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Khatoon S.,New Hill | Chalbot S.,New Hill | Bolognin S.,New Hill | Puolivali J.,Charles River Discovery Research Services | Iqbal K.,New Hill
Journal of Alzheimer's Disease | Year: 2015

Alzheimer's disease (AD) is the single major cause of dementia in middle- to old-Age individuals, and, as of yet, no disease-modifying therapeutic drug is available for its treatment. A major obstacle in the successful development of diseasemodifying therapeutic drugs has been the lack of suitable animal models of the sporadic form of AD as well as a biomarker that can be used both for therapeutic preclinical studies and for human clinical trials. Previously we showed neurogenesis and neuronal plasticity deficits and cognitive impairment and their rescue with a neurotrophic peptidergic compound, DGGLAG named P021, in aged Fisher rats. Here we show that P021 is blood-brain-barrier-permeable, and chronic oral treatment with this compound can reduce the brain level of total tau in the aged rats. Furthermore, cerebrospinal fluid (CSF) levels of both tau and Aβ/AβPP are elevated in the aged animals, and chronic treatment with P021 can reduce tau but not Aβ/AβPP to that of the levels found in young adult rats. Importantly, P021 does not induce any detectable immune reaction in rats. Collectively, these studies show the therapeutic potential of P021 as a disease-modifying compound and the suitability of the aged Fisher rats as a model of cerebral aging in which the therapeutic efficacy of a tau-reducing compound can be monitored in the CSF. © 2015 - IOS Press and the authors. All rights reserved. Source

Lansdell T.A.,Michigan State University | O'Reilly S.,Michigan State University | Woolliscroft T.,Charles River Discovery Research Services | Azevedo L.M.,Michigan State University | And 6 more authors.
Bioorganic and Medicinal Chemistry Letters | Year: 2012

The pathogenesis of rheumatoid arthritis is mainly driven by NF-κB-mediated production of cytokines, such as TNF-α. We report herein that the orally available imidazoline-based NF-κB inhibitor, TCH-013, was found to significantly reduce TNF-α signaling and attenuate collagen antibody induced arthritis in BALB/c mice. © 2012 Elsevier Ltd. All rights reserved. Source

Menalled L.B.,Psychogenics, Inc. | Kudwa A.E.,Psychogenics, Inc. | Oakeshott S.,Psychogenics, Inc. | Farrar A.,Psychogenics, Inc. | And 25 more authors.
PLoS ONE | Year: 2014

Huntington's disease (HD) is an autosomal dominant, progressive neurodegenerative disorder caused by expansion of CAG repeats in the huntingtin gene. Tissue transglutaminase 2 (TG2), a multi-functional enzyme, was found to be increased both in HD patients and in mouse models of the disease. Furthermore, beneficial effects have been reported from the genetic ablation of TG2 in R6/2 and R6/1 mouse lines. To further evaluate the validity of this target for the treatment of HD, we examined the effects of TG2 deletion in two genetic mouse models of HD: R6/2 CAG 240 and zQ175 knock in (KI). Contrary to previous reports, under rigorous experimental conditions we found that TG2 ablation had no effect on either motor or cognitive deficits, or on the weight loss. In addition, under optimal husbandry conditions, TG2 ablation did not extend R6/2 lifespan. Moreover, TG2 deletion did not change the huntingtin aggregate load in cortex or striatum and did not decrease the brain atrophy observed in either mouse line. Finally, no amelioration of the dysregulation of striatal and cortical gene markers was detected. We conclude that TG2 is not a valid therapeutic target for the treatment of HD. © 2014 Menalled et al. Source

Northrup R.,Helsinn Therapeutics U.S. Inc. | Kuroda K.,Safety Research Laboratories | Duus E.M.,Helsinn Therapeutics U.S. Inc. | Barnes S.R.,Charles River Discovery Research Services | And 3 more authors.
Supportive Care in Cancer | Year: 2013

Purpose: Anamorelin (ONO-7643) is an orally active ghrelin receptor agonist in development for non-small cell lung cancer (NSCLC)-related anorexia/cachexia. It displays both orexigenic and anabolic properties via ghrelin mimetic activity and transient increases in growth hormone (GH). However, increasing GH and insulin-like growth factor-1 in cancer patients raises concerns of potentially stimulating tumor growth. Therefore, we investigated the effect of ghrelin and anamorelin on tumor growth in a murine NSCLC xenograft model. Methods: Female nude mice (15-21/group) with established A549 tumors were administered ghrelin (2 mg/kg i.p.), anamorelin (3, 10, or 30 mg/kg p.o.), or vehicle controls daily for 28 days. Tumor growth, food consumption, and body weight were monitored. Murine growth hormone (mGH) and murine insulin-like growth factor-1 (mIGF-1) were measured in plasma. Results: Tumor growth progressed throughout the study, with no significant differences between treatment groups. Daily food consumption was also relatively unchanged, while the percentage of mean body weight gain at the end of treatment was significantly increased in animals administered 10 and 30 mg/kg compared with controls (p < 0.01). Peak mGH levels were significantly higher in ghrelin- and anamorelin-treated animals than in controls, while peak mIGF-1 levels were slightly elevated but not statistically significant. All regimens were well tolerated. Conclusions: These findings demonstrate that neither anamorelin nor ghrelin promoted tumor growth in this model, despite increased levels of mGH and a trend of increased mIGF-1. Together with anamorelin's ability to increase body weight, these results support the clinical development of ghrelin receptor agonist treatments for managing NSCLC-related anorexia/cachexia. © 2013 The Author(s). Source

Beaumont V.,CHDI Management CHDI Foundation | Park L.,CHDI Management CHDI Foundation | Rassoulpour A.,Brains On line LLC | Dijkman U.,Brains On line LLC | And 12 more authors.
PLoS Currents | Year: 2014

Huntington's disease is a neurodegenerative disorder caused by mutations in the CAG tract of huntingtin. Several studies in HD cellular and rodent systems have identified disturbances in cyclic nucleotide signaling, which might be relevant to pathogenesis and therapeutic intervention. To investigate whether selective phosphodiesterase (PDE) inhibitors can improve some aspects of disease pathogenesis in HD models, we have systematically evaluated the effects of a variety of cAMP and cGMP selective PDE inhibitors in various HD models. Here we present the lack of effect in a variety of endpoints of the PDE subtype selective inhibitor SCH-51866, a PDE1/5 inhibitor, in the R6/2 mouse model of HD, after chronic oral dosing. Source

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