ABSTRACT
Recent neuroimaging studies reported complex changes in cerebral blood flow (CBF) in early-staged Huntington's disease (HD) patients. Deckel and co-workers [Deckel and Duffy, Brain Res. (in press); Deckel and Cohen, Prog. Neuro-Psychopharmacol. Biol. Psychiatry 24 (2000) 193; Deckel et al., Neurology 51 (1998) 1576; Deckel et al., J. Nucl. Med. 41 (2000) 773] suggested that these findings might be accounted for, in part, by alterations in cerebral nitric oxide (NO) and its byproduct, peroxynitrite. The current experiment tested this hypothesis by altering NO levels via manipulations of dietary L-arginine (ARG), the dietary precursor of NO, in mice transgenic for HD. Seventy-one mice were assigned at 12 weeks of age to one of three isocaloric diets that varied in their content of ARG. These diets included: (a) 0% ARG, (b) 1.2% ARG (i.e. typical mouse chow), or (c) 5% ARG. The 5% ARG diets in HD mice accelerated the time of onset of body weight loss (P<0.05) and motor impairments (P<0.05), and increased resting CBF in HD relative to control (P<0.05). Conversely, the 0% ARG diet demonstrated no loss of body weight and had no changes in CBF relative to controls. However, the 0% ARG HD group continued to show significant deficits on motor testing (P<0. 05). The 1.2% ARG HD group showed reduced body weight loss, better motor functioning, and fewer changes in CBF compared to the 5% ARG HD group. Immunocytochemistry analysis found greater deposition of nitrotyrosine in the cortex, and vasculature, of HD+ mice, 5% and 1. 2%>0% arginine diets. When collapsed across all conditions, CBF inversely correlated (P<0.05) both with the body weight and motor changes suggesting that changes in CBF are associated with behavioral decline in HD mice. Collectively, these findings indicate that dietary consumption of the NO precursor ARG has a measurable, but complex, effect on symptom progression in HD transgenic mice, and implicates NO in the pathophysiology of HD.
Subject(s)
Arginine/administration & dosage , Huntington Disease/physiopathology , Tyrosine/analogs & derivatives , Animals , Arginine/pharmacology , Blood Glucose/analysis , Brain/drug effects , Brain/metabolism , Cerebrovascular Circulation/drug effects , Diet , Huntington Disease/complications , Huntington Disease/genetics , Huntington Disease/pathology , Mice , Mice, Transgenic/genetics , Movement Disorders/etiology , Time Factors , Tyrosine/metabolism , Weight LossSubject(s)
Cat Diseases/chemically induced , Insecticides/poisoning , Pyrethrins/poisoning , Seizures/veterinary , Tremor/veterinary , Administration, Topical , Animals , Cat Diseases/therapy , Cats , Fever/prevention & control , Fever/veterinary , Hypothermia/prevention & control , Hypothermia/veterinary , Insecticides/administration & dosage , Permethrin , Poisoning/therapy , Poisoning/veterinary , Pyrethrins/administration & dosage , Seizures/chemically induced , Seizures/therapy , Tremor/chemically induced , Tremor/therapyABSTRACT
Cisapride is an oral prokinetic agent used to facilitate or restore motility in the gastrointestinal tract. The National Animal Control Center has received 17 reports of accidental overexposure of dogs to cisapride since 1994. Doses of 640 mg/kg in dogs were reported to be lethal, but severe clinical signs have been noted at acute exposures as low as 18 mg/kg. The most common signs include diarrhea, muscle tremors and fasciculations, ataxia and incoordination, and hyperthermia. Available treatment is symptomatic and supportive. Activated charcoal is effective in reducing plasma cisapride levels.
