?7 Nicotinic Acetylcholine Receptor Mediated Neuroprotection in Parkinson's Disease

Kawamata, Jun; Suzuki, Syuuichirou; Shimohama, Shun

doi:10.2174/138945012800399026

Cited by 41 publications

(30 citation statements)

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“…In the second case, nicotinic action is a microcircuit correlate of the already described anti-Parkinsonian actions of nicotine (Fagerström et al, 1994; Gorell et al, 1999; Costa et al, 2001; Herman et al, 2001; Villafane et al, 2007; Driver et al, 2009; Quik et al, 2007; García-Montes et al, 2012; Kawamata et al, 2012). Indeed, in comparison to our early Parkinsonian animal models (Jáidar et al, 2010), we show that the action of nicotine is almost as strong as that of L-DOPA (Plata et al, 2013).…”

Section: Discussionmentioning

confidence: 88%

“…The importance of answering this question resides in the suspected neuro-protective action of nicotine in the prevention and development of PD (e.g., Costa et al, 2001; Quik et al, 2007; Kawamata et al, 2012). Although this postulate is still controversial (García-Montes et al, 2012), the hypothesis has its origin in epidemiological studies that claim less incidence of PD in smokers (Gorell et al, 1999; Herman et al, 2001; Driver et al, 2009), and in clinical studies that claim improvements of motor and cognitive symptoms in PD patients subjected to nicotine analogs (Fagerström et al, 1994; Villafane et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

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Global actions of nicotine on the striatal microcircuit

Plata

Duhne

Pérez-Ortega

et al. 2013

Front. Syst. Neurosci.

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The question to solve in the present work is: what is the predominant action induced by the activation of cholinergic-nicotinic receptors (nAChrs) in the striatal network given that nAChrs are expressed by several elements of the circuit: cortical terminals, dopamine terminals, and various striatal GABAergic interneurons. To answer this question some type of multicellular recording has to be used without losing single cell resolution. Here, we used calcium imaging and nicotine. It is known that in the presence of low micromolar N-Methyl-D-aspartate (NMDA), the striatal microcircuit exhibits neuronal activity consisting in the spontaneous synchronization of different neuron pools that interchange their activity following determined sequences. The striatal circuit also exhibits profuse spontaneous activity in pathological states (without NMDA) such as dopamine depletion. However, in this case, most pathological activity is mostly generated by the same neuron pool. Here, we show that both types of activity are inhibited during the application of nicotine. Nicotine actions were blocked by mecamylamine, a non-specific antagonist of nAChrs. Interestingly, inhibitory actions of nicotine were also blocked by the GABAA-receptor antagonist bicuculline, in which case, the actions of nicotine on the circuit became excitatory and facilitated neuronal synchronization. We conclude that the predominant action of nicotine in the striatal microcircuit is indirect, via the activation of networks of inhibitory interneurons. This action inhibits striatal pathological activity in early Parkinsonian animals almost as potently as L-DOPA.

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Section: Discussionmentioning

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Global actions of nicotine on the striatal microcircuit

Plata

Duhne

Pérez-Ortega

et al. 2013

Front. Syst. Neurosci.

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“…While much evidence indicates that key residues in the M2 domain and the intracellular loop of the channel are involved in cationic selectivity and permeation [7, 17], including the glutamate at residue 237 of the α7 nAChR that when mutated to alanine abolishes calcium permeability of this receptor [4], little is known about the influence that the ECD plays in ion permeation. Recently, the α7 nAChRs have emerged as potential targets in the treatment of many neurological disorders, such as Parkinson’s and Alzheimer’s diseases, and schizophrenia, and even for chemotherapy-induced cognitive impairments [15, 21, 31, 41]. Furthermore, it has been shown that α7 nAChRs are expressed in macrophages where they play a key role in the cholinergic anti-inflammatory pathway [45], and they have proven to be an effective target in the treatment of sepsis, myocardial ischemia, and rheumatoid arthritis [30].…”

