CENTRAL NERVOUS SYSTEM CHANGES IN DEFICIENCY OF VITAMIN B6 AND OTHER B-COMPLEX VITAMINS The effects of vitamin B , deficiency on the central nervous sytem are not confined to the critical pre weanling period of brain development. Central nervous system abnormalities are associated with deficiencies of thiam in, rib oflavin, niacin, fo lic acid, and biotin, besides pyridoxine.

Key Words: central nervous system, electrophysiological changes, vitamin B6-deficiency, postweaning period

Nutritional deficiencies cause defects in cellular metabolism of the brain, which lead to electrophysiological changes and finally manifest as behavioral (sensory, motor, intellective, and personality) abnorm a lities. Neurodietetic research has primarily relied on behavioral tests based on conditioning and learning experiments, where appetitive behavior or reflex and locomotor responses t o electric shock are used as criteria for assessment. Such tests cannot distinguish between effects on appet i t e and motor system from those on learning. Further, central nervous system (CNS) involvement can only be inferred through behavioral tests. A more objective and direct assessment of CNS involvement is based on a electrophysiological approach. In recent years electroencephalographic (EEG) techniques of resting tracings, activated tracings, frequency analysis, and evoked response from p h o t i c, a u d it o ry, and somatosensory stimuli have been used for measuring and monitoring electrophysiological changes in malnutrition. Detrimental effects of vitamin B, deficiency on CNS as reflected in behavioral and electrophysiological changes have been reported in animals and humans.' A study in rats suggests that the deficit in avoidance

learning seen in post-weaning vitamin B, deficient rats, is distinct from the slight but significant motor deficit suffered by those animals.* M. C. Stephens e t al.3 reported that vitamin B, deficiency induced in rats during the preweaning period, when active brain development is in progress, can result i n the onset of seizures and EEG changes. The deficient animals also show abnormalit i e s in the auditory evoked cortical potentials with respect t o their latency, wave form, and response to repetitive stimuli. In a recent report, C.N. Stewart e t al.4 showed that the deleterious effects of €3, deficiency on CNS can be observed even when the deficiency is induced in the postweaning period (from the age of 21 days onwards) when the brain development has been almost completed. Latency of visually evoked cortical response was used as a measure of CNS reaction t o stimulation. Chronic electrodes were implanted in the brain with the electrode tips located on the surface of the dura over the visual cortex and vertex. A third electrode which served as ground was placed on the 0 s nasale, t o minimize the movement artifact. Each animal was exposed t o 50 successive stimuli a t five different light intensities. Signals from the visual cortex were amplified and fed into a computer. Averages of 50 stimuli were recorded. With an increase in intensity of photic stimulation, the latency of response diminNUTRITION REVIEWSIVOL. 33, NO. 7 /JANUARY 1975 21

ished in control as well as deficient groups. The vitamin B, deficient animals showed significantly higher latency a t each intensity and this improved after treatment with pyridoxine. These data suggest that the effects of vitamin B, deficiency on CNS are not necessarily confined t o the critical preweanling period of brain development. The possibility of the observed changes as being due t o inanition was ruled out since in an earlier study, these workers had failed to observe the effect of food restriction on cortical evoked response^.^ Besides, the CNS abnormalities could be reversed by the administration of pyridoxine. The neurochemical basis of CNS lesions in vitamin B, deficiency i s not understood. Induction of vitamin B, deficiency in the preweaning stage reduces the DNA, RNA, and protein content of the brain, but similar changes are not observed when the deficiency i s induced i n the postweaning ~ t a g e . The ~ levels of serotonin and noradrenaline are not altered in vitamin B, deficiency., The depletion of pyridoxal phosphate (PLP) in the brain of rats fed on vitamin B, deficient diet is 50 percent, and not as high as that in other t i ~ s u e s .The ~ activities of some PLP enzymes in the brain f a l l 3 and t h e synthesis of gammaaminobutyric acid in the brain decreases in B, d e f i ~ i e n c y . ~The . ~ latter may lead t o increased CNS excitability. Behavioral and/or electrophysiological abnormalities were also observed in the deficiencies of other B-complex vitamins such as thiamin,8 r i b ~ f l a v i n , ~O niacin,’ f o l i c acid,’ * * 1 3 and biotin.14 These changes i n some instances were found t o precede other clinical manifestations of the deficiency syndrome.8 O Some early literature on the effects of B-complex vitamin deficiencies on brain function has been reviewed by J. Brozek and G. Vaes.” Much of the older data is difficult t o evaluate since experiments were carried out with only semi-pure diets. The recent studies, however, leave little doubt that the deficiency of many B-complex vitamins in early or adult life can have profound effects on the CNS. The implications and

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consequences of such abnormalities in brain function on the overall performance of populations where widespread malnutrition exists need attention and investigation. 0

