N-methyl-D-aspartate receptor (NMDAR) mediated excitotoxicity is a probable proximate mechanism of neurodegeneration in Huntington disease (HD). Striatal neurons express the NR2B-NMDAR subunit at high levels, and this subunit is thought to be instrumental in causing excitotoxic striatal neuron injury. We evaluated the efficacy of 3 NR2B-selective antagonists in the R6/2 transgenic fragment model of HD. We evaluated ifenprodil (10 mg/kg; 100 mg/kg), RO25,6981 (10 mg/kg), and CP101,606 (30 mg/kg). Doses were chosen on the basis of pilot acute maximally tolerated dose studies. Mice were treated with twice daily subcutaneous injections. Outcomes included survival, motor performance declines assessed with the rotarod, balance beam task, and activity measurements, and post-mortem striatal volumes. No outcome measure demonstrated any benefit of treatments. Lack of efficacy of NR2B antagonists in the R6/2 model has several possible explanations including blockade of beneficial NMDAR mediated effects, inadequacy of the R6/2 model, and the existence of multiple proximate mechanisms of neurodegeneration in HD. KeywordsHuntington disease; striatum; excitoxicity; glutamate Huntington disease (HD) is an incurable, autosomal dominant neurodegenerative disorder characterized by involuntary movements, psychiatric problems, and dementia (Warby et al., 2007). The median onset of HD is around age 40 with inexorable progression to death over a period of approximately 15-20 years. HD is uncommon with an approximate prevalence of 5-10/100000 among populations of European descent but its onset in midlife and prolonged course causes costs disproportionate to prevalence. The pathologic hallmark of HD is striatal degeneration though recent neuroimaging data indicates early neocortical atrophy as well (Vonsattel and DiFiglia, 1998;Rosas et al., 2008).HD and 7 other neurodegenerative disorders are caused by increased CAG repeats within coding portions of their respective genes. Neurodegeneration results primarily from "gain of function" neurotoxicity of expanded polyglutamine (polyQ) repeats. While expanded polyQ * Corresponding Author: Roger L. Albin, MD, 5023 BSRB, 109 Zina Pitcher Place, Ann Arbor, MI, 48109-2200, Tel# 734-764-1347.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. domains are the primary agents of neurotoxicity, the surrounding protein sequences are thought to modulate expanded polyQ domain interactions with other cellular constituents, suggesting that the precise neurotoxic effects of different expanded polyQ proteins will vary from disease to disease (Imarisio et al.,...
Summary Seven patients with acute illnesses developed hypophosphataemia whilst receiving intravenous nutrition which included a fat emulsion, Intralipid, a possible source of phosphorus. The authors' observations cast doubt on the bio-availability of the phosphorus contained in the phospholipid content of the fat emulsion. The currently recommended allowance of phosphorus for this type of patient appears to be too low and it is suggested that 0-5-0-75 mmol/kg body weight be provided, preferably as a neutral phosphate solution. Sine hypophosphataemia can occur at various time intervals after starting intravenous nutrition and precede clinical sequelae it is recommended that routine serum phosphate measurements are made in all patients receiving this treatment.
SummaryCimetidine has been reported as suppressing the excess parathyroid hormone secretion and hypercalcaemia seen in hyperparathyroidism. A case of primary hyperparathyroidism is described, in which the level of circulating parathyroid hormone and hypercalcaemia remain entirely unaffected by cimetidine. The drug is implicated in the management of primary hyperparathyroidism unsuitable for surgery, but present evidence, as reviewed, is insufficient to recommend the use of cimetidine in this way. IntroductionThe available precision of serum calcium estimations, and the sensitivity of radioimmune assay techniques, have identified primary hyperparathyroidism as a common disorder. The prevalence of this condition increases with age and the incidence is greater in women. The mechanism of primary hyperparathyroidism is not yet clear, unlike the hallmarks of the disease: hypercalcaemia and increased production of parathyroid hormone (PTH). A series of patients with primary hyperparathyroidism has been reported in which hypersecretion of parathyroid hormone, and to a lesser extent hypercalcaemia, was suppressed by cimetidine in all cases. This present report refers to the view that such suppression may confer no benefit in the hyperparathyroid state, does not always occur and so is unpredictable, and that a place for cimetidine in the diagnosis and management of primary hyperparathyroidism is not proved.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.