Cancer ‘survivor-care’: I. the α7 nAChR as potential target for chemotherapy-related cognitive impairment

SUMMARY

What is known and Objective

Far more patients are now surviving cancer than ever before because of major advances in the diagnosis and treatment of primary and metastatic malignancy. Adjuvant chemotherapeutic drug and combination regimens have contributed to the success. However, persistent residual adverse effects involving mild impairment of cognitive impairment have been reported. Our objective is to review and to comment on the basic science and clinical evidence of potential pharmacologic targets for managing this emerging concern.

Comment

A search was conducted of basic science and clinical literature related to the objective and the information obtained was organized and evaluated from the perspective of its insight into potential pharmacotherapeutic targets. A large body of evidence suggests that the nicotinic acetylcholine receptor (nAChR), and in particular the α7 subtype, is involved in memory and that agonists and positive allosteric modulators of this receptor have potential in schizophrenia and Alzheimer animal models and patients.

What is new and Conclusion

We identify significant indirect evidence that the selective α7 nAChR drugs that are currently being investigated for cognitive improvement in schizophrenia and Alzheimer disease patients may be useful in cancer chemotherapy-related cognitive impairment. The clinical use of those drugs should be explored.

WHAT IS KNOWN AND OBJECTIVE

It is estimated that in 2008 there were more than 12 million new cases of cancer, 7 million deaths from cancer, and 25 million persons alive with cancer worldwide (1). For 2030, the projected worldwide figures are: 27, 17 and 75 million, respectively (1). Multiple factors, such as earlier detection, better diagnostic tools, and more effective treatment options are responsible for noteworthy improved survival rates. Cancer chemotherapeutic agents play a significant role in the increasing success. However, they are also cytotoxic because of their intended antineoplastic action. It is therefore not surprising that if these drugs can penetrate the blood–brain barrier, even to a small extent, they might produce adverse effects on brain function. As previously reviewed in this journal (2–4) and more comprehensively described in a recent monograph (5), a reported CNS adverse effect of cancer chemotherapy is a mild, but possibly long-lasting impairment of cognitive function. This chemotherapy-related cognitive impairment is called ‘chemo-fog’, ‘chemo-brain’, or some similar term.

The physiological mechanism(s) by which cancer chemotherapeutic drugs might produce cognitive impairment is not known, but plausible hypotheses have been proposed (6). In the absence of a definitive physiological target, yet need for ameliorative treatment in a growing population of patients, it seems worthwhile to examine whether pharmacologic approaches to cognitive enhancement that are being investigated for other disorders might also be applicable to ‘chemo-fog’. The present article examines the recent reports of agonists and allosteric modulators of the α7 subtype of the nicotinic acetylcholine receptor (nAChR) that are in various stages of development for the treatment of cognitive disorders in schizophrenia and Alzheimer disease. Together, basic science aspects of the α7 nAChR and preclinical animal models suggest that the α7 nAChR is a promising target for pro-cognitive enhancement and the available clinical data is encouraging. If such drugs prove to be safe and effective for the currently targeted populations, they might offer novel pharmacotherapeutic approaches for consideration for clinical use and drug discovery efforts for cancer chemotherapy-related cognitive impairment.

‘CHEMO-FOG’ / ’CHEMO-BRAIN’

It seems logical that treating brain cancer patients with radiotherapy could lead to CNS toxicity manifested as some form of cognitive impairment. Some of the earliest references to cognitive adverse effects following cancer chemotherapy, at least in the English language literature, dates to 1980 (7, 8). The authors reported that mild cognitive impairment was a relatively common occurrence in patients, was independent of affective disorders or other psychopathology, and indeed occurred in the absence of such disorders. The authors attributed the adverse effect to the chemotherapy, since it was the major variable associated with cognitive impairment in these patients. Subsequent studies reported cognitive impairment as an adverse effect of cancer treatment (9–13) and an increasing interest in the (proposed) effect has resulted in an increasing number of publications on the topic, appearing at an increasing rate (e.g., 128 in the 5-year period 2000–2004 compared to 20 from 10 years previously, 1990–1994).

van Dam and colleagues (14) published the results of a seminal study in 1998 that reported cognitive impairment in patients undergoing adjuvant chemotherapy for breast cancer. Because these patients did not have brain cancer and they did not receive brain irradiation, the reported cognitive impairment more clearly implicated the adjuvant chemotherapy. An editorial that accompanied publication of the paper summarizes its results and the possible confounders. In many ways it represents a succinct representation of the current state of the field (15):