Section: Discussionmentioning

confidence: 99%

A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability

Colón-Sáez

Yakel

2013

Pflugers Arch - Eur J Physiol

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The α7 neuronal nicotinic acetylcholine receptor (nAChR) displays the highest calcium permeability among the different subtypes of nAChRs expressed in the mammalian brain and can impact cellular events including neurotransmitter release, second messenger cascades, cell survival, and apoptosis. The selectivity for cations in nAChRs is thought to be achieved in part by anionic residues which are located on either side of the channel mouth and increase relative cationic concentration. Mutagenesis studies have improved our understanding of the role of the second transmembrane domain and the intracellular loop of the channel in ion selectivity. However, little is known about the influence that the extracellular domain (ECD) plays in ion permeation. In the α7 nAChR, it has been found that the ECD contains a ring of ten aspartates (two per subunit) that is believed to face the lumen of the pore and could attract cations for permeation. Using mutagenesis and a combination of electrophysiology and imaging techniques, we tested the possible involvement of these aspartate residues in the calcium permeability of the rat α7 nAChR. We found that one of these residues (the aspartate at position 44) appears to be essential since mutating it to alanine resulted in a decrease in amplitude for both whole cell and single-channel responses and in the complete disappearance of detectable calcium changes in most cells, which indicates that the ECD of the α7 nAChR plays a key role in calcium permeation.

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“…The use of subtype selective α7 nAChR agonists and antagonists also supports a protective role for α7 nAChRs (Table 2) [74, 75, 94]. Drugs with varying agonist properties, such as the α7 nAChR allosteric modulator galantamine, and the α7 agonists DMXB and ABT-107 all protected against 6-OHDA-induced nigrostriatal damage in rats [95–97].…”

Section: α7 Nachrs and Neuroprotectionmentioning

confidence: 99%

Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease

Quik

Zhang

McGregor

et al. 2015

Biochemical Pharmacology

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Accumulating evidence suggests that CNS α7 nicotinic acetylcholine receptors (nAChRs) are important targets for the development of therapeutic approaches for Parkinson’s disease. This progressive neurodegenerative disorder is characterized by debilitating motor deficits, as well as autonomic problems, cognitive declines, changes in affect and sleep disturbances. Currently L-dopa is the gold standard treatment for Parkinson’s disease motor problems, particularly in the early disease stages. However, it does not improve the other symptoms, nor does it reduce the inevitable disease progression. Novel therapeutic strategies for Parkinson’s disease are therefore critical. Extensive pre-clinical work using a wide variety of experimental models shows that nicotine and nAChR agonists protect against damage to nigrostriatal and other neuronal cells. This observation suggests that nicotine and/or nAChR agonists may be useful as disease modifying agents. Additionally, studies in several parkinsonian animal models including nonhuman primates show that nicotine reduces L-dopa-induced dyskinesias, a side effect of L-dopa therapy that may be as incapacitating as Parkinson’s disease itself. Work with subtype selective nAChR agonists indicate that α7 nAChRs are involved in mediating both the neuroprotective and antidyskinetic effects, thus offering a targeted strategy with optimal beneficial effects and minimal adverse responses. Here, we review studies demonstrating a role for α7 nAChRs in protection against neurodegenerative effects and for the reduction of L-dopa-induced dyskinesias. Altogether, this work suggests that α7 nAChRs may be useful targets for reducing Parkinson’s disease progression and for the management of the dyskinesias that arise with L-dopa therapy.

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?7 Nicotinic Acetylcholine Receptor Mediated Neuroprotection in Parkinson's Disease

Cited by 41 publications

References 0 publications

Global actions of nicotine on the striatal microcircuit

Global actions of nicotine on the striatal microcircuit

A mutation in the extracellular domain of the α7 nAChR reduces calcium permeability

Alpha7 nicotinic receptors as therapeutic targets for Parkinson's disease

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