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Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood. Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts--AD and a transgenic mouse model--to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology. Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types. Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential. [ABSTRACT FROM AUTHOR]

Introduction: The neuronal mechanism driving Alzheimer's disease (AD) is incompletely understood., Methods: Immunohistochemistry, pharmacology, biochemistry, and behavioral testing are employed in two pathological contexts-AD and a transgenic mouse model-to investigate T14, a 14mer peptide, as a key signaling molecule in the neuropathology., Results: T14 increases in AD brains as the disease progresses and is conspicuous in 5XFAD mice, where its immunoreactivity corresponds to that seen in AD: neurons immunoreactive for T14 in proximity to T14-immunoreactive plaques. NBP14 is a cyclized version of T14, which dose-dependently displaces binding of its linear counterpart to alpha-7 nicotinic receptors in AD brains. In 5XFAD mice, intranasal NBP14 for 14 weeks decreases brain amyloid and restores novel object recognition to that in wild-types., Discussion: These findings indicate that the T14 system, for which the signaling pathway is described here, contributes to the neuropathological process and that NBP14 warrants consideration for its therapeutic potential., Competing Interests: Susan Greenfield is the founder and CEO of Neuro‐Bio Limited and holds shares in the Company. She is the inventor in all Neuro‐Bio patents. Neuro‐Bio has a patent portfolio that currently includes 15 patent families (granted patents in Australia ( AU), China (CN), Europe (EP), Japan (JP), Mexico (MX), and United States of America (USA)). The bulk of this patent protection is in the field of neurodegeneration and, in particular, Alzheimer's disease. Of these, there are granted patents (in AU x2, CN, EP, JP, MX, and USA) and pending patent applications (in Brazil (BR), Canada (CA), India (IN), Republic of Korea (KR), New Zeland (NZ), and South Africa (ZA)) all based on WO2015/004430 (use of cyclic peptides from the C‐terminus of AChE for the diagnosis, prevention and treatment of neurodegeneration). In addition, Neuro‐Bio has a published international patent application with 12 corresponding national phases at different stages of prosecution based on each of WO2016/083809 (Novel linear peptides for treating neurodegeneration); WO2018/033724 (Peptidomimetics for treating Alzheimer's disease); and WO2016/156803 (Antibody that recognizes the T14 peptide of AChE). Neuro‐Bio also has published international patent application based on WO2018/178665 (Quantitative predictive biomarker for predicting cognitive decline) with national phases proceeding in the USA and EP. Neuro‐Bio additionally has an unpublished UK patent application drawn to Braak staging and positron emision tomography (PET) scanning for diagnosing Alzheimer's disease, and an unpublished international patent cooperation treaty (PCT) application protecting an in vivo animal model of Alzheimer's disease for testing novel therapies. In addition to Neuro‐Bio's core focus of detection and therapy of neurodegenerative disorders (in particular, Alzheimer's disease), it has two patent families concerning cancer and metastasis, that is, WO2017/130003 (diagnosing cancer) and WO2015/054068 (treating cancer with cyclic peptides), both of which have 12 national phases currently pending. All are owned by Neuro‐Bio with no encumbrance. Recent inventions have led to patent applications relating to various skin conditions. Neuro‐Bio has also recently filed a United Kingdom (UK) patent application for the treatment of Down's syndrome. Susan Greenfield is a member of the House of Lords in the United Kingdom's Parliament; this is a non‐stipendiary appointment. Clive Coen holds shares in the company and sits on the Neuro‐Bio Science Advisory Board (non‐stipendiary). He is Editor of Neuroendocrinology and the Chair of the Rationalist Association [UK]; neither of these entities has made payments to him or his institution. His research has been supported by