Stimulation of α4β2 nicotinic acetylcholine receptors inhibits β-amyloid toxicity

doi:10.1016/S0006-8993(98)00138-3

Brain Research

Volume 792, Issue 2, 11 May 1998, Pages 331-334

https://doi.org/10.1016/S0006-8993(98)00138-3 Get rights and content

Abstract

We examined the effects of nicotinic receptor agonists against beta amyloid (Aβ) cytotoxicity to rat cortical neurons. Administration of nicotine protected against Aβ-induced neuronal death. This neuroprotection was blocked by dihydro-beta-erythroidine, an α4β2 nicotinic receptor antagonist. Furthermore, incubation with cytisine, a selective α4β2 nicotinic receptor agonist, inhibited Aβ cytotoxicity. These results suggest that α4β2 nicotinic receptor activation plays an important role in neuroprotection against Aβ cytotoxicity.

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Acknowledgements

This study was supported in part by Grants-in-Aid from the Ministry of Education, Science, Sports, and Culture of Japan, and grants from the Ministry of Welfare of Japan, the Smoking Research Foundation, the Mitsui Life Social Welfare Foundation, the Takeda Medical Research Foundation, and the Kato Memorial Trust for Nambyo Research.

References (19)

A. Akaike et al.
Cholecystokinin-induced protection of cultured cortical neurons against glutamate neurotoxicity
Brain Res.
(1991)
T. Kume et al.
BDNF prevents NO mediated glutamate cytotoxicity in cultured cortical neurons
Brain Res.
(1997)
W.D. Le et al.
Cell death induced by beta-amyloid 1–40 in MES 23.5 hybrid clone: the role of nitric oxide and NMDA-gated channel activation leading to apoptosis
Brain Res.
(1995)
A. Parpura-Gill et al.
The inhibitory effects of beta-amyloid on glutamate and glucose uptakes by cultured astrocytes
Brain Res.
(1997)
E.K. Perry et al.
Alteration in nicotine binding sites in Parkinson's disease, Lewy body dementia and Alzheimer's disease: possible index of early neuropathology
Neuroscience
(1995)
D.J. Selkoe
The molecular pathology of Alzheimer's disease
Neuron
(1991)
S. Shimohama et al.
Protective effect of nerve growth factor against glutamate-induced neurotoxicity in cultured cortical neurons
Brain. Res.
(1993)
P.J. Whitehouse et al.
Nicotinic acetylcholine binding sites in Alzheimer's disease
Brain Res.
(1986)
J.R. Brorson et al.
The Ca²⁺ influx induced by beta-amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation
J. Neurobiol.
(1995)

There are more references available in the full text version of this article.

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Citation Excerpt :
In rat cell culture experiments nicotine protects neurons from the cytotoxic effects of beta amyloid peptide, well known to be associated with the pathobiology of Alzheimer's Disease (Kihara et al., 1998). Further, these protective effects are mediated by the α4β2 nAChR, and cytisine, a α4β2 nAChR selective agonist, also produces similar protective effects (Kihara et al., 1998). Taken together, pharmacotherapies that selectively target the α4β2* subtype of nAChR may be useful as therapeutics to treat neurological diseases that impact cognitive function.
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Short communicationStimulation of α4β2 nicotinic acetylcholine receptors inhibits β-amyloid toxicity

Abstract

Section snippets

Acknowledgements

Brain Res.

Brain Res.

Brain Res.

Brain Res.

Neuroscience

Neuron

Brain. Res.

Brain Res.

The Ca2+ influx induced by beta-amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation

J. Neurobiol.

Short communication
Stimulation of α4β2 nicotinic acetylcholine receptors inhibits β-amyloid toxicity

The Ca²⁺ influx induced by beta-amyloid peptide 25–35 in cultured hippocampal neurons results from network excitation