Alpha-7 nicotinic agonists for cognitive deficits in neuropsychiatric disorders: A translational meta-analysis of rodent and human studies

Abstract

Cognitive dysfunction in schizophrenia (SCZ) and Alzheimer’s disease (AD) is a major driver of functional disability but is largely unresponsive to current therapeutics. Animal models of cognitive dysfunction relevant to both disorders suggest the α7 nicotinic acetylcholine receptor (nAChR) may be a promising drug development target, with multiple clinical trials subsequently testing this hypothesis in individuals with SCZ and AD. However, the translational value of rodent cognitive tasks for predicting the overall efficacy of this therapeutic target in clinical trials is unknown. To compare effect sizes between rodent and human studies, we searched PubMed and the Cochrane Library for all randomized, placebo-controlled trials of compounds with pharmacological activity at the α7 nAChR for treatment of cognitive dysfunction in SCZ and AD and identified 18 studies comprising 2670 subjects treated with eight different compounds acting as full or partial agonists. Cognitive outcomes were standardized, and random-effects meta-analyses revealed no statistically significant effects of α7 nAChR agonists on overall cognition or any of eight cognitive subdomains when all doses were included (Range of all cognitive outcomes: Cohen’s d = −0.077 to 0.12, negative favoring drug). In contrast, analysis of 29 rodent studies testing the same α7 agonists revealed large effect sizes in multiple commonly used preclinical behavioral tests of cognition (Range: d = −1.18 to −0.73). Our results suggest that targeting the α7 nAChR with agonists is not a robust treatment for cognitive dysfunction in SCZ or AD and necessitate a better understanding of the translational gap for therapeutics targeting the α7 nAChR.

PET Brain imaging of α7-nAChR with [18F]ASEM

“…Selected drugs show some degree of cognitive improvement in trials of patients with schizophrenia, although none has yet proceeded to late phase or FDA approval. A common trend is the improvement of cognition with an inverted U-shaped dose-response curve, when increasing the dose of α7 agonist above a threshold resulted in loss of drug effect (Wallace and Bertrand, 2015;Lewis et al, 2017). The latest research has revealed a new generation of promising α7-targeting drugs (Beinat et al, 2016).…”

Olig2 Silence Ameliorates Cuprizone-Induced Schizophrenia-Like Symptoms in Mice

“…There are still no effective approaches to prohibit the development and progression of schizophrenia. The available symptom-relieving compounds have ameliorated some sufferings of patients [ 21 , 22 ], however, drug development is still restricted by the unknown mechanisms of schizophrenia. A number of animal models have been established to investigate the mechanisms for schizophrenia, the cuprizone model uses the application of a chemical compound (cuprizone) to model schizophrenia-like symptoms [ 12 , 23 – 25 ].…”

A second wind for the cholinergic system in Alzheimer’s therapy

“…Several molecules are currently under test but α7 receptor-based therapies might yield less promising results than their M1 counterparts. In general, it must be recognized that recent clinical trials with cholinergic compounds have been disappointing at the level of efficiency on cognitive symptoms as well as undesirable side effects (Lewis et al, 2017;McArthur et al, 2010). This certainly emphasizes that we need a better understanding of the translational gap for therapeutics targeting nicotinic and muscarinic receptors.…”