the Biotechnology and Biological Sciences Research Council. Sara Garcia‐Ratés, Paul Morrill, Owen Hollings, Matthew Passmore, and Sibah Hasan are employees of Neuro‐Bio. Gregory Cole and his colleagues at University of California, Los Angeles (UCLA) (Sally Fraustchy, Ram P Singh, and Marisa Mekkittikul), have received partial support for consumables from Neuro‐Bio. Nikisha Carty, Silvia Bison, Laura Piccoli, Renzo Carletti, Stephano Tacconi, Anna Chalidou, Matthew Pedercini, Tim Kroecher, Hubert Astner, and Philip Gerrard are employees of Evotec. Evotec, a provider of scientific expertise to the global health care industry and academia, was contracted by Neuro‐Bio to undertake the behavioral part of the project and the immunohistochemical studies on amyloid. In the past 36 months, Gregory Cole has received grants and contracts: Veterans administration (VA) Merit BX004332, 2019‐2023 (Cole Principal Investigator (PI)): Tauopathy in mice and humans: surrogate plasma biomarkers for brain trauma‐initiated neurodegenerative disease. Akros/Japan Tobacco Contract, 2018‐2020 (Cole PI): Enhancing pyruvate dehydrogenase activity. NIH NIA R01AG057658, 2017‐2022 (Cole Co‐PI): Treating Alzheimer's disease by reducing brain insulin resistance with incretin receptor agonists. AstraZeneca NCR‐19‐14517, 2019‐2020 (Ajit Divakaruni PI; Cole Co‐I): Determining the role of brain nutrient preference in cognitive impairment and AD. National Neurological Aids Bank 3U24MH100929‐08S1, 2021‐2023 (Elyse Singer PI; Cole Co‐I): Alzheimer's related biomarker neuropathology in HIV post‐mortem brains. NIH/NIA R21 AG069100‐01, 2020 (Qiulan Ma PI; Cole Co‐I): Modulation of TGF‐beta signaling by omega‐6 polyunsaturated fatty acids for treating Alzheimer's disease. NIH NINR R01NR017190‐03, 2020‐2021 (Sarah Choi & Rajesh Kumar MPI; Cole Co‐I): Relationships between brain tissue integrity and self‐care abilities in adults with type 2 diabetes administrative supplement. Michael J Fox Foundation, 2021 (David Eisenberg PI; Cole Co‐I): Completion of pre‐clinical study of a safe and effective image‐based biomarker for Parkinson's disease. Michael J Fox Foundation, 2021‐2022 (Sally Frautschy PI; Cole Co‐I): Liganded nanoparticles to inhibit alpha‐synuclein aggregate deficits in endosomal/lysosomal/autophagy. In the past 36 months, Gregory Cole has received royalties or licenses from a curcumin formulation patent and Ram Singh has received consulting fees from UCLA., (© 2022 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Sodium channel inhibition is a well precedented mechanism used to treat epilepsy and other hyperexcitability disorders. The established sodium channel blocker and broad-spectrum anticonvulsant lamotrigine is also effective in the treatment of bipolar disorder and has been evaluated in patients with schizophrenia. Double-blind placebo-controlled clinical trials found that the drug has potential to reduce cognitive symptoms of the disorder. However, because of compound-related side-effects and the need for dose titration, a conclusive evaluation of the drug's efficacy in patients with schizophrenia has not been possible. (5R)-5-(4-{[(2-Fluorophenyl)methyl]oxy}phenyl)-l-prolinamide (GSK2) and (2R,5R)-2-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-7-methyl-1,7-diazaspiro[4.4]nonan-6-one (GSK3) are two new structurally diverse sodium channel blockers with potent anticonvulsant activity. In this series of studies in the rat, we compared the efficacy of the two new molecules to prevent a cognitive deficit induced by the N-methyl-d-aspartic acid receptor antagonist phencyclidine (PCP) in the reversal-learning paradigm in the rat. We also explored the effects of the drugs to prevent brain activation and neurochemical effects of PCP. We found that, like lamotrigine, both GSK2 and GSK3 were able to prevent the deficit in reversal learning produced by PCP, thus confirming their potential in the treatment of cognitive symptoms of schizophrenia. However, higher doses than those required for anticonvulsant efficacy of the drugs were needed for activity in the reversal-learning model, suggesting a lower therapeutic window relative to mechanism-dependent central side effects for this indication.

