α7 nicotinic acetylcholine receptor mediated neuroprotection in parkinson’s disease

Current Drug Targets, 2012, 13, 623-630 623

1873-5592/12 $58.00+.00 © 2012 Bentham Science Publishers

��7 Nicotinic Acetylcholine Receptor Mediated Neuroprotection in Parkinson’s Disease

Jun Kawamata, Syuuichirou Suzuki and Shun Shimohama*

Department of Neurology, School of Medicine, Sapporo Medical University, Sapporo, Hokkaido, Japan

Abstract: Parkinson’s disease (PD) is characterized by relatively selective degeneration of dopaminergic neurons in the

substantia nigra and loss of dopamine in the striatum. More than 50 epidemiological studies confirmed the low incidence

of PD in smokers. Examining the distribution of subtypes of nicotinic acetylcholine receptors (nAChRs) in dopaminergic

neurons of nigrostriatal system and its change in PD patients is quite important to elucidate possible neuroprotective

cascade triggered by nicotine. Evidences of nAChR-mediated protection against neurotoxicity induced by rotenone, 6-

hydroxydopamine (6-OHDA), and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are briefly reviewed. In

rotenone- and 6-OHDA-induced PD models, nAChR-mediated neuroprotection was blocked not only by �4�2 but also by

�7 nAChR antagonists. The survival signal transduction, �7 nAChR-Src family-PI3K-Akt/PKB cascade and subsequent

upregulation of Bcl-2, would lead to neuroprotection. These findings suggest that nAChR-mediated neuroprotection is

achieved through subtypes of nAChRs and common signal cascades. An early diagnosis and protective therapy with

specific nAChR modulations could be effective in delaying the progression of PD.

Keywords: Parkinson’s disease, nicotine, nAChR, rotenone, 6-OHDA, MPTP.

INTRODUCTION

Parkinson’s disease (PD) is the second most common neurodegenerative disorder following Alzheimer’s disease (AD) and its socio-economic impacts have been increasing especially in the developed countries. The main discordance of the neurotransmitter system in PD is nigrostriatal dopa-minergic deficit, but the other systems including cholinergic, noradrenergic, and serotonergic are also involved. Close mutual interaction between dopaminergic and cholinergic systems is crucial not only in motor but also in cognitive and reward related processing [1, 2]. In terms of therapeutic aspect, nowadays the main therapeutic agents, l-dopa and dopamine agonists, are targeting dopaminergic system, whereas an anti-cholinergic drug, trihexyphenidyl hydro-chloride, initially introduced effective therapeutic agent against PD, had shown the importance of cholinergic system in PD pathogenesis and therapeutic alternatives.

Apart from rare familial cases, the causes of PD still remain unidentified, but it has long been acknowledged that genetic as well as environmental factors to be highly relevant to the causes. Many epidemiological studies recognized the smoking habits as a factor working against the development of PD. These epidemiological evidences clearly show that placing the importance on modulation of acetylcholine systems can be the key therapeutic targets of the neuro-degenerative disease.

This review presents evidence for nicotinic acetylcholine receptor (nAChR)-mediated protection against rotenone, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) induced neurotoxicity in vitro and PD animal models and perspective of cholinotherapy against PD.

*Address correspondence to this author at the Department of Neurology,

School of Medicine, Sapporo Medical University, S1W17 Chuo-ku,

Sapporo, Hokkaido, 060-8556, Japan; Tel: +81-11-611-2111; Fax: +81-11-

622-7668; E-mail: [email protected]

PD AND ITS PATHOGENESIS

PD is the second most common progressive neuro-degenerative disorder following AD. It is characterized by relatively selective degeneration of dopaminergic neurons in the substantia nigra (SN) and loss of dopamine in the stria-tum resulting in resting tremor, rigidity, bradykinesia and postural instability [3]. In the central nervous system (CNS), the dopaminergic neurons of the nigrostriatal projection are selectively impaired in PD before motor symptom becomes apparent [4]. Formerly PD was regarded as a dopaminergic deficit disease, but today many accumulating evidences show that PD is systemic disease involving not only CNS but also autonomic systems, for example cardiac sympathetic nerve [4, 5]. Many nonmotor features of PD are related to the degeneration of nondopaminergic transmitter systems [3]. Although the pathogenesis of PD is still unclear, it is considered that the interaction of gene and the environment plays roles in causing the multi-factorial disease. Genetic studies revealed several mutations in familial PD genes such as �-synuclein, parkin, PINK1, LRRK2, DJ-1, UCHL1, and ATP13A2 [6]. Rural residency, pesticides and intrinsic toxic agents were reported as environmental risk factors for sporadic PD. Epidemiological studies suggest that the use of pesticides increases the risk of PD, possibly via reduced activity of complex I in the mitochondrial respiratory chain in the SN [7-9]. Above all the strongest environmental factor relevant to PD is smoking habits, which is discussed below.

