Are positive allosteric modulators of α7 <scp>nAChR</scp>s clinically safe?

Uteshev, Victor V.

doi:10.1111/jnc.13236

Cited by 11 publications

(10 citation statements)

References 13 publications

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“…[65-70] Thus, it is essential for future ex vivo and in vitro studies to employ physiologically- and clinically-relevant drug concentrations and treatment conditions available in the literature. [42,2,37,25,24,68] The use of clinically-relevant experimental conditions in ex vivo and in vitro studies should not be a matter of preference because in the absence of clinically-effective therapies, the continuing suffering of stroke victims and the associated financial burden demand prompt effective solutions.…”

Section: Discussionmentioning

confidence: 99%

Boosting Endogenous Resistance of Brain to Ischemia

Sun

Johnson²,

Jin

et al. 2016

Mol Neurobiol

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Most survivors of ischemic stroke remain physically disabled and require prolonged rehabilitation. However, some stroke victims achieve a full neurological recovery suggesting that human brain can defend itself against ischemic injury, but the protective mechanisms are unknown. This study used selective pharmacological agents and a rat model of cerebral ischemic stroke to detect endogenous brain protective mechanisms that require activation of α7 nicotinic acetylcholine receptors (nAChRs). This endogenous protection was found to be: 1) limited to less severe injuries; 2) significantly augmented by intranasal administration of a positive allosteric modulator of α7 nAChRs, significantly reducing brain injury and neurological deficits after more severe ischemic injuries; and 3) reduced by inhibition of calcium/calmodulin-dependent kinase-II. The physiological role of α7 nAChRs remains largely unknown. The therapeutic activation of α7 nAChRs after cerebral ischemia may serve as an important physiological responsibility of these ubiquitous receptors and holds a significant translational potential.

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Section: Discussionmentioning

confidence: 99%

Boosting Endogenous Resistance of Brain to Ischemia

Sun

Johnson²,

Jin

et al. 2016

Mol Neurobiol

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“…Nevertheless, there is a controversy about the possible cytotoxicity of PAMs due to the high increase in intracellular calcium levels (Ng et al, 2007;Liu et al, 2009;Guerra-Álvarez et al, 2015;Uteshev, 2016). Type II PAMs are the most controversial due to their ability to potentiate 7 currents with high efficacy, decrease desensitization and reactivate desensitized receptors (Guerra-Álvarez et al, 2015;Hu et al, 2009;Ng et al, 2007;Uteshev, 2016;Williams et al, 2012).…”

Section: Therapeutic Impact Of Flavonoids Acting As α7 Pamsmentioning

confidence: 99%

Flavonoids as positive allosteric modulators of α7 nicotinic receptors

2019

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The use of positive allosteric modulators (PAM) of α7 nicotinic receptors is a promising therapy for neurodegenerative, inflammatory and cognitive disorders. Flavonoids are polyphenolic compounds showing neuroprotective, anti-inflammatory and pro-cognitive actions. Besides their well-known antioxidant activity, flavonoids trigger intracellular pathways and interact with receptors, including α7. To reveal how the beneficial actions of flavonoids are linked to α7 function, we evaluated the effects of three representative flavonoids-genistein, quercetin and the neoflavonoid 5,7-dihydroxy-4-phenylcoumarinon whole-cell and single-channel currents. All flavonoids increase the maximal currents elicited by acetylcholine with minimal effects on desensitization and do not reactivate desensitized receptors, a behaviour consistent with type I PAMs. At the single-channel level, they increase the duration of the open state and produce activation in longduration episodes with a rank order of efficacy of genistein > quercetin ≥ neoflavonoid. By using mutant and chimeric α7 receptors, we demonstrated that flavonoids share transmembrane structural determinants with other PAMs. The 7-PAM activity of flavonoids results in decreased cell levels of reactive oxygen species. Thus, allosteric potentiation of α7 may be an additional mechanism underlying neuroprotective actions of flavonoids, which may be used as scaffolds for designing new therapeutic agents.

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“…However, they cover a wide spectrum of degrees of potentiation and mechanisms and, therefore, different PAMs may be used in different pathological situations. Several further points to explore include: (i) the potential toxic effects due to increased calcium in the presence of non-desensitizing efficacious PAMs, which is an issue of controversy (Guerra-Álvarez et al 2015;Uteshev, 2016); (ii) the fact that increased α7 activity is associated with several types of cancer for which NAMs should be the preferred therapeutic drugs; (iii) the fact that due to the ubiquitous presence of α7 its modulation may produce beneficial effects in some tissues but adverse effects in others; (iv) the long-term effects mediated by potentiated α7 due to its metabotropic action; (v) how PAMs affect α7 heteromeric receptors or intracellular receptors such as those found in mitochondria (Gergalova et al 2014), and (vi) the fact that PAMs targeting multiple receptors might show better efficacy (Möller-Acuña et al 2015;Iturriaga-Vásquez et al 2015), indicating that for each pathological context their actions at other involved receptors should be tested.…”

Section: Perspectivesmentioning

confidence: 99%

Molecular function of α7 nicotinic receptors as drug targets

Bouzat

Lasala

Nielsen

et al. 2017

The Journal of Physiology

120

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Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels involved in many physiological and pathological processes. In vertebrates, there are seventeen different nAChR subunits that combine to yield a variety of receptors with different pharmacology, function, and localization. The homomeric α7 receptor is one of the most abundant nAChRs in the nervous system and it is also present in non-neuronal cells. It plays important roles in cognition, memory, pain, neuroprotection, and inflammation. Its diverse physiological actions and associated disorders have made of α7 an attractive novel target for drug modulation. Potentiation of the α7 receptor has emerged as a novel therapeutic strategy for several neurological diseases, such as Alzheimer's and Parkinson's diseases, and inflammatory disorders. In contrast, increased α7 activity has been associated with cancer cell proliferation. The presence of different drug target sites offers a great potential for α7 modulation in different pathological contexts. In particular, compounds that target allosteric sites offer significant advantages over orthosteric agonists due to higher selectivity and a broader spectrum of degrees and mechanisms of modulation. Heterologous expression of α7, together with chaperone proteins, combined with patch clamp recordings have provided important advances in our knowledge of the molecular basis of α7 responses and their potential modulation for pathological processes. This review gives a synthetic view of α7 and its molecular function, focusing on how its unique activation and desensitization features can be modified by pharmacological agents. This fundamental information offers insights into therapeutic strategies.

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Are positive allosteric modulators of α7 nAChRs clinically safe?

Abstract: A comment on “Positive allosteric modulation of alpha‐7 nicotinic receptors promotes cell death by inducing Ca2+ release from the endoplasmic reticulum” by M. Cano‐Abad et al. (2014) J Neurochem 133(3), 309–319 (DOI: ).

Cited by 11 publications

References 13 publications

Boosting Endogenous Resistance of Brain to Ischemia

Boosting Endogenous Resistance of Brain to Ischemia

Flavonoids as positive allosteric modulators of α7 nicotinic receptors

Molecular function of α7 nicotinic receptors as drug targets

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