… van Dam et al. take an important first step in assessing the prevalence of cognitive dysfunction in women who received adjuvant treatment for high risk breast cancer. … The design of the study is important, for it is probably the first to examine comprehensively cognitive functioning in patients with breast cancer within the context of a randomized trial. A further strength is the inclusion of a stage I breast cancer comparison control group that had not received any adjuvant treatment. The use of a disease-specific comparison group permits control for the impact of the diagnosis of cancer on psychologic distress and quality of life, both of which might affect cognitive functioning. Finally, the use of a battery of standardized neuropsychologic tests with healthy population normative reference data provides another important comparison. The key findings from the study include the following: 1) any adjuvant therapy increases the likelihood of women reporting cognitive problems in daily life in comparison with breast cancer patients who have not had adjuvant therapy; 2) emotional well-being, as determined by a standardized measure of QOL, does not differ in breast cancer survivors according to receipt of adjuvant chemotherapy; 3) there is a strong correlation between depression and anxiety and self-reported daily difficulties with concentration, memory, and thinking; 4) breast cancer patients who have received adjuvant therapy are significantly more likely to be classified as cognitively impaired on standardized tests; and 5) logistic regression analysis demonstrates that the risk of cognitive impairment is substantially increased for patients who receive high-dose chemotherapy when compared with patients in the control group and when compared with the patients in the standard-dose chemotherapy group … we are not told whether the measured differences in cognitive functioning in these survivors were associated with clinical disability or an inability to work … Nevertheless, the study suggests a credible dose–effect relationship between adjuvant therapy and cognitive impairment.

A small set of studies, that have used neuroimaging techniques such as PET (positron emission tomography) and MRI (magnetic resonance imaging) in an effort to correlate cognitive deficits with neuroanatomical changes, supports the existence of a true condition [reviewed in (3)].

NICOTINE AND COGNITIVE ENHANCEMENT

There is an extensive literature on the effect of nicotine on various types of memory (e.g., short-and long-term, prospective, working, olfactory, spatial, etc.) and other aspects involved in cognitive performance. In general, acute nicotine enhances the cognitive performance of laboratory animals and humans, and specific brain regions have been associated with these positive effects. Recent studies have investigated the mechanisms by which nicotine modifies prefrontal cortex and other cortical circuit neuronal activity, synaptic plasticity, and gene expression and how these effects might influence cognitive functioning [e.g., (16)]. There is considerable debate about what particular aspect(s) of cognitive function nicotine influences. Is nicotine’s positive action due to an effect on learning, memory, executive processes, or some other aspect(s) of cognitive function? Or is the effect instead on collateral processes that indirectly favour cognitive performance, such as increasing attention or motivation? These unresolved questions continue to be investigated in studies in human volunteers [e.g., (17–19)].

In cases of cognitive impairment, the details of how nicotine might improve performance (i.e., whether by direct vs. indirect action) is of less importance than a demonstration that it is effective. In this regard, there is substantial evidence that nicotine has ‘pro-cognitive’ effects in Alzheimer disease and schizophrenia.

One of the earliest suggestions that there might be some beneficial effect of nicotine on schizophrenia arose from an apparent ‘self-medication’ (20) exhibited by the high incidence of cigarette smoking by patients with schizophrenia (21–23) compared to the general population or patients with other types of mental illnesses (24). Initial speculation that the nicotine might be counteracting one or more of the adverse effects of neuroleptic drugs has been discounted, because smoking precedes neuroleptic treatment (25). The ability of nicotine to improve attention in patients with schizophrenia (26–29), even transiently, provides evidence of a positive effect on cognitive performance. Similarly, cigarette smoking is associated with Alzheimer disease (30–34). Multiple lines of evidence indicate that nicotine’s effect on these disorders is mediated by the nicotinic cholinergic receptor; more specifically, by the α7 subtype of the nicotinic cholinergic receptor [e.g., (35–37), and reviewed in (38)].

THE α7 nAChR AND COGNITION

The α7 nAChR is an ionotropic (cation-selective) subtype of nicotinic cholinergic receptor. Five identical (homopentameric) symmetrically arranged transmembrane subunits form a centralized ion-conducting pore (39, 40) (Fig. 1). The binding of acetylcholine and other ligands occurs at the interface between adjacent subunits (five possible orthosteric binding sites) (41) (Fig. 2). The α7 nAChR (one of at least 17 distinct nAChR identified subunits) is widely distributed throughout rodent and human brain, with a relatively high density in brain regions that are relevant to a role in cognition (42, 43). Together with the α4β2 subtype, the nAChR make up the majority of nAChR in the brain. The α7 nAChR has a highly selective permeability for Ca²⁺ (e.g., >10-fold higher than for Na⁺), more so than other nAChR subtypes, which are permeable to Ca²⁺, Na⁺, and K⁺ (44–46). Agonist activation of α7 nAChR promotes the influx of Ca²⁺ at presynaptic neuronal sites in amounts sufficient to modify Ca²⁺-dependent signalling processes, such as neurotransmitter release and several 2nd-messenger pathways (39, 47). The α7 nAChR subtype differs from the other subtypes in that it has lower affinity or efficacy for either acetylcholine or for nicotine and it is activated by choline (48).

Fig. 1.