PD AND SMOKING

Epidemiological studies confirmed the smoking habits as a factor working against the development of PD [10]. To date more than 50 epidemical studies have been reported since the first paper was published in 1959 [11-13]. Mono-zygotic twin studies confirmed that the inverse effect of smoking against PD, which means bias from genetic factors of participants, e.g. easiness to quit smoking or intolerance

624 Current Drug Targets, 2012, Vol. 13, No. 5 Kawamata et al.

of smoking, is not the main cause of the inverse effect [14, 15]. Chen et al.’s study suggests that duration rather than the intensity of smoking is crucial [16]. Although the cigarettes contains numerous chemical compounds, these epidemio-logical evidences show that placing the importance on modu-lation of acetylcholine systems can be the key therapeutic targets of the neurodegenerative disease.

Similar inverse effect of smoking habit is also reported in patients with ulcerative colitis, a characteristic inflammatory bowel disorder. Patients who have history of smoking get the disease after cessation of smoking. This tendency is exp-lained by anti-inflammatory potential of nicotine [17].

Mann et al. showed that smokers have higher cytochrome P450 (CYP) 2D6 in the brain especially in the basal ganglia. To evaluate whether nicotine induce CYP2D6, an enzyme possibly inactivate neurotoxins in PD pathogenesis, they injected nicotine subcutaneously to monkeys for 22 days and analyzed the change of CYP2D6 expression and distribu-tions in the brains. Induction of CYP2D6 was observed in SN, putamen, and brainstem, regions affected in PD. They hypothesize that smokers have higher level of CYP2D6 that may inactivate neurotoxins related to PD pathogenesis [18]. Genome wide association (GWA) meta-analyses for the number of cigarettes smoked per day of smokers and smok-ing initiation revealed associated loci in the area encoding nicotine metabolizing enzymes (CYP2A6 and CYP2B6) [19].

SUBUNITS OF ACETYLCHOLINE RECEPTORS IN CENTRAL NERVOUS SYSTEM

Acetylcholine (ACh) is one of the major neurotrans-mitters in the CNS and its receptors are classified into two

groups; nicotinic (nAChRs) and muscarinic ACh receptors (mAChRs). In the brain, nAChRs show additional com-plexity, as there are multiple receptor subtypes with differing properties and functions [20-22]. At least ten � subunits (�2–�7, �9, and �10 in mammals; �8 in chicks) and three � subunits (�2–�4) have been identified in the brain (Fig. 1).

Implication of heterometric nAChR containing �6 sub-units, �6�2*, is also emphasized in dopaminergic systems in the CNS [10, 23-25,]. (*indicates possible additional subunits).

Recent genetic analysis on nicotine addiction reports the possible SNPs association with several loci, one is in the �5/�3/�4 gene (CHRNA5, CHRNA3, and CHRNB4) region on Ch15q25 and the other is in the �3/�6 gene (CHRNB3 and CHRNA6) region on Ch8p11. These data are consistent in several groups analyzing different populations [26, 27].

There are evidences that neuronal nAChRs are involved in synaptic plasticity as well as in neuronal survival and neuroprotection. Moreover, presynaptic nAChRs can modu-late the release of many neurotransmitters, including dopa-mine, noradrenaline, serotonin, ACh, �-aminobutyric acid (GABA), and glutamate. These neurotransmitter systems play an important role in cognitive and non-cognitive func-tions such as learning, memory, attention, locomotion, moti-vation, reward, reinforcement, and anxiety. Thus, nAChRs are considered promising therapeutic targets for new treat-ments of neurodegenerative disorders and its affiliated complications.

It is also known that �4 and �2 nAChR genes, CHRNA4 and CHRNB2, are causative genes of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) [28, 29]. Benign nature of the epilepsy is explained by compensatory mecha-nism of the nAChRs.

Fig. (1). Composition of Major nAChRs, ��4�2, �7, and �6�2* in the Dopaminergic Systems. In the CNS, functional receptors consist

of heteropentametric � and � subunits, with the exception of �7-10 subunits, which apparently form functional homopentameric receptors.

