Edited by: Alfredo Meneses, Centro de Investigación y de Estudios Avanzados (CINVESTAV), Mexico
Reviewed by: Massimo Grilli, Università di Genova, Italy; Eddy A. Van Der Zee, University of Groningen, Netherlands
This article was submitted to Neuropharmacology, a section of the journal Frontiers in Neuroscience
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The procognitive effects of nicotine are controversial. Some studies have shown positive effects of nicotine on learning and memory impairment in specific neurological disorders (López-Hidalgo et al.,
After systemic administration, nicotine is extensively metabolized by the liver. Nicotine and some of its metabolites are biotransformed in the brain where they affect cognitive outcomes (Benowitz et al.,
As the target of nicotine and its metabolites, nicotinic acetylcholine receptors (nAChR) modulate specific aspects of learning and memory (Majdi et al.,
Systematic reviews are tools that find relevant and unbiased answers to a research question (Sena et al.,
We electronically searched Embase, ISI Web of Science, MEDLINE via PubMed, and SCOPUS for studies that had investigated (1) nicotine metabolites in the brain as follows: [(nicotine)] AND [(metabolite)] AND [(brain) OR (central nervous system) OR (CNS)] and (2) the effects of nicotine metabolites on cognitive impairment as follows: [(memory) OR (learning) OR (cognition)] AND [(cotinine) OR (nicotine metabolite) OR (nornicotine) OR (nor-nicotine) OR (norcotinine) OR (nor-cotinine)]. Two investigators independently screened title, abstract and, where necessary, the full text, based on the inclusion and exclusion criteria. Where there were disagreements, the third investigator resolved the controversy. There was no date (all studies until May 2018) or species restriction in the search, but the search was limited to texts in English and original articles.
We included all experimental and clinical studies reporting the effects of nicotine metabolites (i.e., cotinine, nornicotine, and norcotinine) as opposed to placebo or vehicle on learning and memory. Because cognition is a broad topic, and because evaluation of each domain requires comprehensive review, we focused on learning and memory in this systematic review, regardless of type or assessment task. All other domains of cognition were not investigated in this review. We excluded every study of the effects of smoking cigarettes, cigars, or pipe, or of ingesting tobacco in any form, on cognitive abilities. We also excluded studies that evaluated the effects of nicotine (rather than its metabolites) on the cognitive function. We examined the effects of nicotine in a previous publication (Majdi et al.,
The primary outcome of this review was evidence of specific biotransformed metabolites of nicotine in the brain, and the secondary outcome was evidence of effects on learning and memory and the mechanisms that mediate these brain functions.
From the included articles, we extracted data of the metabolites, the type of studies (clinical or experimental), the nature of the condition in which metabolites had effects, the actual effect(s) (positive or negative), and the mechanism, dose, duration, and route of metabolite administration. We also noted study quality measures to evaluate the risk of bias (see below).
A modified version of the CAMARADES' study quality checklist (Sadigh-Eteghad et al.,
The electronic search of the mentioned databases identified 426 articles of which 17 studies met the inclusion criteria (Figure
Summary of included and excluded articles. The style was adopted from Moher et al. (
Low methodological quality of studies leads to overvaluation of effect sizes (Sadigh-Eteghad et al.,
Quality assessment of the included animal studies according to modified CAMARADES' study quality checklist.
