Functional vulnerability of developing central nervous system to ...

Brief Report Abdoulaye BAˆ UFR Biosciences Universite´ de Cocody 22 BP 1774 Abidjan 22 Coˆte d’Ivoire, Africa E-mail: [email protected]

Functional Vulnerability of Developing Central Nervous System to Maternal Thiamine Deficiencies in the Rat ABSTRACT: Thiamine deficiency (B1 vitamin) was induced during three periods of rat central nervous system (CNS) ontogenesis. Females were fed a thiamine deficient diet such that developing offspring were exposed either to pre-, peri-, or postnatal thiamine deficiency. To control the effects of undernourishment generated by different thiamine deficiencies, every treatment group had its own pair-fed control pup from a non drug-treated but undernourished dam. Seven different developmental abilities (exploratory activity, emotional reaction, hind paws lifting reflex, wire grasping times, crawling and leap execution latencies, and nociception) were recorded in the offspring from the 10th to the 45th postnatal day. The vulnerability of developing brain to the specific lack of B1 vitamin increases from prenatal (28%) to perinatal (43%) and postnatal periods (57%). ß 2005 Wiley Periodicals, Inc. Dev Psychobiol 47: 408–414, 2005. Keywords: maternal thiamine deficiency; brain ontogenesis; psychomotor functions; developing rats

Thiamine deficiency is commonly found in chronic alcoholics (Leevy, 1982), and is often associated to protein calorie malnutrition (Ahmed, Kimura, & Itokawa, 1988; Hailemariam, Landman, & Jackson, 1985). Thiamine (B1 vitamin) plays a central role in the cerebral metabolism (Greenwood & Craig, 1987; He´roux & Butterworth, 1992). Thiamine pyrophosphate (TPP), the active form of the vitamin, serves as coenzyme of three thiamine-dependent enzymes, i.e., the pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase, and transketolase (He´roux & Butterworth, 1992). Thiaminedependent enzymes are important for the maintenance of cellular energy metabolism, for lipid and nucleotide syntheses in developing brain (Haas, 1988). In addition to its metabolic function, this vitamin was considered

Received 28 September 2003; Accepted 30 June 2005 ˆ Correspondence to: A. BA Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/dev.20105 ß 2005 Wiley Periodicals, Inc.

exerting a specific role on the central nervous tissues, but the mechanism of this action has not been clarified (Itokawa, Schultz, & Cooper, 1972; Matsuda & Cooper, 1981). Previous studies reported that the brain is especially vulnerable to B1 avitaminosis during ontogenesis (Butterworth, 1987; Greenwood, Pratt, & Thomson, 1985), and that a maternal thiamine deficiency is actually transmitted to the fetus (Rœcklin, Levin, Comly, & Mukherjee, 1985). Indeed, maternal thiamine deficiency provokes cell death and atrophy in fetal brain that persist in adulthood (Baˆ, Seri, Aka, Glin, & Tako, 1999). Offspring exposed to maternal thiamine deficiency showed reduction of thiamine-dependent enzymes activities (Butterworth, 1993) and lipid content in their brain, as well as alteration of myelination (Trostler, Guggenheim, Havivi, & Sklan, 1977). It has been demonstrated (Bell & Stewart, 1979) that rat pups suckling from dams receiving a thiamine deficient diet demonstrate permanent deficit of learning and memory, suggesting that the metabolic consequence of maternal thiamine deficiency may result in permanent neurological dysfunction in the offspring. Indeed, the developing brain appears to be more