�7 homometric and �4�2 heterometric nAChRs are the major two subtypes. In dopaminergic systems the �6 containing nAChRs,

�4�6�2�3, �6�2�3, and �6�2, may play important roles. The black squares indicate the nicotine binding sites of the receptors.

�6

�2�4 �7 �4/6�3

�2

Ca2+

�� 7 Nicotinic Acetylcholine Receptor Mediated Neuroprotection in Parkinson’s Disease Current Drug Targets, 2012, Vol. 13, No. 5 625

DIFFERENTIAL EXPRESSION OF SUBTYPES OF

NICOTINIC RECEPTORS IN SUBSTANTIA NIGRA

In rodents and primates studies, the distribution of the subunits of nAChRs was documented with radioautography methods and transcriptional and expression levels are also measured by RT-PCR and western blotting. Among the nAChRs, the �4�2 and �7 nAChRs are the most widely expressed subtypes in the brain. Similarity of �3 and �6 subunits had hampered the precise analysis of these subunits before introduction of �6 selective antagonists, �-Contoxin MII and �-Contoxin PIA. Presently the precise analysis of �6 subunit distribution is available. Grady et al. [30] exa-mine mouse brain using in situ hybridization to characterize the mRNA expression pattern. The ventral tegmental area (VTA) and SN express high concentrations of �4 and �6 and �2, and �3 mRNAs, intermediate levels of �5 mRNA, and low levels of the �3 and �7 mRNAs. No signal for �2 and �4 mRNA was detected [30, 31]. They reviewed the subtypes of nAChRs on dopaminergic terminals of mouse striatum reporting five nAChR subtypes that expressed on dopaminergic nerve terminals, three of which are �6 containing subunits, namely �4�6�2�3, �6�2�3, and �6�2. The remaining 2 subtypes, �4�2, �4�5�2, are more nume-rous than the �6-containg subtypes. The �6 containing nAChRs, which do not contribute to dopamine release induced by nicotine, are mainly located on dopaminergic neuronal terminals and probably mediating the endogenous cholinergic modulation of dopamine release at the terminal level. In contrast, �4�2 nAChR represent the majority of functional heteromeric nAChRs on dopaminergic neuronal soma. �7 nAChRs are present on dopaminergic neuronal soma, contributing to nicotine reinforcement [32] (Fig. 2).

There are several studies analyzing the decline of specific nAChRs in PD patients. Court et al. [33] reported the decline

of �3 subunits and no change of �7 subunits. Gotti et al. [34] and Court et al. [33] reported decreased level of �4 subunits but Guan et al. [35] reported not. Bordia et al. [25] reported the decline of �6 subunits in caudate and putamen. Guan et al. [35] reported up regulation of �7 subunit in temporal cortex, whereas the �7 mRNA level was unchanged. Bordia et al. [25] further specified that the most vulnerable subtype in striatum of MPTP treated mice and monkeys is �6�4�2�3 rather than �6�2�3 and further identified the specific loss of �6�4�2�3 subtype in PD brains.

These results seem to indicate that the decline of nigro-striatal specific �6* subtypes is highly specific and relevant to the PD pathogenesis but not is �7 subtype. Functional studies on �6* nAChRs should be undertaken to confirm its pathological importance in PD. For this purpose, Drenan et al. [36] generated the gain-of-function �6* nAChR trans-genic mouse, which turned to present locomotive hyperact-ivity. With low dose of nicotine by the way of stimulating dopamine but not GABA, its phenotype was exaggerated and hyperdopaminergic state in vivo was observed. Furthermore, complexity of the networks should be taken into considera-tion, e.g. Nomikos et al. [37] reported that nicotine acts on �7 nAChRs located on cortical glutamatergic terminals and stimulates intra-VTA glutamate release and alters the firing pattern of dopaminergic neuron via NMDA receptor activation.

NEUROPROTECTION AGAINST ROTENONE CYTOTOXICITY

Rotenone is a naturally occurring complex ketone pesti-cide derived from the roots of Lonchocarpus species. It can rapidly cross over cellular membranes without the aid of

Fig. (2). Composition of nAChRs Subunits on Neurons in Substantia Nigra and Striatum. �4�2 nAChR represents the majority of

functional heteromeric nAChRs on dopaminergic neuronal soma in SN and also on the terminal in the striatum. �7 nAChRs are present on

dopaminergic neuronal soma, contributing to nicotine reinforcement. The �6 containing nAChRs are mainly located on dopaminergic

neuronal terminals and probably mediating the endogenous cholinergic modulation of dopamine release at the terminal level.

