Dietary restriction attenuates the neuronal loss, induction of heme oxygenase-1 and blood-brain barrier breakdown induced by impaired oxidative metabolism

Experimental thiamine deficiency (TD) is a model of impaired oxidative meta bolism associated with region-selective neuronal loss in the brain. Oxidati ve stress is a prominent feature of TD neuropathology, as evidenced by the accumulation of heme oxygenase-1 (HO-1), ferritin, reactive iron and supero xide dismutase in microglia, nitrotyrosine and 4-hydroxynonenal in neurons, as well as induction of endothelial nitric oxide synthase within the vulne rable areas. Dietary restriction (DR) reduces oxidative stress in several o rgan systems including the brain. DR increases lifespan and reduces neurode generation in a variety of models of neuronal injury. The possibility that DR can protect vulnerable neurons against TD-induced oxidative insults has not been tested. The current studies tested whether approximately 3 months of DR (60% of ad libitum intake) altered the response to TD. Six month-old ad libitum-fed or dietary restricted C57BL/6 mice received a thiamine-defic ient diet either ad libitum, or under a DR regimen respectively for eleven days. The TD mice also received daily injections of the thiamine antagonist pyrithiamine. Control ad libitum-fed or DR mice received an unlimited amou nt, or 60% of ad libitum intake, respectively, of thiamine-supplemented die t. As in past studies, TD produced region-selective neuronal loss (-60%), H O-1 induction, and IgG extravasation in the thalamus of ad libitum-fed mice . DR attenuated the TD-induced neuronal loss (-30%), HO-1 induction and IgG extravasation in the thalamus. These studies suggest that oxidative damage is critical to the pathogenesis of TD, and that DR modulates the extent of free radical damage in the brain. Thus, TD is an important model for study ing the relationship between aging, oxidative stress and nutrition. (C) 200 0 Elsevier Science B.V. All rights reserved.