Vulnerability of Developing Brain to the Thiamine Deficiencies

susceptible to dietary thiamine deficiency than the adult brain (Butterworth, 1993). In the present work, we study the periods of susceptibility of the developing central nervous system (CNS) to the maternal thiamine deficiency and relate those periods to the stages of neural development. In the rat, neuronal proliferation and migration are essentially prenatal (Angevine & Sidman, 1961; Bisconte & Marty, 1975); the cellular differentiation is perinatal (Hattori & McGeer, 1973; Miller, 1986); myelinogenesis as well as synaptic connections establishment are some extensively postnatal phenomena (Aghajanian & Bloom, 1967; Johnson & Quarles, 1986). By manipulating the period of the dam’s thiamine deficiency, we attempted to identify the stages of CNS development particularly vulnerable to a specific lack of thiamine. Nulliparous female rats of a Wistar strain (bred in our colony), weighing 180–200 g, were housed individually in plastic cages (27
37
18 cm) with the floor covered by wood-dust. A Wistar male was placed into each female’s cage at 18.00 hr daily. Presence of a vaginal plug indicated Day 1 of gestation. Approximately 1 week prior to parturition, the dams were checked daily for pups. The date of parturition was designated as Postnatal Day 1 (P1). Litter sizes were adjusted within 24 hr following birth so that every mother nursed 8–10 pups. After birth, offspring were left undisturbed until 10 days of age. Testing sessions were performed at 10, 15, 20, 25, 30, and 45 days of age. Mothers remained with the pups at all times, except during testing sessions. At weaning, those pups subjected to the same treatment were housed in same sex groups of three by cage. The colony was bred in an aerated noiseless vivarium room subjected to diurnal daylight/ night cycles, humidity (75%), and ambient temperature (25
2 C). The method used for thiamine deprivation is the simple absorption of food lacking of B1 vitamin (U.A.R diet, no. 211 B1, France). We avoided the use of antithiaminics (pyrithiamine or oxythiamine) that could have some poisonous secondary effects (Troncoso, Johnson, Hess, Griffin, & Price, 1981). Consequently, experimental dams were fed a synthetic thiamine-deficient diet (U.A.R, no. 211 B1, France). Because the developing brain is especially vulnerable to thiamine lack (Greenwood et al., 1985), thiamine deficiency was induced during three main periods of CNS development: during fetal life (prenatal thiamine deficiency); from the end of fetal life to the 10th postnatal day (perinatal thiamine deficiency); from birth to the 25th postnatal day (postnatal thiamine deficiency), (Baˆ et al., 1999). At the start of the experiment, three or four dams were randomly assigned to one of the following experimental group. Induction of prenatal thiamine deficiency: A 10 day thiamine deprivation is efficient to provoke anoestrus in

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the female rat (Greenwood, Love, & Pratt, 1983), which exhibits a short gestation period (20–21 days). Thus, to obtain maximum deficiency days before parturition, dams were fed a thiamine-deficient diet beginning 3 days before introducing the male into female’s cage. Then, females were given thiamine-deficient diet from conception to parturition. At the day of parturition, females were returned to normal synthetic diet (U.A.R no. 210 B1), which also was given to pups after weaning until the 45th postnatal day. The average length of this thiamine deficiency induction period was about 26
2 days. Induction of perinatal thiamine deficiency: Females were fed thiamine-deficient diet 7 days after copulation, so that thiamine deprivation actually starts around the gestation Day 17. This diet was kept on during gestation and the first 10 days of lactation. On the 10th postnatal day, females were given normal diet and pups received this ‘‘normal’’ maternal diet after weaning until the 45th postnatal day. Again, this period of thiamine deficiency induction averaged about 26
1 day. Induction of postnatal thiamine deficiency: Females received thiamine-deficient diet from birth to the weaning corresponding to the 25th postnatal day. At the weaning, the pups received the normal diet until the age of 45 days. All during the experimental induction of thiamine deficiency and the subsequent dietary reversion, all the groups were allowed access ad libitum to their diets and water. Two groups provided control animals. In the first group, dams were fed a normal synthetic diet (U.A.R, no. 210 B1, France) ad libitum through gestation and lactation. After weaning, pups received the same treatment until 45 days of age. The second group consisted of pair-fed dams. Since thiamine deficiency induces anorexia, to control the effect of undernourishment generated by the different thiamine deficiencies, the equivalent of the quantity of food consumed daily by the animals of every treatment group pre-, peri-, and postnatal, was given to dams which constituted the pair-fed groups. Thus, every treatment group had its own pair-fed control. The food of the pairfed groups was composed of the same elements that the thiamine-deficient diet, but contained the thiamine (diet normal U.A.R no. 210 B1). The number of pups used in pair feeding experiments was presented as follows: prenatal (n ¼ 7), perinatal (n ¼ 7), postnatal (n ¼ 8). In the continuation of our studies the U.A.R no. 210 B1 denomination amounts to B 210. Note that this study does not completely control for litter effects. Neural development was assessed by a battery of behavioral tests (described previously in Baˆ & Seri, 1995) that examine the development of psychomotor and sensory functions of the offspring. The same pups were tested from the 10th to 45th postnatal day on:

0.00
0 0.30
0 0.62
0.27 0.82
0.29 3.62
0.51 3.87
0.49

2.75
0.39 5.87
1.17 16.62
1.46 12.37
1.86 5.62
0.80 1.87
0.37

0.28
0 0.86
0.31 1.85
0.49 3.14
0.52 3.14
0.52 3.43
0.45

0.0
0 0.3
0.15 1.1
0.18 2.6
0.34 4.5
0.37 4.4
0.49

0.00
0 0.28
0.25 1.86
0.28 2.80
0.44 3.10
0.47 3.50
0.49

4.25
0.76 3.51
0.68 24.00
2.1 17.54
0.71 12.27
0.98 3.80
0.61 ** ,*** 0.25
0.13 0.62
0.22 0.60
0.25 1.03
0.29 2.08
0.38 3.58
0.33 ** 8.57
0.93 5.71
1.11 10.57
1.47 13.00
1.69 9.00
0.96 4.71
0.81 4.4
0.71 6.0
0.73 9.2
0.96 18.8
1.94 12.4
1.29 4.2
0.71 6.00
0.85 5.28
1.15 12.00
1.35 11.86
1.76 6.00
0.8 1.28
0.56

0.09
0.09 0.27
0.14 3.18
0.37 2.70
0.23 2.60
0.36 3.00
0.38

3.5
1.03 4.0
0.55 10.0
1.03 11.8
1.47 5.2
0.55 2.1
0.59 ** 0.00
0 0.10
0.11 0.88
0.39 2.44
0.44 2.44
0.44 2.88
0.63 ** ,*** 5.17
0.67 4.72
0.88 10.81
1.01 14.63
1.49 10.81
0.99 6.00
0.69

10 15 20 25 30 45 Statistics 10 15 20 25 30 45 Statistics Emotional reaction

Functions

Exploratory activity

Postnatal Deficiency (n ¼ 12) Perinatal PF (n ¼ 7) Perinatal Deficiency (n ¼ 10) Prenatal PF (n ¼ 7) Prenatal Deficiency (n ¼ 9) Control B210 (n ¼ 11) Age (Days)

Effects of Maternal Thiamine Deficiencies on the Development of Psychomotor and Sensory Functions in the Rat Pups*