Striatum

- �4�2

- �7Substantia nigra

- �7

- �6�2*


transporters, including the blood brain barrier (BBB). Rotenone is a strong inhibitor of complex I, which is located at the inner mitochondrial membrane and protrudes into the matrix. In 2000, Betarbet et al. [38] demonstrated with rat model that chronic systemic exposure to rotenone causes many features of PD, including slow-progressive dopamine neuronal loss in nigrostriatal dopaminergic system, and Lewy body-like particles, which are primarily aggregations of �-synuclein [9, 39].

Rotenone works as a mitochondrial complex I inhibitor. Acute lethal doses of rotenone eliminate the mitochondrial respiratory system of the cell, resulting in an anoxic status that immediately causes cell death. At sub-lethal doses it causes partial inhibition of mitochondrial complex I, and in this situation mitochondrial dysfunction leads to increased oxidative stress, decreased ATP production, increased aggre-gation of unfolded proteins, and then activated apoptotic pathway(s) that result in cell death [38], resembling dopa-minergic neurodegeneration in PD.

In Vitro Model

In cultures of rat fetus mesencephalic neurons, 48h exposure to rotenone caused dose-dependent neurotoxicity, more evident in dopaminergic neurons than in other neuronal cells. This result showed that dopaminergic neurons were more vulnerable to rotenone-induced neurotoxicity. Simulta-neous administration of nicotine resulted in a dose-depend-ent increase of the viability of dopaminergic neurons. This neuroprotective effect was inhibited by 100 μM mecamyl-amine, a broad-spectrum nAChR antagonist, 100 nM �BuTx, an �7 nAChR antagonist, and 1 μM DH�E, an �4�2 antagonist. Nicotine-induced neuroprotection was therefore shown to occur via nAChRs, especially through �7 and �4�2 receptors. Furthermore nicotinic neuroprotection is

inhibited by LY294002, a PI3K inhibitor, and triciribine, an Akt/PKB inhibitor. This means that nicotine could activate the PI3K-Akt/PKB pathways and increase the survival of mesencephalic dopaminergic cells against rotenone-induced cell death [40]. From our previous studies the PI3K-Akt/PKB pathways would lead to subsequent upregulation of Bcl-2 and neuroprotection [41, 42] (Fig. 3).

In Vivo Model (Rotenone Induced Rodent Model)

We confirmed that orally rotenone-treated mouse model showed motor deficits, dopaminergic cell death in the SN, and nerve terminal/axonal loss in the striatum. These find-ings are relevant to some previous reports on rotenone PD models [43-45]. Simultaneous subcutaneous administration of nicotine mitigated both motor deficits and dopaminergic neuronal cell loss in the SN of rotenone-treated mice.

NEUROPROTECTION AGAINST 6-OHDA CYTO-TOXICITY

6-OHDA’s strong neurotoxic effects were described by Ungerstedt in 1971, in a study presenting the first example of using a chemical agent to produce an animal model of PD [45]. Since 6-OHDA cannot cross over the BBB, systemic administration fails to induce parkinsonism. This induction model requires 6-OHDA to be injected into the SN, medial forebrain bundle, and striatum. The intrastriatal injection of 6-OHDA causes progressive retrograde neuronal degenera-tion in the VTA and SN.

In Vitro Model

Using the SH-SY5Y human neuroblastoma cell line, Riveles et al. proved the neuroprotection effect of nicotine at

Fig. (3). Proposed Hypothesis for the Mechanism of nAChR-mediated Survival Signal Transduction in Dopaminergic Systems.

Nicotine-induced neuroprotection is mediated via nAChRs, especially through �7 and �4�2 receptors, and inhibited by a PI3K inhibitor and

an Akt/PKB inhibitor. This means that nicotine activates the PI3K-Akt/PKB pathways and increase survival of dopaminergic neurons. From

our previous studies JAK2 and Fyn are key molecules trigger activation of the PI3K-Akt/PKB pathways which lead to subsequent

upregulation of Bcl-2 and neuroprotection [41, 42].

Ca2+

α7 nAChR

JAK2 Fyn

Pl3K

p-AktMAPK

NicotineCa2+

α4β2 nAChR

Bcl-2

Survival


concentrations ranging from 10-7

to 10-5

M against 6-OHDA induced neurotoxicity on vulnerable dopaminergic neurons [46].

