Nicotinic Receptor Agonists: Potential Therapeutic Drugs for Treatment of Cognitive Impairments in Schizophrenia and Alzheimer’s Disease. Open Med Chem J 4:37-56

Division of Clinical Neuroscience, Chiba University Center for Forensic Mental Health, Chiba, Japan.
The Open Medicinal Chemistry Journal 05/2010; 4:37-56. DOI: 10.2174/1874104501004010037
Source: PubMed


Accumulating evidence suggests that α7 nicotinic receptors (α7 nAChRs), a subtype of nAChRs, play a role in the pathophysiology of neuropsychiatric diseases, including schizophrenia and Alzheimer's disease (AD). A number of psychopharmacological and genetic studies shown that α7 nAChRs play an important role in the deficits of P50 auditory evoked potential in patients with schizophrenia, and that (α nAChR agonists would be potential therapeutic drugs for cognitive impairments associated with P50 deficits in schizophrenia. Furthermore, some studies have demonstrated that α7 nAChRs might play a key role in the amyloid-β (Aβ)-mediated pathology of AD, and that α7 nAChR agonists would be potential therapeutic drugs for Aβ deposition in the brains of patients with AD. Interestingly, the altered expression of α7 nAChRs in the postmortem brain tissues from patients with schizophrenia and AD has been reported. Based on all these findings, selective α7 nAChR agonists can be considered potential therapeutic drugs for cognitive impairments in both schizophrenia and AD. In this article, we review the recent research into the role of α7 nAChRs in the pathophysiology of these diseases and into the potential use of novel α7 nAChR agonists as therapeutic drugs.

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Available from: Jun Toyohara
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    • "Several α7 nAChR-selective radioligands such as PNU- 282987 [8], [9],PHA-543613 [10],AR-R17779 [11],SSR180711[12]–[15] and A-582941 [16] have already been tested in animal and human studies. It is therefore likely that α7 nAChR agonists will be useful as therapeutic drugs for cognitive deficits in several neuropsychiatric diseases [17]. "
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    ABSTRACT: The α7 nicotinic acetylcholine receptors (nAChRs) play a vital role in the pathophysiology of neuropsychiatric diseases such as Alzheimer's disease and depression. However, there is currently no suitable positron emission tomography (PET) or Single-Photon Emission Computed Tomography (SPECT) radioligands for imaging α7 nAChRs in brain. Here our aim is to radiosynthesize a novel SPECT radioligand (131)I-CHIBA-1001 for whole body biodistribution study and in vivo imaging of α7 nAChRs in brain. (131)I-CHIBA-1001 was radiosynthesized by chloramine-T method. Different conditions of reaction time and temperature were tested to get a better radiolabeling yield. Radiolabeling yield and radiochemical purities of (131)I-CHIBA-1001 were analyzed by thin layer chromatography (TLC) and high-performance liquid chromatography (HPLC) system. Whole body biodistribution study was performed at different time points post injection of (131)I-CHIBA-1001 in KM mice. Monkey subject was used for in vivo SPECT imaging in brain. The radiolabeling yield of (131)I-CHIBA-1001 reached 96% within 1.5∼2.0 h at 90∼95°C. The radiochemical purity reached more than 99% after HPLC purification. (131)I-CHIBA-1001 was highly stable in saline and fresh human serum in room temperature and 37°C separately. The biodistribution data of brain at 15, 30, and 60 min were 11.05±1.04%ID/g, 8.8±0.04%ID/g and 6.28±1.13%ID/g, respectively. In experimental SPECT imaging, the distribution of radioactivity in the brain regions was paralleled with the distribution of α7 nAChRs in the monkey brain. Moreover, in the blocking SPECT imaging study, the selective α7 nAChR agonist SSR180711 blocked the radioactive uptake in the brain successfully. The CHIBA-1001 can be successfully radiolabeled with (131)I using the chloramine-T method. (131)I-CHIBA-1001 can successfully accumulate in the monkey brain and image the α7 acetylcholine receptors. (131)I-CHIBA-1001 can be a candidate for imagingα7 acetylcholine receptors, which will be of great value for the diagnosis and treatment of mental diseases.
    Preview · Article · Jul 2013 · PLoS ONE
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    • "Growing evidence suggests that a deficit in cholinergic neurotransmission plays an important role in mediating cognitive deficits (Araki et al., 2002; Levin, 2002; Money et al., 2012). This evidence suggests that activation of the nicotinic receptors can be useful in treating some symptoms of schizophrenia particularly the cognitive deficits (Taly et al., 2009; Toyohara and Hashimoto, 2010). "
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    ABSTRACT: A greater incidence of tobacco consumption occurs among individuals with psychiatric conditions including post-traumatic stress disorder (PTSD), bipolar disorder, major depression, and schizophrenia, compared with the general population. Even when still controversial, it has been postulated that smoking is a form of self-medication that reduces psychiatric symptoms among individuals with these disorders. To better understand the component(s) of tobacco-inducing smoking behavior, greater attention has been directed toward nicotine. However, in recent years, new evidence has shown that cotinine, the main metabolite of nicotine, exhibits beneficial effects over psychiatric symptoms and may therefore promote smoking within this population. Some of the behavioral effects of cotinine compared to nicotine are discussed here. Cotinine, which accumulates in the body as a result of tobacco exposure, crosses the blood-brain barrier and has different pharmacological properties compared with nicotine. Cotinine has a longer plasma half-life than nicotine and showed no addictive or cardiovascular effects in humans. In addition, at the preclinical level, cotinine facilitated the extinction of fear memory and anxiety after fear conditioning, improved working memory in a mouse model of Alzheimer's disease (AD) and in a monkey model of schizophrenia. Altogether, the new evidence suggests that the pharmacological and behavioral effects of cotinine may play a key role in promoting tobacco smoking in individuals that suffer from psychiatric conditions and represents a new potential therapeutic agent against psychiatric conditions such as AD and PTSD.
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    • "The final evidence that the vagal anti-inflammatory pathway is indeed a breakthrough for the clinical management of immune-mediated inflammatory disease will ultimately have to come from clinical trials evaluating the different strategies discussed above. Selective α7nAChR agonists are currently evaluated as potential therapeutic drugs for the treatment of cognitive impairments in schizophrenia and Alzheimer's disease.110–114 To date, however, only a very limited number of studies have been performed to evaluate their anti-inflammatory potential in humans. "
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    ABSTRACT: The central nervous system interacts dynamically with the immune system to modulate inflammation through humoral and neural pathways. Recently, in animal models of sepsis, the vagus nerve (VN) has been proposed to play a crucial role in the regulation of the immune response, also referred to as the cholinergic anti-inflammatory pathway. The VN, through release of acetylcholine, dampens immune cell activation by interacting with α-7 nicotinic acetylcholine receptors. Recent evidence suggests that the vagal innervation of the gastrointestinal tract also plays a major role controlling intestinal immune activation. Indeed, VN electrical stimulation potently reduces intestinal inflammation restoring intestinal homeostasis, whereas vagotomy has the reverse effect. In this review, we will discuss the current understanding concerning the mechanisms and effects involved in the cholinergic anti-inflammatory pathway in the gastrointestinal tract. Deeper investigation on this counter-regulatory neuroimmune mechanism will provide new insights in the cross-talk between the nervous and immune system leading to the identification of new therapeutic targets to treat intestinal immune disease.
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