock out mice (Shati/Nat8l KO mice), which exhibit hyper locomotion, anxiety behaviors, and social dysfunction. These mice have a high sensitivity to methamphetamine, as evidenced by their results in assessments of locomotor activity and conditioned place preference, as well as their elevated dopamine levels. We used an adeno-associated virus (AAV) vector containing (AAV-) to overexpress the protein in different brain regions such as the striatum and the nucleus accumbens, in order to investigate their involvement in methamphetamine-induced behavioral and pharmacological changes. We showed that overexpression of accumbal Shati/Nat8l attenuates methamphetamine-induced behaviors.

Recent clinical studies have revealed further novel roles of Shati/Nat8l in psychiatric and neuronal diseases. We are just beginning to appreciate the various actions of this intriguing, recently discovered molecule in the central nervous system.

Cerebrovascular disorders including ischemic stroke, intracerebral hemorrhage and subarachnoid hemorrhage are among the major clinical concerns for which effective therapies are poorly available. Accumulating lines of evidence indicate that drugs acting on nicotinic acetylcholine receptors (nAChRs) may provide therapeutic effects on these disorders, based on their neuroprotective and anti-inflammatory actions. For example, the cholinergic neurotransmission in the central nervous system via nAChRs may function as an endogenous neuroprotective system that prevents pathogenic events associated with ischemic stroke. On the other hand, exogenous administration of nicotine or nAChR agonists to experimental models of ischemic stroke has been reported to produce conflicting results (either protective or deleterious), which may be largely dependent on the different regiments of drug treatments. With regard to intracerebral hemorrhage, preclinical findings suggest that post-treatment with nAChR agonists is effective in alleviating brain tissue damage and neurological outcome. The beneficial actions of nAChR agonist have also been reported for an experimental model of subarachnoid hemorrhage, which should be confirmed by further investigations. Although smoking has been considered as an important risk factor for stroke episodes, specific targeting of the central nAChRs may prove to be an effective and novel strategy for the treatment of diverse types of cerebrovascular disorders.

Both of the two most common neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), have multiple lines of evidence, from molecular and cellular to epidemiological, that nicotinic transmission is implicated in those pathogenesis. This review presents evidences of nicotinic acetylcholine receptor (nAChR)-mediated protection against neurotoxicity induced by β amyloid (Aβ), glutamate, rotenone, and 6-hydroxydopamine (6-OHDA) and the signal transduction involved in this mechanism. Our studies clarified that survival signal transduction, α7 nAChR-Src family-PI3K-AKT pathway and subsequent upregulation of Bcl-2 and Bcl-x, would lead to neuroprotection. Recently analyzing the properties of galantamine, we clarified the neuroprotective pathway, which is mediated by enhancement of microglial α7 nAChR resulting in upregulation of Aβ phagocytosis. Galantamine sensitizes microglial α7 nAChRs to choline and induce Ca influx into microglia. The Ca-induced intracellular signaling cascades may then stimulate Aβ phagocytosis through the actin reorganization. This discovery would facilitate further investigation of possible nAChRs enhancing drugs targeting not only neuronal but also microglial nAChRs.

Cholinergic neurotransmission plays a critical role in neuronal plasticity and cell survival in the central nervous system (CNS). Two types of acetylcholine receptors (AChRs), muscarinic AChRs (mAChRs) and nicotinic AChRs (nAChRs), trigger intracellular signaling through G protein activity and ion influx, respectively. To assess mechanisms underlying neuroprotection through nAChRs, we developed SAK3, a novel modulator of nAChR activity. Recently, we found that SAK3 enhances T-type calcium channel activity, promoting ACh release in the hippocampal CA1 region of olfactory-bulbectomized mice. Here, we observed potent SAK3 neuroprotective activity in mice with 20-min bilateral common carotid artery occlusion (BCCAO) or hypothyroidism. Treatment of mice with the α7 nAChR-selective inhibitor methyllycaconitine (0.5 mg/kg/day, p.o.) antagonized SAK3-mediated neuroprotection and memory improvement in BCCAO mice. Single administration of the anti-Graves’ disease therapeutic methimazole (MMI) to female mice disrupted olfactory bulb (OB) glomerular structure, and cholinergic neurons largely disappeared in the medial septum followed by memory loss. Chronic SAK3 (0.5–1 mg/kg, p.o.) administration significantly rescued the number of cholinergic medial septum neurons in MMI-treated mice and improved cognitive deficits seen in those mice. Overall, our study suggests that, in mice, the novel nAChR modulator SAK3 can rescue neurons impaired by transient ischemia and hypothyroidism. We also address mechanisms common to SAK3-induced neuroprotection in both conditions.

Accumulation of amyloid β protein (Aβ) in the brain causes cognitive impairment in Alzheimer’s disease (AD). The nature of the relationship between smoking and AD or dementia has been controversial. However, a recent meta-analysis revealed that smoking is a risk factor for AD. With regard to nicotinic acetylcholinergic receptors (nAChRs), both AD and control patients that smoke have been reported to show an increase in H-cytisine (an α4β4 nAChR agonist) binding in the temporal cortex. The α7 nAChR is also a key factor in AD pathology, particularly in relation to internalization of Aβs. Furthermore, there are many reports showing the neuroprotective effects of nicotine. The internalization of Aβ may lead to Aβ clearance in the brain.

We hypothesized that an extracorporeal system that rapidly removes Aβ from the blood may accelerate Aβ clearance from the brain. We have reported that (1) several medical materials including hemodialyzers can effectively remove blood Aβ, (2) the concentrations of blood Aβs decreased during hemodialysis, (3) removal of blood Aβ enhanced Aβ influx into the blood (ideally from the brain), resulting in maintenance or improvement of cognitive function, and (4) Aβ deposition in the brain of hemodialysis patients was significantly lower than in controls. Smoking affected blood Aβ removal efficiencies and brain atrophy. We believe this Extracorporeal Blood Aβ Removal Systems (E-BARS) may contribute as a therapy for AD.