From ref (41): the structural determinants for nicotinic acetylcholine receptor (nAChR) subtype specificity. Top: Two non-conserved amino acid residues differentiate ligand binding sites (left: α4β2, center: α4β4, right: α7α7). The difference of the van der Waals boundary is shown at amino acid 183 of subunit 1 (gold), and 135 of subunit 2 (cyan). Nicotine (magenta) is shown docked to the site. Bottom: Limited variation in electrostatic potential (charge distribution) between α4β2 (left) and α7α7 (right) (red = negative, grey = hydrophobic, blue = positive). The electronic version of this article is the complete one and can be found online at: http://www.biomedcentral.com/1472–6807/2/1 ©2002 Schapira et al. (41); licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article’s original URL.

Fig. 2.

The membrane-bound homopentameric α7 nicotinic acetylcholine receptor (nAChR). Ligand molecule binds at five possible orthostatic sites (red filled circles) and modulates cation influx, with high selectivity for Ca²⁺.

In their comprehensive review, Thomsen et al. (38) tabulate a large number of studies that demonstrate the ‘pro-cognitive’ effects of α7 nAChR agonists in animal models. These include the cognitive domains of spatial memory / learning, associative learning, social interaction, short-term recognition memory, short- and long-term episodic memory, memory consolidation / retrieval, sequential memory, working memory, and various aspects of attention, among other effects. In another comprehensive review, Leiser et al. (49) summarize the extensive preclinical and clinical studies using electroencephalogram that implicate α7 nAChR activation in attention, arousal, and cognitive performance.

α7 nAChR gene knock-out mice display deficits in several prefrontal cortex-mediated cognitive functions, such as attention and working memory. They show impairments in: sustained attention (50), particularly under conditions of a high attentional load (51); acquisition rate (52) and performance under high attentional demand (53); and working memory (54).

SELECTIVE AGONISTS / MODULATORS

Several compounds with selective affinity for the α7 nAChR have been developed and provide a means to directly test the effect of manipulation of α7 nAChR as a target for cognitive improvement (55–58). Among these are (Fig. 3) several spiro-oxazolirinones (e.g., AR-R 17779) (37), quinuclidine carbamates (59), quinuclidine ethers (60), quinuclidine amides (e.g., PHA-543613 and PHA-568487) (61, 62), GTS-21 (63), and some non-quinuclidine amine compounds, such as SR-180711 (64–66), PHA-709829 (67), A-582941 (68), and a series of 1,4-diazabicyclo[3·2·2]nonane aryl carbamates (69). The need for improved safety profile continues to drive discovery efforts. Recently, O’Donnell et al. (70) explored the structure–activity relationship (in particular, probing the steric and electronic requirements) of benzoxazole and azabenzoxazole replacements of the carbamate functional group of a previous series (69) by substituent substitutions around the heteroaromatic ring system. A good balance of potency, selectivity, and high affinity agonist activity was found with CP-810,123 (4-(5-Methyloxazoleo[4,5-b]pyridin-2-yl)-1,4-diazabicycl o[3·2·2]nonane) (Fig. 3). Several of these compounds are currently, or have been, in various stages of development.

Fig. 3.

Chemical structures of several selective α7 nicotinic acetylcholine receptor (nAChR) compounds.

These α7 nAChR selective compounds have provided pharmacologic tools for examining the potential pro-cognitive effects of α7 nAChR activation (by agonists or allosteric modulators). Evidence of pro-cognitive effects of such ligands includes: GTS-21 significantly improved the performance of non-smoking schizophrenic patients (n = 12) in standardized test measures in a randomized, double- blind, placebo-controlled cross-over trial (71) (the largest improvement was in the attentional domain); and a follow-up randomized, double-blind, placebo-controlled, cross-over study of nonsmoking schizophrenic patients (n = 31) (72) reported positive effect on the domains of attention / vigilance and working memory.

AGONISTS OR ANTAGONISTS?

For pro-cognitive effect, the majority of effort is directed at activation of α7 nAChR. However, Dziewczapolski et al. (73) recently reported that deletion of the α7 nAChR gene improved the cognitive deficits displayed in the Morris water maze by a mouse model (APPα7KO) of Alzheimer disease. The authors therefore suggested that the antagonism of α7 nAChR function could be pro-cognitive. Acknowledging that this view is contrary to the view that cognitive enhancement results from activation of α7 nAChR (56, 68, 74), they point out that α7 nAChR agonists and antagonists share certain effects (75–77) and that the rapid desensitization of α7 nAChR following its activation (78–81) makes it difficult to distinguish agonist from antagonist action at α7 nAChR. These investigators suggest that it might not be receptor activation per se that accounts for the pro-cognitive effects of α7 nAChR agonists, but might rather be due to the activation-induced desensitization of α7 nAChR by agonists (82) that accounts for the beneficial effects.

WHAT IS NEW AND CONCLUSION

We identify significant preclinical and clinical evidence to suggest that α7 nAChR is an attractive pharmacologic target for improving cognitive function in patients with schizophrenia or Alzheimer disease. Although there is no direct evidence that cancer patients and survivors who report chemotherapy-related cognitive impairments have dysfunction in α7 nAChR, such persons might benefit from these α7 nAChR-directed agents (agonist, antagonist, or allosteric modulator?).