Upon delivery to the systemic circulation, nicotine is distributed throughout the body as ionized (69%) and unionized (31%) forms, and its binding to proteins is insignificant (Benowitz et al.,
After distribution throughout the body, including the liver, nicotine is extensively metabolized by the liver, and the metabolites or the remaining nicotine are then excreted in the urine. A main first pass pathway of nicotine metabolism in the human liver is
Nicotine distributes to the brain shortly after peripheral administration (whether intraperitoneal, intravenous, oral, or subcutaneous) with maximum between 30 and 60 min, and can be detected in the CNS as late as 4 h after injection (Crooks and Dwoskin,
Until recently, little attention has been paid to nicotine's metabolism in the central nervous system (CNS). The current urge to study nicotine and its metabolites in the brain arose from the evidence that the metabolites are pharmacologically active and may mediate nicotine's apparent effects in the brain (Crooks et al.,
Besides nicotine, five metabolites of nicotine can be identified in the brain, including cotinine, norcotinine, nornicotine, and two minor
Although a large body of evidence supports the procognitive effects of nicotine, there is insufficient knowledge of the metabolites and their impact in the brain (White and Levin,
Cotinine [(
Cotinine does not cause tachyphylaxis, addiction, or nicotine-like withdrawal symptoms, and it has no negative cardiovascular effects as opposed to nicotine (Terry et al.,
As a type 1 PAM of nAChR, cotinine's affinity is low compared to that of nicotine (Riah et al.,
The findings cited above are not universally replicated, and some studies yielded opposite results. Rezvani and Levin (
A growing body of evidence supports a procognitive effect of cotinine in animals (Herzig et al.,
Selected studies investigating the effects of cotinine on cognitive performance in various neurological disorders.
Mouse | Tg6799 Model of AD | Prevents memory loss | Reduction of Aβ aggregation and stimulation of the Akt/GSK3β pathway | 2.5 mg/kg | 3.5 months | Oral gavage | Echeverria et al., |
Improved spatial working memory | Lowering Aβ burden in the hippocampus and entorhinal cortex | 5 mg/kg | 3 months | Oral gavage | Patel et al., |
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Improved visual recognition memory | Changes in the cerebral Tau phosphorylation | 5 mg/kg | 3.5 months | Oral gavage | Grizzell et al., |
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Model of chronic stress | Enhanced learning and memory | Improvement of the expression of the neurogenesis factor VEGF | 5 mg/kg | 13 days | Oral gavage | Grizzell et al., |
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Enhanced working memory impairment | Increase in the synaptic density and activates the Akt/GSK3β pathway in hippocampus | 5 mg/kg | 37 days | Oral gavage | Grizzell et al., |
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Improved memory | Enhancement of expression of GFAP in the hippocampus and |
10 mg/ml | 2 weeks | Intranasal | Perez-Urrutia et al., |
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PTSD model | Improved the extinction of fear memory | Increase in the levels of the active forms of ERK1/2 | 5 mg/kg | NM | Oral gavage | Zeitlin et al., |
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Prevented working memory loss induced by model of chronic stress | Increase in the synaptophysin, in the CA1 region of hippocampus, entorhinal and prefrontal cortices | 5 mg/kg | 3 weeks | Oral gavage | Alex Grizzell et al., |
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Model of Fragile X syndrome | Improved coordinate and categorical spatial processing, novel object recognition, and temporal ordering | Increase in the phosphorylation of GSK3β and Akt in the |
3 mg/kg | Acute | Intraperitoneal | Pardo et al., |
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DBA/2 model of sensory inhibition deficit | No improvement of sensory inhibition | Probable activation of α7 nAChR |
0.033, 0.1, 0.33, 1, 3.3 mg/kg | Single dose | Subcutaneous | Wildeboer-Andrud et al., |
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0.33, 1, 3.3 mg/kg | 7 days | ||||||
Rat | NMDAR-blocked dementia model | Improved recognition memory | Attenuation of NMDA antagonist-induced memory impairment | 2 mg/kg | Chronic | Oral gavage | Terry et al., |
Improved working memory | Attenuation of NMDA antagonist-induced memory impairment | 0.03–10.0 mg/kg |
Single dose | Subcutaneous | Terry et al., |
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Chronic | Oral gavage | ||||||
Healthy | Improved the extinction of fear memory | Increase in pERK/tERK ratios and pERK 1/2 (without impairment of cognition) | 2.0 mg/kg | Chronic | Oral gavage | de Aguiar et al., |
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Healthy | Enhanced recognition memory | Sensitize α7 nAChR to low levels of acetylcholine | 3.0 and 10.0 mg/kg | Single dose | Intraperitoneal | Terry et al., |
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Chemotherapy model | Improved working memory | Probable modulation of α7 nAChR | 5 mg/kg | 2 weeks | Oral gavage | Iarkov et al., |
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Human | Non-smokers | Impaired verbal recall on the long word list | no data | 0.5, 1, and 1.5 mg/kg | Single dose | Oral capsule | Herzig et al., |
Abstinent cigarette smokers | No significant effects in symbol digit modalities test | no data | 40, 80, or 160 mg/daily | 10 days | Oral capsule | Hatsukami et al., |
Schematic illustration of metabolites of nicotine in brain and mechanisms involved in the procognitive effects of cotinine (the main procognitive metabolite). As a type 1 PAM, cotinine modulates the function of α7 nAChR that in turn leads to reduced Aβ1−42 production and decreased neuroinflammation, tau hyperphosphorylation, and apoptosis. It also improves synaptic plasticity. In the end, the changes may contribute to the reduction of age-related cognitive impairment. PAM, positive allosteric modulator; nAChR, nicotinic acetylcholine receptor; NMDAR, N-methyl-D-aspartic acid receptor; ER, endoplasmic reticulum; PKA, protein kinase A; Aβ, amyloid-beta.