In Vivo Model (6-OHDA Induced Hemiparkinsonian Rodent Model)

Costa et al. evaluated the neuroprotection of nicotine in 6-OHDA induced hemiparkinsonian rat model. They injec-ted 6μg 6-OHDA in the SN, and confirmed that the dopamine level in the corpus striatum was decreased nearly by half. Repeated subcutaneous nicotine administration at 4h before and 20, 44 and 68 h after 6-OHDA injection signifi-cantly prevented the striatal dopamine loss and the protection reverted by nAChR antagonist. The protective effect was not achieved by one -off administration of nicotine before or after 6-OHDA injection [47].

In Vivo Model (Synergistic Effect of Galantamine in 6-OHDA-Induced Hemiparkinsonian Rodent Model)

In the rat 6-OHDA-induced hemiparkinsonian model, the neuroprotective effects of galantamine and nicotine were evaluated. 6-OHDA with or without galantamine and/or nicotine was injected into unilateral SN of rats. Although methamphetamine-stimulated rotational behavior and dopa-minergic neuronal loss induced by 6-OHDA were not inhi-bited by galantamine alone, those were moderately inhibited by nicotine alone. In addition, 6-OHDA-induced neuronal loss and rotational behavior were synergistically inhibited by co-injection of galantamine and nicotine. These protective effects were abolished by mecamylamine, a nAChR anta-gonist. �7nAChR was expressed on both dopaminergic and non-dopaminergic neurons in the rat substantia nigra pars compacta (SNpc). A combination of galantamine and nico-tine greatly suppressed 6-OHDA-induced reduction of �7nAChR-immunopositive dopaminergic neurons. These results suggest that galantamine synergistically enhances the neuroprotective effect of nicotine against 6-OHDA-induced dopaminergic neuronal loss through an allosteric modulation of �7nAChR activation [48].

NEUROPROTECTION AGAINST MPTP CYTOTOXI-CITY

In 1979 and 1983, MPTP was initially identified as a strong neurotoxin when heroin addicts accidentally self-administered MPTP and developed an acute form of parkinsonism that was indistinguishable from idiopathic PD [49, 50]. The tragic results of MPTP poisoning in the heroin addicts led to the development of MPTP-induced rodent and non-human primate animal models of PD.

In Vitro Model

Jeyarasasingam et al. reported exposure of rat primary mesencephalic cultures to 10

-7 and 10

-4 M nicotine partially

protect against dopaminergic neurotoxicity induced by 1-methyl-4-phenylpyridinium (MPP+). The optimal protective effect was observed when pre-exposure to nicotine for 24h before administration of MPP+. They also showed the nico-tine protection was mediated by non-�7 nAChR stimulation but not through �7 nAChR stimulation [51].

In Vivo Model (MPTP Induced Parkinsonian Rodent Model)

In MPTP induced animal model, the neuroprotective effect of nicotine is not consistent probably due to different experimental methods. Besides small number of negative reports [52], several independent groups confirmed the neuroprotective effects of nicotine against MPTP in rodents. The pretreatment of nicotine is essential and post treatment did not show any neuroprotective effect in MPTP induced rat as well as in primate models. There are many reports attri-buting the neuroprotective effect of cigarette smoking against MPTP cytotoxicity to inhibition of monoamine oxidase B (MAO-B), which converts MPTP to active MPP+. But because of the fact that nicotine does not inhibit brain MAO-B, the nicotinic neuroprotection against MPTP cyto-toxicity is not mediated through MAO-B inhibition. A blockade of MPP+ uptake into the dopaminergic cells via increased dopamine release may be the reason of the pro-tective effect. Jasons et al. [53] reported the chronic infusion of nicotine via minipumps produced a dose-related enhance-ment of MPTP-induced dopaminergic neurotoxicity in mouse, which might be caused by a failure of the nicotinic cholinoceptors to desensitized to the chronic nicotine exposure [54, 55].

In Vivo Model (MPTP Induced Parkinsonian Primate Model)

So far, there have been only several papers from one group examining the nicotine neuronal protection in MPTP induced primate PD motor deficit model [56-59]. In their reports, neuroprotection was observed only when nicotine is given orally before the MPTP exposure. Decamp and Schneider established stable cognitive deficit primate model injecting low dose of MPTP (0.025 to 0.10 mg/kg) over a period ranging from 98 to 158 days, without the confounding effect of significant motor impairment. They examined the effect of nicotine, l-dopa, and SIB-1553A, �4�4 nAChR agonist, on spatial delayed response task performance and reported that nicotine and SIB-1153A improved performance whereas l-dopa impaired [60]. The effect of �7 nAChR specific stimulation on the task performance was not evaluated in their study.