Measure of exploratory activity: Each animal was placed singly in the center of the board and the number of head-dip responses was recorded. Only one 5 min trial was performed at every age. Measure of emotional reaction: The new situation evoked by the experimental context of the hole-board generates anxiety in the animal (Boissier, Simon, & Lwoff, 1964). The number of emitted droppings was counted during a 5 min trial of exposure at every age. Hind paws lifting reflex: The animal was left gripped by its fore paws at the middle of the wire. The time spent by the animal to retrieve its balance by bringing its hind paws upon the wire, was measured. Measure of the wire grasping time: The rat is compelled to get the grip in the middle of the wire by its forepaws and the observer counts time until the fall of the animal. Crawling and leap execution latencies: The rat was compelled to get the grip on the middle of the wire. The time spent to reach one of the two vertical bars by crawling execution, or to leap on to the ground was timed. Nociception: Baseline pain responsiveness was assessed as described previously (Baˆ & Seri, 1993). Briefly, the tail-flick was evoked using a feedback-controlled projector lamp (24 V and 100 W, 55 C) focused on the dorsal surface of the tail, at the half-length. At the beginning of a trial, a latency timer and the radiant heat were activated simultaneously. The heat source and timer automatically stopped as soon as a flick of the tail out of the path of the emitted heat was obtained. The effects of thiamine deficiency and age are tested on the behavioral data using a two-way analysis of variance or ANOVA. Generally, four factors of treatment, and 4–6 factors of age are used in these studies for the ANOVA. The same multifactorial analysis is used for post-hoc means comparisons (Wayne, 1987). Table 1 shows the mean performance on each measure of behavioral development for each of the seven treatment groups at each age. We can note a specific (s) effect of thiamine deficiency, when the diet lacking thiamine results in a functional change, which differs significantly from both the effects of normal diet B 210 and of pair-fed regimen. When effect of thiamine deficiency significantly differs from the normal diet B 210, but not from its pairfed control, then we speak of non-specific effect (ns) of thiamine deficiency. This effect would be assigned to the undernourishment that comes with the thiamine deficiency. Thus, the behavioral performances in the thiamine deficiency-exposed pups were compared to those of the control pups fed with the normal regimen B 210. The resulting two-way ANOVA indicates the main treatment effect on all the studied functions, i.e., exploratory activity [F (3, 168) ¼ 21.51, p < .0001], emotional re-

Postnatal PF (n ¼ 8)

BAˆ

Table 1.

410

10 15 20 25 30 45 Statistics 10 15 20 25 Statistics 20 25 30 45 Statistics 20 25 30 45 Statistics 10 15 20 25 30 45 Statistics 4.71
0.26 3.15
0.11 2.62
0.11 2.43
0.09 2.43
0.1 2.43
0.11

15
1.22 7
1.08 7
0.97 3
0.49

17.6
1.77 11.8
1.14 9.2
1.63 7.8
1.16

42.2
5.2 80.3
8.91 231.0
24.95 482.0
45.69

2.02
0.18 1.22
0.14 0.45
0.15 0.41
0.07 0.67
0.12 0.76
0.19

2.7
0.29 2.9
0.35 0.45
0.05 0.43
0.08 0.56
0.25 0.71
0.13 ** ,*** 20.74
3 51.98
4.64 72.15
13.42 120.00
25.5 ** 22.4
1.39 14.6
1.22 11.7
1.05 11.2
1.42 ** 19
1.4 8
0.72 8
1.27 5
1.1 ** 6.00
0.22 5.00
0.29 2.31
0.07 2.33
0.15 2.12
0.11 2.25
0.11 ** 5.6
0.20 4.0
0.22 3.4
0.16 3.2
0.12 3.0
0.14 3.2
0.19

21.78
1.55 7.67
1.46 9.12
1.15 6.92
0.84

19.78
2.09 13.80
1.95 10.07
1.55 10.00
1.44

30.25
4.5 57.45
6.4 83.74
16.3 113.80
22.1

1.34
0.17 1.21
0.15 0.67
0.16 0.25
0.08 0.38
0.07 0.83
0.06

2.51
0.16 3.39
0.47 0.55
0.05 0.38
0.12 0.81
0.1 0.59
0.19 ** ,*** 23.67
5.73 61.86
13.77 89.16
20.31 137.87
25 ** 26.32
2.48 28.32
2.13 19.32
1.49 10.02
1.6 ** ,*** 21
1.85 16
2 12
1.79 12
1.42 ** ,*** 4.88
0.39 4.00
0.31 3.65
0.23 3.22
0.19 3.00
0.11 3.00
0.49 ** 3.8
0.41 3.9
0.36 3.4
0.33 3.3
0.16 3.2
0.21 2.8
0.23

