Effects of α7 nicotinic acetylcholine receptor agonists on antipsychotic efficacy in a preclinical mouse model of psychosis

Kohlhaas, Kathy L.; Bitner, Robert S.; Gopalakrishnan, Murali; Rueter, Lynne E.

doi:10.1007/s00213-011-2535-6

Cited by 19 publications

(9 citation statements)

References 40 publications

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“…Other molecules such as TC-5619, SSR-180711, A-582941, or encenicline also demonstrated efficacy in cognitive models (Pichat et al, 2007;Tietje et al, 2008;Mazurov et al, 2012;Prickaerts et al, 2012). Although application of an a7 nAChR agonist alone was ineffective in a DBA/2 mouse model of sensorimotor gating (prepulse inhibition), it increased the effects of haloperidol or risperidone (Kohlhaas et al, 2012). TC-5619 showed a statistically significant effect on executive function based on measurements for the Groton Maze Learning Task but not on other cognitive domains (Lieberman et al, 2013).…”

Section: B Schizophreniamentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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Section: B Schizophreniamentioning

confidence: 99%

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

et al. 2015

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“…Type II PAMs (e.g., ABT-779, PNU 120596 and RO5126946) have also been shown to improve cognition [138,141–144] and sensory gating (auditory-evoked potentials and PPI; [140,142,145,146] in animal models. Similarly, JNJ-1930942 (described as an intermediate type α7 PAM with characteristics falling between the profiles of Type I and Type II modulators) has beneficial effects on the auditory-evoked sensory inhibition deficits in DBA/2 mice [147].…”

Section: Nachr Positive Allosteric Modulators-role As Standalone Amentioning

confidence: 99%

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Terry

Callahan

Hernandez

2015

Biochemical Pharmacology

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The challenges associated with developing more effective treatments for neurologic and psychiatric illness such as Alzheimer’s disease and schizophrenia are considerable. Both the symptoms and the pathophysiology of these conditions are complex and poorly understood and the clinical presentations across different patients can be very heterogeneous. Moreover, it has become apparent that the reductionist approach to drug discovery for these illnesses that has dominated the field for decades (i.e., the development of highly selective compounds or other treatment modalities focused on a very specific pathophysiologic target) has not been widely successful. Accordingly, a variety of new strategies have emerged including the development of “multitarget-directed ligands” (MTDLs), the development and/or identification of compounds that exhibit “multifunctional” activity (e.g., pro-cognitive plus neuroprotective, pro-cognitive plus antipsychotic activity), “repurposing” strategies for existing compounds that have other clinical indications, and novel “adjunctive” treatment strategies that might enhance the efficacy of the currently available treatments. Interestingly, a variety of ligands at nicotinic acetylcholine receptors (nAChRs) appear to have the potential to fulfill one or more of these desirable properties (i.e., multifunctional, repurposing, or adjunctive treatment potential). The purpose of this review (while not all-inclusive) is to provide an overview of a variety of nAChR ligands that demonstrate potential in these categories, particularly, “multifunctional” properties. Due to their densities in the mammalian brain and the amount of literature available, the review will focus on ligands of the high affinity α4β2 nAChR and affinity α7 nAChR.

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“…We implanted Alzet osmotic mini-pumps in Grn −/− mice to infuse vehicle, nicotine, or PHA-568487 for 14 days. Additionally, we tested the efficacy of a second specific agonist of the α7 nAChR, ABT-107, which has previously been shown to decrease secretion of inflammatory cytokines [24–25]. ABT-107 was administered daily for 14 days (I.P).…”

Section: Resultsmentioning

confidence: 99%

Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists

Minami

Shen

et al. 2015

Biochemical Pharmacology

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Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific α7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or α7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective α7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-κB in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNFα levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the α7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.

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Effects of α7 nicotinic acetylcholine receptor agonists on antipsychotic efficacy in a preclinical mouse model of psychosis

Cited by 19 publications

References 40 publications

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Therapeutic Potential ofα7 Nicotinic Acetylcholine Receptors

Nicotinic ligands as multifunctional agents for the treatment of neuropsychiatric disorders

Reducing inflammation and rescuing FTD-related behavioral deficits in progranulin-deficient mice with α7 nicotinic acetylcholine receptor agonists

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