Apoptosis, a programmed form of cell death, has been implicated in the pathogenesis of memory disorders, such as AD (Majdi et al.,
Synaptic plasticity and density are of central importance to learning and memory (Silva,
As the main neurotoxic forms of Aβ, amyloid-beta1−42 (Aβ1−42) oligomers are believed by some to cause the cognitive dysfunction of AD (Resende et al.,
Hyperphosphorylated tau is the major component of neurofibrillary tangles (NFT) that are a key pathological finding in AD and other cognitive disorders (Mitchell et al.,
Controlled release of glutamate in the cortex regulates high cortical functions, such as learning and memory (Rahn et al.,
Activation of α7 receptors stimulates calcium release from intracellular sources (Dajas-Bailador et al.,
The anti-inflammatory properties of nAChR, especially the α7 subtype, are well-known from numerous studies (Metz and Tracey,
Under controlled circumstances, cotinine blocks Fenton's reaction and prevents free radical production in the brain (Soto-Otero et al.,
Nornicotine or demethylcotinine is a major pharmacologically active metabolite of nicotine in the brain which possibly acts via nAChR (Dwoskin et al.,
Although nornicotine is as potent as nicotine, it is less desensitizing at the major nAChR subtypes in the brain, and nornicotine's presence leads to the activation of α7 nAChR. Nornicotine's potency and efficacy differ by several folds, but it has been shown that peak currents caused by nornicotine acting at α7 nAChR are equal to those of acetylcholine. Considering nornicotine's durable presence in the brain, the molecule may mediate some of the neuroprotective effects of nicotine. A study showed that α7 receptors are responsive to nornicotine, and the action at the receptors of this nicotine metabolite leads to improved cognition and attention (Papke,
In addition to the major metabolites mentioned above, there are minor CNS biotransformation products of nicotine, including norcotinine. After peripheral injection of nicotine, norcotinine is detected in the brain, and it is likely produced by 5′-C-oxidation of brain nornicotine. This fate is different from the processing in the periphery where
Nicotine lowers learning and memory impairment in some neurological disorders. However, its adverse cardiovascular and addictive effects limit the application in the clinical setting. Possible biological effects of nicotine in the human brain in principle could be mediated by nicotine itself or by its metabolites, but there is a considerable lack of evidence of the mechanistic effects of specific compounds in humans. This shortage of evidence can be rectified only by focused research in the future. On the other hand, evidence suggests that the biotransformation product cotinine is pharmacologically active in the brain of animal models with no adverse effects. Accumulating evidence makes it likely that this metabolite mediates the memory supportive effects of nicotine in the brain. Thus, a great deal of effort has been exerted to clinically apply cotinine as a treatment of learning and memory impairment and its underlying disorders. Taken together, we claim that this biologically active metabolite is more than just a biomarker of nicotine consumption and has potentially novel therapeutic value in the treatment of learning and memory declines.
AM, FK, and SS-E performed the searches, interpreted the results and wrote the manuscript. AG, SS-E, and AM designed the study. AG critically interpreted data and critically revised and approved the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
This research was supported by a grant from Neurosciences Research Centre—Tabriz University of Medical Sciences (grant number: 61017) to SS-E, and publication grants from Danish Alzheimer Foundation and University of Southern Denmark to AG.