13.92
2.31 9.60
2.17 8.27
1.63 6.01
1.33

18.25
1.32 13.67
1.26 12.57
0.98 11.10
1.48

53.42
5.5 42.62
43.37 66.54
9.77 127.50
19.33

1.65
0.25 1.04
0.16 0.35
0.07 0.51
0.19 0.27
0.09 0.38
0.16

35.82
3.57 36.75
3.69 28.32
2.13 22.41
1.55 ** ,*** 27
1.73 21
2.53 18
1.76 12
2.26 ** ,*** 5.45
0.14 4.48
0.18 4.53
0.22 5.00
0.16 4.67
0.23 3.00
0.09 ** ,***

25.16
3 55.94
8.17 219.26
44.2 472.25
152

1.61
0.26 0.91
0.21 0.28
0.06 0.25
0.01 0.37
0.1 0.56
0.12

4.7
0.19 4.0
0.17 3.5
0.18 3.1
0.21 2.9
0.19 2.8
0.12

24.67
1.88 18.85
1.47 10.58
1.36 4.95
1.77

21.27
1.52 16.25
1.42 15.91
1.44 11.70
1.83

44.70
5.8 38.42
6.02 178.62
38.4 469.25
57.6

1.88
0.21 1.28
0.17 0.65
0.15 0.31
0.08 0.48
0.1 0.56
0.09

*Values are given as means
SEM. Values in parentheses (n) represent the number of subjects in each experiment. Each pattern of thiamine deficiency was compared to both normal regimen (B 210) and its own pair-fed group (PF). **p < .01 versus control. ***p < .01 versus the correspondent pair-fed control.

Tail-flick latency (s)

Leap execution latency (s)

Crawling execution latency (s)

Wire grasping time (s)

Hind paws lifting latency (s)

Vulnerability of Developing Brain to the Thiamine Deficiencies 411

412

BAˆ

action [F (3, 168) ¼ 7.17, p < .0001], hind paws lifting reflex latencies [F (3, 168) ¼ 7.34, p < .0001], wiregrasping times [F (3, 115) ¼ 58.41, p < .0001], crawling [F (3, 112) ¼ 70.17, p < .0001], and leap [F (3, 112) ¼ 46.31, p < .0001] execution latencies and tail-flick latencies [F (3, 168) ¼ 30.52, p < .0001 (Table 1); a significant variation of these activities over days: exploratory activity [F (5, 168) ¼ 55.51, p < .0001], emotional reaction F [(5, 168) ¼ 69.43, p < .0001], hind paws lifting reflex latencies [F (5, 168) ¼ 19.01, p < .0001], wiregrasping times [F (3, 115) ¼ 143.16, p < .0001], crawling [F (3, 112) ¼ 35.66, p < .0001], and leap [F (3, 112) ¼ 45.75, p < .0001] execution latencies and tail-flick latencies [F (5, 168) ¼ 66.11, p < .0001], (Table 1). The same multifactorial analysis of variance shows a reliable age  treatments interaction on exploratory activity [F (15, 168) ¼ 9.36, p < .001], emotional reaction [F (15, 168) ¼ 2.64, p ¼ .0002], hind paws lifting reflex latencies [F (15, 168) ¼ 6.75, p < .0001], wire-grasping times [F (9, 115) ¼ 21.32, p < .0001], crawling execution [(9, 112) ¼ 2.71, p ¼ .007], and tail-flick latencies [F (15, 168) ¼ 8.07, p < .001]; however, analysis of leap execution latencies indicates no significant interaction between age and treatments [F (9, 112) ¼ 1.02, p ¼ .43]. Post-hoc means comparisons between groups of thiamine deficiencies and the normal regimen B 210 showed exploratory activity and emotional reaction to be altered by prenatal [F (1, 108) ¼ 20.77, p < .0001; F (1, 108) ¼ 7.01, p ¼ .0093, respectively] and postnatal thiamine deficiencies [F (1, 126) ¼ 12.329, p ¼ .0006; F (1, 126) ¼ 11.06, p ¼ .0012, respectively], whereas perinatal thiamine deficiency had no effect on both functions [F (1, 114) ¼ 0.57, p ¼ .45; F (1, 114) ¼ .92, p ¼ .34, respectively], (Table 1). On the other hand, hind paws lifting reflex latencies and wire grasping times were significantly affected by prenatal [F (1, 108) ¼ 33.75, p < .0001; [F (1, 72) ¼ 129.38, p < .0001, respectively] and perinatal thiamine deficiencies [F (1, 114) ¼ 19.89, p < .0001; F (1, 75) ¼ 106.1, p < .0001, respectively], while postnatal thiamine deficiency had no effect on both functions [F (1, 126) ¼ .32, p < .57; F (1, 84) ¼ .65, p ¼ .42, respectively]. Generally, the latencies of leap and crawling execution and of tail-flick were delayed by the three patterns of thiamine deficiencies: prenatal thiamine deficiency [F (1, 56) ¼ 5.58, p ¼ .02; F (1, 56) ¼ 8.62, p ¼ .005; F (1, 108) ¼ 17.12, p < .0001, respectively], perinatal thiamine deficiency [F (1, 56) ¼ 29.06, p < .0001; F (1, 56) ¼ 55.99, p < .0001; F (1, 114) ¼ 36.45, p < .0001, respectively], postnatal thiamine deficiency [F (1, 56) ¼ 96.21, p < .0001; F (1, 56) ¼ 104.53, p < .0001; F (1, 126) ¼ 281.53, p < .0001, respectively], (Table 1). The pair-fed animals were used to control the specificity of each pattern of thiamine deficiency. Thus,