In an effort to identify selective drug like pan-antagonists of the 5-HT1 autoreceptors, studies were conducted to elaborate a previously reported dual acting 5-HT1 antagonist/SSRI structure. A novel series of compounds was identified showing low intrinsic activities and potent affinities across the 5-HT1A, 5-HT1B, and 5-HT1D receptors as well as high selectivity against the serotonin transporter. From among these compounds, 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (36) was found to combine potent in vivo activity with a strong preclinical developability profile, and on this basis it was selected as a drug candidate with the aim of assessing its potential as a fast-onset antidepressant/anxiolytic.

Bioisoteric replacement of the metabolically labile N-methyl amide group of a series of benzoxazinones with small heterocyclic rings has led to novel series of fused tricyclic benzoxazines which are potent 5-HT(1A/B/D) receptor antagonists with and without concomitant human serotonin transporter (hSerT) activity. Optimizing against multiple parameters in parallel identified 6-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}-4H-imidazo[5,1-c][1,4]benzoxazine-3-carboxamide (GSK588045) as a potent 5-HT(1A/B/D) receptor antagonist with a high degree of selectivity over human ether-a-go-go related gene (hERG) potassium channels, favorable pharmacokinetics, and excellent activity in vivo in rodent pharmacodynamic (PD) models. On the basis of its outstanding overall profile, this compound was progressed as a clinical candidate with the ultimate aim to assess its potential as a faster acting antidepressant/anxiolytic with reduced side-effect burden.

Background: Neuropeptide Y (NPY) is widely expressed in the brain and is known to affect consummatory behaviors including drinking alcohol as well as to play a role in seizures. We investigated the effects of a 4 day binge ethanol treatment model that is known to induce physical dependence and withdrawal seizures to determine the effects of ethanol dependence and withdrawal on NPY expression., Methods: Male Sprague Dawley rats were treated with ethanol or control nutritionally complete diets by intragastric treatment three times per day for 2 or 4 days with an average daily dose of approximately 8 g/kg ethanol per day. Ethanol-fed rats treated for 4 days and then withdrawn for 24, 72, and 168 hr also were studied. Brains were perfused and sectioned for immunohistochemistry for NPY, phospho-cyclic adenosine monophosphate responsive element binding (pCREB), and other proteins., Results: NPY immunoreactivity (NPY-IR) was found in several brain regions, with the hippocampus and cerebral cortex showing the most pronounced changes. NPY-IR was reduced by ethanol treatment in hippocampus and cortex, although at 72 hr of withdrawal there was a dramatic increase in NPY-IR in the hilus of the dentate gyrus and in CA3 and CA2 fields of hippocampus. Ethanol withdrawal seizures occurred around 12 to 24 hr of withdrawal, preceding the changes in NPY-IR at 72 hr. pCREB immunoreactivity (pCREB-IR) tended to decrease during ethanol treatment but showed a dramatic increase in dentate gyrus at 72 hr of withdrawal. Parvalbumin immunoreactivity indicated that some of the pCREB-IR and NPY-IR were within inhibitory interneuron basket cells of the hippocampal hilus. NPY-IR returned to control levels by 168 hr of withdrawal., Conclusions: These studies suggest that hippocampal NPY is reduced during the development of ethanol dependence. Ethanol withdrawal seizures precede a dramatic increase in hippocampal NPY-IR. Previous studies have suggested that NPY in the hippocampus reduces seizure activity and that NPY is induced by seizure activity. Thus, the increase in NPY-IR at 72 hr of withdrawal after binge ethanol treatment may be protective against prolonged withdrawal seizure activity.