The combination of memantine and galantamine improves cognition in rats: The synergistic role of the α7 nicotinic acetylcholine and NMDA receptors

Nikiforuk, Agnieszka; Potasiewicz, Agnieszka; Kos, Tomasz; Popik, Piotr

doi:10.1016/j.bbr.2016.07.023

Cited by 45 publications

(30 citation statements)

References 30 publications

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“…63 Additionally, in a non-injury model, combined doses of memantine and GAL enhanced attentional set-shifting performance and reversed deficits in object recognition. 77 Furthermore, the combination of GAL and melatonin was reported to demonstrate protective …”

Section: Journal Of Neurotraumamentioning

confidence: 99%

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined

Tremblaye

Bondi

Lajud

et al. 2017

Journal of Neurotrauma

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Environmental enrichment (EE) enhances cognition after traumatic brain injury (TBI). Galantamine (GAL) is an acetylcholinesterase inhibitor that also may promote benefits. Hence, the aims of this study were to assess the efficacy of GAL alone (standard [STD] housing) and in combination with EE in adult male rats after TBI. The hypothesis was that both therapies would confer motor, cognitive, and histological benefits when provided singly, but that their combination would be more efficacious. Anesthetized rats received a controlled cortical impact or sham injury, then were randomly assigned to receive GAL (1, 2, or 3 mg/kg; intraperitoneally [i.p.]) or saline vehicle (VEH; 1 mL/kg; i.p.) beginning 24 h after surgery and once daily for 21 days (experiment 1). Motor (beam-balance/walk) and cognitive (Morris water maze [MWM]) assessments were conducted on post-operative Days 1-5 and 14-19, respectively. Cortical lesion volumes were quantified on Day 21. Sham controls were better versus all TBI groups. No differences in motor function or lesion volumes were observed among the TBI groups (p > 0.05). In contrast, GAL (2 mg/kg) enhanced MWM performance versus VEH and GAL (1 and 3 mg/kg; p < 0.05). In experiment 2, GAL (2 mg/kg) or VEH was combined with EE and the data were compared with the STD-housed groups from experiment 1. EE alone enhanced motor performance over the VEH-treated and GAL-treated (2 mg/kg) STD-housed groups (p < 0.05). Moreover, both EE groups (VEH or GAL) facilitated spatial learning and reduced lesion size versus STD + VEH controls (p < 0.05). No additional benefits were observed with the combination paradigm, which does not support the hypothesis. Overall, the data demonstrate that EE and once daily GAL (2 mg/kg) promote cognitive recovery after TBI. Importantly, the combined therapies did not negatively affect outcome and thus this therapeutic protocol may have clinical utility.

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Section: Journal Of Neurotraumamentioning

confidence: 99%

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined

Tremblaye

Bondi

Lajud

et al. 2017

Journal of Neurotrauma

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“…Similar to the previously reported pro-cognitive effects across multiple domains, nicotine, α4β2* (ie, 5IA-85380), α7 nAChR agonists (eg, A-582941, RG 3487, and SSR 180711), and α7 nAChR PAMS (eg, CCMI, PAM-2, and PNU 120596) have been shown to improve executive function in the attentional set-shift task whether given alone or after pharmacologic-induced impairment with either acute or subchronic administration of N-methyl-d-aspartate receptor antagonists (Table 2). 67,72,78,83,116 A literature search indicated that α4β2* PAMs have not been assessed in the attentional set-shifting task to date. Clinically, improvements in executive function following α4β2* and α7 nAChR agonists during early phase clinical trials have been reported, although as observed for the other cognitive domains discussed earlier, results have not been replicated.…”

Section: Executive Function-attentional Set Shifting Tasksmentioning

confidence: 99%

Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery

Terry

Callahan

2018

Nicotine &Amp; Tobacco Research

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The preclinical literature continues to grow in support of the development of nAChR ligands for a variety of illnesses that affect humans. However, to date, no new nAChR ligand has been approved for any condition other than nicotine dependence. As discussed in this review, the studies conducted to date provide the impetus for continuing efforts to develop new nAChR strategies (i.e., beyond simple agonist and partial agonist approaches) as well as to refine current behavioral strategies and create new animal models to address translational gaps in the drug discovery process.

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“…Stimulation of the nicotinic α4β2 receptor enhanced attention and working memory-related firing of dlPFC in monkeys [29]. The combination of galantamine and memantine improved the attentional set-shifting task and novel object recognition task in rodents compared to vehicle-treated rats; the combination was more effective than either medication alone because of the synergistic role of the α7nACh and NMDA receptors [30]. In older rabbits, the galantamine-memantine combination had a superior effect on cognition compared to the donepezil-memantine combination [31]; memantine was common in both combinations, thus this finding suggests a synergistic role of the α7nACh and NMDA receptors.…”

Section: Introductionmentioning

confidence: 99%

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

Koola¹

2018

Complex Psychiatry

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Schizophrenia is, in part, a cognitive illness. There are no approved medications for cognitive impairments associated with schizophrenia (CIAS) and primary negative symptoms. Cholinergic and glutamatergic systems, alpha-7 nicotinic acetylcholine (α-7nACh) and N-methyl-D-aspartate (NMDA) receptors, kynurenic acid (KYNA), and mismatch negativity have been implicated in the pathophysiology of CIAS and negative symptoms. Galantamine is an acetylcholinesterase inhibitor that is also a positive allosteric modulator at the α4β2 and α7nACh receptors. Memantine is a noncompetitive NMDA receptor antagonist. Galantamine and memantine alone and in combination were effective for cognition in animals and people with Alzheimer’s disease. The objective of this article is to critically dissect the published randomized controlled trials with galantamine and memantine for CIAS to highlight the efficacy signal. These studies may have failed to detect a clinically meaningful efficacy signal due to limitations, methodological issues, and possible medication nonadherence. There is evidence from a small open-label study that the galantamine-memantine combination may be effective for CIAS with kynurenine pathway metabolites as biomarkers to detect the severity of cognitive impairments. Given that there are no available treatments for cognitive impairments and primary negative symptoms in schizophrenia, testing of this “five-pronged strategy” (quintuple hypotheses: dopamine, nicotinic-cholinergic, glutamatergic/NMDA, GABA, and KYNA) is a “low-risk high-gain” approach that could be a major breakthrough in the field. The galantamine-memantine combination has the potential to treat positive, cognitive, and negative symptoms, and targeting the quintuple hypotheses concurrently may lead to a major scientific advancement – from antipsychotic treatment to antischizophrenia treatment.

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The combination of memantine and galantamine improves cognition in rats: The synergistic role of the α7 nicotinic acetylcholine and NMDA receptors

Cited by 45 publications

References 30 publications

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined

Nicotinic Acetylcholine Receptor Ligands, Cognitive Function, and Preclinical Approaches to Drug Discovery

Potential Role of Antipsychotic-Galantamine-Memantine Combination in the Treatment of Positive, Cognitive, and Negative Symptoms of Schizophrenia

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