post-hoc means comparisons between groups of thiamine deficiencies and their own pair-fed controls showed that the prenatal thiamine deficiency altered with non-specific effects exploratory activity [F (1, 84) ¼ .651, p ¼ .422], wire-grasping times [F (1, 56) ¼ .51, p ¼ .48], crawling [F (1, 52) ¼ 2.4  105, p ¼ .99], and leap execution latencies [F (1, 52) ¼ 1.93, p ¼ .17], and tail-flick latencies [F (1, 90) ¼ 3.12, p ¼ .08]; however, it exerts specific effects on emotional reaction [F (1, 84) ¼ 6.91, p ¼ .01], hind paws lifting reflex latencies [F (1, 84) ¼ 42.79, p < .0001], (Table 1). The effects of perinatal thiamine deficiency on wire-grasping times [F (1, 59) ¼ .44, p ¼ .51] and tail-flick latencies [F (1, 90) ¼ 3.12, p ¼ .08] were not specific, whereas those exerted on hind paws lifting reflex latencies [F (1, 90) ¼ 19.57, p < .0001], crawling [F (1, 52) ¼ 33.38, p < .0001], and leap execution latencies [F (1, 52) ¼ 6.53, p ¼ .013] were specific. Most of the effects of postnatal thiamine deficiency on the development of these functions were specific, i.e., the effects on exploratory activity [F (1, 108) ¼ 19.48, p < .0001], crawling [F (1, 56) ¼ 101.87, p < .0001], and leap execution latencies [F (1, 52) ¼ 12.77, p ¼ .0008], tail-flick latencies [F (1, 108) ¼ 16.79, p < .0001], and only few effects, i.e., effects on emotional reaction were not specific [F (1, 108) ¼ 1.09, p ¼ .3], (Table 1). The specificity related to each pattern of thiamine deficiency on the development of the functions was resumed in Table 2. It appears that prenatal thiamine deficiency alters the development of 100% of the studied functions, including 71% for non-specific (ns) effects and 29% for specific (s) effects. The perinatal deficiency affects the development of the same functions up to 71% including 28% for non-specific (ns) effects and 43% for specific (s) effects. The postnatal deficiency alters also the development of these functions up to 71%, but 57% for Table 2. Vulnerability of Developing Brain to the Specific (s) and Non-Specific (ns) Effects of Maternal Thiamine Deficiencies Thiamine Deficiency Functions Exploratory activity Emotional reaction Hind paws lifting reflex Wire-grasping time Crawling execution Leap execution Nociception Percentage of altered functions By non-specific effects By specific effects Total percentage