1. D. B. Coursin: Vitamin 6, and Brain Function in Animals and Man. Ann. N. Y. Acad. Sci. 166: 7-15, 1969 2. C. N. Stewart, H. N. Bhagavan, and D. B. Coursin: Some Behavioral Consequences of Pyridoxine Deficiency in Rats in International Symposium on Pyridoxal Enzymes. L. Yamada, N. Katunuma, and H. Wada, Editors, p. 181-183, Maruzen Co., Tokyo, 1968 3. M. C. Stephens, V. Havlicek, and K. Dakshinamurti: Pyridoxine Deficiency and Development of the Central Nervous System in the Rat. J. Neurochem. 18: 2407-2416, 1971 4. C. N. Stewart, D. B. Coursin, and H. N. Bhagavan: Cortical-Evoked Responses I n Pyridoxine-Def icient Rats. J. Nutrition 103: 462-467, 1973 5. H. N. Bhagavan and D. B. Coursin: Effect of Pyridoxine Deficiency on Nucleic Acid and Protein Contents of Brain and Liver in Rats. Int. J. Vit. Nutrition Res. 41: 419-423, 1971 6. H. N. Bhagavan and D. B. Coursin: Effects of Pyridoxine Deficiency and DL-p-Chlorophenylalanine Administration to Rats on 5-Hydroxyptamine Concentrations in Brain and 5-Hydroxyptamine Concentrations in Blood. Biochem. J. 134: 763-767, 1973 7. J. K. Tews and R. A. Lowell: The Effect of Nutritional Pyridoxine Deficiency on Free Amino Acids and Related Substances in Mouse Brain. J. Neurochem. 14: 1-7, 1967 8. M. R. Peskin, G. Newton, and M. Brin: Thiamine Deficiency, Infantile Manipulation and Startle Response in Rats. J. Nutrition 20-24, 1967 9. T. Arakawa, T. Mizuno, F. Chiba, K. Sakai, S. Watanabe, T. Tarnura, S. Tatsumi, and D. B. Coursin: Frequency Analysis o f Electroencephalograms and Latency of Photically Induced Average Evoked Responses in Children with Ariboflavinosis. (Preliminary Report) Tohoku J. Exp. Med. 94: 327-335, 1968 10. R. T. Sterner and W. R. Price: Restricted Riboflavin: Within-Subject Behavioral Effects i n Humans. Am. J. Clin. Nutrition 26: 150-160, 1973 11. S. G. Srikantia, M. V. Reddy, and K. Krishnaswamy: Electroencephalographic Patterns in

Pellagra. Electroenceph. Clin. Neurophysiol. 25: 386-388, 1968 12. T. Arakawa, T. Mizuno, Y. Honda, T. Tamura, J. Sakai, S. Tatsumi, F. Chiba, and D. B. Coursin: Brain Function of Infants Fed on Milk from Mothers with Low Serum Folate Levels. Tohoku J. Exp. Med. 97: 391-397, 1969 13. R. A. Schreiber and J. W. Zempi: Neonatal Folate Deficiency: Effect on Audiogenic

Seizures in DBAl2J Mice. Nutrition Rep. Int.

8 : 237-244, 1973 14. C. N. Stewart, H. N. Bhagavan, D. 6. Coursin, and K. Dahshinamurthi: Effect of Biotin Deficiency on Escape and Avoidance Learning in Rats. J. Nutrition 88: 427-433, 1966 15. J. Brozek and G. Vaes: Experimental Investigations on the Effects o f Dietary Deficiencies on Animal and Human Bahavior. Vitamins Hormones 19: 43-94.1961

COMPETITION BETWEEN PHLORlZlN AND GOLD THIOGLUCOSE FOR GLUCORECEPTOR CELL TRANSPORT MECHANISMS IN THE HYPOTHALAMUS Phlorizin injected locally in the region o f the medial hypothalamus protects glucoreceptor cells from necrosis due to gold thioglucose injections and defines a group of cells which are particularly associated with the regulation of food intake i n mice.

Key Words: glucose transport, hy pot haIa mus, p hlo riz in

food

intake,

The proposed mechanism by which glucoreceptor cells of the hypothalamus regulate food intake depends on the uptake of glucose by the cells through specific transporting processes. Some substances which inhibit or compete for carrier mechanisms involved with glucose uptake in other cells of the body have been investigated as they relate both t o changes in glucose transport in the glucoreceptor cell and to changes in food intake. Phlorizin inhibits glucose transport by the enterocyte of the gut and if phlorizin inhibits glucose transport in these cells, then the cells should not respond to high blood glucose concentrations and fail t o shut off food intake. When phlorizin was injected locally into the lateral cerebral ventricle of the rat, a state of hyperphagia and weight gain was produced.' Similar amounts given intraperitoneally failed t o produce effects on food intake. A hypothesis was developed that local instilla-

tion of phlorizin inhibited the adjustment of food intake according to caloric expenditure as it relates to glucose concentration in blood by the inhibition of glucose transporting mechanisms. A. F. Debons and associates* further extended the test of this hypothesis by injecting phlorizi n intra hy potha1am icall y . They followed this injection with gold thioglucose which, as has been shown in t h e past, destroys glucoreceptor cells. P h I orizin was labeled with radioactive hydrogen so that autoradiographic localization of phlorizin in brain sections could be done t o define the region of phlorizin inhibition in the hypothalamus. Phlorizin protected 16 of 18 mice studied from the usual necrosis of the ventromedial area of the hypothalamus produced after gold thioglucose injection. In 13 of the animals, prevention was unilateral, on the side of the injection; in the remaining three, prevention was bilateral. These data suggested a local action of phlorizin which was enlarged due to diffusion across tissue in the region of the NUTRITION REVIEWSfYOL. 33, NO. 1 f JANUARY 1975 23

Central nervous system changes in deficiency of vitamin B6 and other B-complex vitamins.

CENTRAL NERVOUS SYSTEM CHANGES IN DEFICIENCY OF VITAMIN B6 AND OTHER B-COMPLEX VITAMINS The effects of vitamin B , deficiency on the central nervous s...
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