Dietary arginine alters time of symptom onset in Huntington's disease transgenic mice

Recent neuroimaging studies reported complex changes in cerebral blood how (CBF) in early-staged Huntington's disease (HD) patients. Deckel and co-wor kers [Deckel and Duffy, Brain Res. (in press); Deckel and Cohen, Frog. Neur o-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. S eventy-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% AR G, (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 m otor impairments (P<0.05), and increased resting CBF in HD relative to cont rol (P<0.05). Conversely, the 0% ARG diet demonstrated no loss of body weig ht and had no changes in CBF relative to controls. However, the 0% ARG HD g roup 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. Immunocytochemi stry analysis found greater deposition of nitrotyrosine in the cortex, and vasculature, of HD+ mice, 58 and 1.2%>0% arginine diets. When collapsed acr oss all conditions, CBF inversely correlated (P<0.05) both with the body we ight and motor changes suggesting that changes in CBF are associated with b ehavioral decline in HD mice. Collectively, these findings indicate that di etary consumption of the NO precursor ARG has a measurable, but complex, ef fect on symptom progression in HD transgenic mice, and implicates NO in the pathophysiology of HD. (C) 2000 Elsevier Science BN. All rights reserved.