Effect of oral administration of L-arginine on senile dementia

Abstract

Many reports confirm that nitric oxide (NO) functions as a diffusible messenger in learning and memory (1Noda Y. Yamada K. Nabeshima T. Role of nitric oxide in the effect of aging on spatial memory in rats.Behav Brain Res. 1997; 83: 153-158Crossref PubMed Scopus (56) Google Scholar). Concentrations of tissue NO and arginine (the substrate for NO synthase) decrease with age (2Reckelhoff J.F. Kellum J.A. Racusen L.C. Hildebrandt D.A. Long-term dietary supplementation of L-arginine prevents age-related reduction in renal function.Am J Physiol. 1997; 272: R1768-R1774PubMed Google Scholar). Increased oxidative stress may also be involved in the aging process, particularly with deficits in learning and memory (3Shukitt H.B. Erat S.A. Joseph J.A. Spatial learning and memory deficits induced by dopamine administration with decreased glutathione.Free Rad Biol Med. 1998; 24: 1149-1158Crossref PubMed Scopus (48) Google Scholar). Serum levels of lipid peroxides, which are markers of oxidative stress, decrease after treatment with L-arginine (4Lubec B. Hayn M. Kitzmüller E. et al.L-arginine reduced lipid peroxidation in patients with diabetes mellitus.Free Rad Biol Med. 1997; 22: 355-357Crossref PubMed Scopus (58) Google Scholar). Thus, we hypothesized that L-arginine administration might be useful for improving learning and memory in the elderly. We studied 16 elderly patients (mean ± SD age of 79 ± 7 years; 13 women and 3 men) with cerebrovascular disease who had been living in a nursing home for 2 to 4 years. Patients were treated with oral L-arginine at a dose of 1.6 g per day for 3 months. At baseline, 3 months, and 6 months, we measured cognitive function using the revised version of Hasegawa’s Dementia Scale (HDS-R), which is widely used in Japan and is comparable with the Mini-Mental State Examination (5Hosokawa T. Yamada Y. Isagoda A. Nakamura R. Psychometric equivalence of the Hasegawa Dementia Scale-Revised with the Mini-Mental State Examination in stroke patients.Percept Mot Skills. 1994; 79: 664-666Crossref PubMed Google Scholar). A perfect score is 30 points, and scores <20 are considered to reflect dementia. Serum lipid peroxide levels were also measured. Following 3-month treatment with L-arginine, lipid peroxide levels declined from 4.3 ± 0.3 to 4.1 ± 0.3 nmol/mL (P<0.001). Three months later, the mean level had increased to 4.9 ± 1.9 nmol/mL. Cognitive function increased in all patients after L-arginine administration, from a score of 16 ± 8 to 23 ± 7 (P <0.0001), and returned to 17 ± 7 by 3 months after the end of the treatment (P <0.0001 versus after treatment). In general, patients showed more expressive faces and quicker responses. No side effects of L-arginine administration were observed. In Japan, dietary supplementation of L-arginine is not common. High-dose oral supplementation of L-arginine is limited by gastrointestinal symptoms. However, low doses (2 g/day) of L-arginine are effective at reducing lipid peroxidation (4Lubec B. Hayn M. Kitzmüller E. et al.L-arginine reduced lipid peroxidation in patients with diabetes mellitus.Free Rad Biol Med. 1997; 22: 355-357Crossref PubMed Scopus (58) Google Scholar), which led us to choose a daily dose of 1.6 g. We hypothesize that increases in the concentrations of NO as a neurotransmitter, increases in brain blood flow due to increased NO levels, or reductions in oxidative stress may have resulted in the apparent benefits in cognitive function.