Prenatal

Perinatal

Postnatal

ns s s ns ns ns ns

o o s ns s s ns

s ns o o s s s

71.42 28.57 100

28.57 42.85 71.43

14.3 57.14 71.44

Vulnerability of Developing Brain to the Thiamine Deficiencies

specific effects against only 14% for non-specific effects. Consequently, the vulnerability of developing brain to the specific lack of B1 vitamin increases from prenatal (28%) to perinatal (43%) and postnatal periods (57%). The three types of thiamine deficiencies overlap the stages well differentiated of the CNS development. The prenatal thiamine deficiency would interfere with the stages of cellular proliferation and migration (Angevine & Sidman, 1961; Bisconte & Marty, 1975); the perinatal thiamine deficiency would cover the period of cellular differentiation (Hattori & McGeer, 1973; Miller, 1986); the postnatal thiamine deficiency would interfere with the stages of synapses formation, axonal growth, myelinogenesis, and the start of physiological function (Aghajanian & Bloom, 1967; Hattori & McGeer, 1973). Cellular proliferation and migration would be affected by the non-specific effects predominantly mediated by prenatal thiamine deficiency. Cellular differentiation would be altered by the specific effects largely mediated by perinatal thiamine deficiency. Synapses formation, axonal growth, myelinogenesis, and the start of physiological function could be altered by the specific effects predominantly mediated by postnatal thiamine deficiency. The predominant non-specific effect of thiamine deficiency on cellular proliferation and migration could be attributable to the metabolic role of the thiamine. Indeed, the thiamine acts on catabolism to synthesize ATP for the maintenance of cellular energy metabolism; it intervenes also in anabolism for proteins and nucleotides syntheses (Haas, 1988). The lack of thiamine to accomplish its vital metabolic role during cellular proliferation and migration should result in massive cellular death. These non-specific effects of thiamine deficiency would not be separable to the effects of malnutrition that comes with theses deficiencies, because pair-feeding experimentation produces some similar effects. These results agree with the studies of Hammer (1981) reporting that the simple prenatal undernourishment reduced the rate of DNA of 24% in the cerebral trunk, whereas the postnatal undernourishment does not have any effect. The specific effects of thiamine deficiency on nervous tissues seem to be its action on biological membranes, i.e., cellular differentiation, synapses formation, axonal growth, and myelinogenesis. Some previous studies reported that thiamine would be an active component of axoplasmic, mitochondrial (Itokawa et al., 1972; Tanaka & Cooper, 1968), and synaptosomal membranes (Matsuda & Cooper, 1981). It undergoes axonal transportation, as very anterograde that retrograde (Bergquist & Hanson, 1983; McLane, Khan, & Held, 1987; Tanaka, Itokawa, & Tanaka, 1973), and intervenes in the synaptic transmission (Csillik, 1975; Siegel, Agranoff, Albers, & Molinoff, 1989). The action potential of the nervous fiber is blocked by the pyrithiamin, an

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antagonist of the thiamine (Goldberg & Cooper, 1975; Von Muralt, 1962). Besides, induction of thiamine deficiency in the rat would reduce significantly the nervous conduction speed (Claus, Eggers, Warecka, & Neundo¨rfer, 1985; Kunze & Muskat, 1969), as well as the diameter of myelinic fibers (Claus et al., 1985) and would alter specifically myelinogenesis (Reddy & Ramakrishnan, 1982; Trostler et al., 1977). Consequently, the stages of the cerebral development vulnerable to the specific lack of B1 vitamin in the food seem to be cellular differentiation during perinatal life, and particularly axonal growth, synapses formation, and myelinogenesis during the postnatal development.

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