CURRENT DRUG THERAPY STIMULATING nAChRs

Current drug therapy against PD is limited to supple-menting dopamine or enhancing dopamine effect. Some may have neuroprotective effects, but their effects remain controversial [10, 61, 62]. Nicotine may upregulate dopa-mine release at striatum from nigral dopaminergic neurons [63], followed by stimulation of �4�2 nAChRs but not of �6 containing subtypes [32]. Furthermore, nicotine could pro-tect mitochondria and have protective effect from oxidative stress [64, 65]. Although several clinical trials to evaluate possible therapeutic effect of nicotine to PD patients have been conducted, whether nicotine has therapeutic effects on PD is still inconclusive. The relatively high dose transdermal nicotine administration might have therapeutic effect on PD patients [66]. Regarding motor complications, even nicotine,


a broad agonist, is reported to have an effect of reducing l-dopa-induced dyskinesias in MPTP-treated monkeys [67].

Recently Karachi et al. [68] evaluated the gait disorders and postural instability, which respond poorly to dopa-minergic agents, in PD patients and MPTP induce PD primate model using fMRI technique and immunohisto-chemical studies and concluded that cholinergic mesen-cephalic neurons plays a central role in controlling gait and posture and represent a possible target for pharmacological treatment of gait disorders in PD.

Cholinotherapy is currently being applied with clinically symptomatic benefit in terms of AChE inhibition in AD and related disorders. It has been suggested that some of the inhibitors used in this therapy, including galantamine, which has additional nAChR modulating properties [69], may have disease-slowing effects. Selective �7 nAChR agonists including DMXB [70], S 24795 [71], R3487/MEM3454 [72] or ABT-107 [73] are proved to be effective in AD animal disease models and regarded as therapeutic alternatives besides AChEIs. Allosteric �7 nAChR modulators, e.g. Galantamine and PNU-120596, are also promising thera-peutic candidates [74].

The specific expression of �6 subunit in VTA and SN leads us to expect specific therapy without worsening so called “no-motor complications” of PD, especially apparent in the late phase. So far �6 specific agonist is not available [75] and the �6�2* are mainly located on DA terminals and do not contribute to DA release induced by nicotine adminis-tration whereas (non �6)�4�2 do on DA neuronal soma.

Other properties of nicotine are anti-inflammatory poten-tials and modulating innate immune pathways mainly via �7 nAChR. Nicotine exerts its anti-inflammatory effect in activated immune cells, macrophages and microglia, by interacting �7 nAChR. Activated �7 nAChR binds directory to JAK2 and triggers the JAK2/STAT3 pathway to interfere with the activation of TLR-induced NF-kB, which is res-ponsible for pro-inflammatory cytokine transcription. Microarray analysis in SH-SY5Y cell culture with acute nicotine administration, Cui et al. detected six immune-related pathways, namely TLR, ERK, p38, death receptor, PI3K/AKT, and IL6 [17].

CONCLUSIONS

In drug induced PD models, nAChR stimulation pro-tected neurons from rotenone-, 6-OHDA, and MPTP-induced neurotoxicity. From these experimental data, our hypothesis for the mechanism of nAChR-mediated survival signal transduction is as follows: activation of �7 nAChRs stimulates the Src family, which in turn activates PI3K. PI3K phosphorylates Akt, which causes upregulation of Bcl-2. �4�2 nAChR stimulation also triggers neuroprotection cascade without direct involvement of PI3K system. Stimu-lation of nAChRs initiates these survival signal-cascades in addition to its role as neurotransmitter receptors. To date, information on signal cascade triggered by �6* nAChRs has not been published as it is difficult to analyze �6* nAChRs specifically.

As common therapeutic strategies, the re-generations of the specific as well as vulnerable neurons are far more

difficult than utilizing the spared subunits and networks weaved in defective systems and maximizing the compensa-tion mechanism of the system. Considering the fact, together with other findings, it is important to give attention to the fact that targeting �7 nAChRs conjugating with ongoing dopamine replenishment therapies is worth developing and promising.

CONFLICT OF INTEREST STATEMENT

The author has no conflicts of interest.

ACKNOWLEDGEMENTS

This work was supported in part by the grants from Ministry of Education, Culture, Sports, Science and Techno-logy of Japan, and Smoking Research Foundation.

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Received: April 15, 2011 Revised: June 10, 2011 Accepted: June 15, 2011

PMID: 22300030

α7 nicotinic acetylcholine receptor mediated neuroprotection in parkinson’s disease

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