High content screen microscopy analysis of Aβ1–42-induced neurite outgrowth reduction in rat primary cortical neurons: Neuroprotective effects of α7 neuronal nicotinic acetylcholine receptor ligands

Hu, Min; Schurdak, Mark E.; Puttfarcken, Pamela S.; Kouhen, Rachid El; Gopalakrishnan, Murali; Li, Jinhe

doi:10.1016/j.brainres.2007.03.051

Cited by 58 publications

(41 citation statements)

References 49 publications

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“…In agreement with this hypothesis, the prototypical nAChR agonist nicotine, as well as more selective ␣7 agonists described more recently, has been shown to improve cognitive performance in animal models and humans (Newhouse et al, 2004;Van Kampen et al, 2004;Hajós et al, 2005;Pichat et al, 2007). Several reports also suggest that ␣7 nAChRs mediate protection against neurotoxicity induced by amyloid ␤ and excitotoxic insults (Kihara et al, 2001;O'Neill et al, 2002;Hellström-Lindahl et al, 2004;Hu et al, 2007).…”

mentioning

confidence: 72%

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Roncarati¹,

Scali²,

Comery³

et al. 2009

J Pharmacol Exp Ther

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The ␣7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of ␣7 nAChR. SEN12333 shows high affinity for the rat ␣7 receptor expressed in GH4C1 cells (K i ϭ 260 nM) and acts as full agonist in functional Ca 2ϩ flux studies (EC 50 ϭ 1.6 M). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC 50 ϭ 12 M). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at ␣3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the ␣7-selective antagonist methyllycaconitine, indicating that it is mediated by ␣7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel ␣7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of ␣7 agonists for treatment of neurodegenerative and cognitive disorders.The family of nicotinic acetylcholine receptors, which comprises 16 different subunits in human (␣1-7, ␣9 -10, ␤1-4, ␦, ε, and ␥) that can form many functional homo-and heteropentameric receptor ion channel combinations, contributes to cholinergic neurotransmission in the nervous system and at the neuromuscular junction. The ␣7 nicotinic acetylcholine receptors (nAChRs) are rapidly desensitizing ligand-gated ion channels that are abundantly expressed in the cerebral cortex and the hippocampus, a limbic structure intimately linked to attention processing and memory formation (Gotti et al., 2006). In the hippocampus, ␣7 nAChRs are present in interneurons and glutamatergic pyramidal neurons, in which they are localized presynaptically in nerve terminals and postsynaptically in dendritic spines and soma. In line with their localization, ␣7 nAChRs modulate neurotransmitter release and are responsible for direct fast excitatory neuroArticle, publication date, and citation information can be found at

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confidence: 72%

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Roncarati¹,

Scali²,

Comery³

et al. 2009

J Pharmacol Exp Ther

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“…2A). Since a7 receptors can be glycosylated as well as palmitoylated (Hu et al, 2007), it is possible that these bands represent post-translational modifications to the a7.…”

Section: Resultsmentioning

confidence: 99%

An α7 nicotinic receptor-G protein pathway complex regulates neurite growth in neural cells*

Nordman

Kabbani

2012

Journal of Cell Science

120

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SummaryThe a7 acetylcholine nicotinic receptor (a7) is an important mediator of cholinergic transmission during brain development. Here we present an intracellular signaling mechanism for the a7 receptor. Proteomic analysis of immunoprecipitated a7 subunits reveals an interaction with a G protein pathway complex (GPC) comprising Ga i/o , GAP-43 and G protein regulated inducer of neurite outgrowth 1 (Gprin1) in differentiating cells. Morphological studies indicate that a7 receptors regulate neurite length and complexity via a Gprin1-dependent mechanism that directs the expression of a7 to the cell surface. a7-GPC interactions were confirmed in embryonic cortical neurons and were found to modulate the growth of axons. Taken together, these findings reveal a novel intracellular pathway of signaling for a7 within neurons, and suggest a role for its interactions with the GPC in brain development.

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“…Thus, this fertile shift of research focus from toxicity to synaptic mechanisms needs to be matched with similar studies on the nontoxic effects of A␤ on cultured neurons and the effects of nAChR activation on such effects. For example, a recent study has shown that ␣7-specific ligands rescue the A␤-induced decrease in neurite outgrowth of cultured mouse neurons (Hu et al, 2007).…”

Section: Nicotinic Acetylcholine Receptors Mediate ␤-Amyloid Peptimentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection

et al. 2009

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High content screen microscopy analysis of Aβ1–42-induced neurite outgrowth reduction in rat primary cortical neurons: Neuroprotective effects of α7 neuronal nicotinic acetylcholine receptor ligands

Cited by 58 publications

References 49 publications

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

Procognitive and Neuroprotective Activity of a Novel α7 Nicotinic Acetylcholine Receptor Agonist for Treatment of Neurodegenerative and Cognitive Disorders

An α7 nicotinic receptor-G protein pathway complex regulates neurite growth in neural cells*

Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection

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