effect of selenium on lipids, lipid peroxidation, and sulfhydryl group in neuroendocrine centers of...

Effect of Selenium on Lipids, Lipid Peroxidation,

and Sulfhydryl Group in Neuroendocrine Centers of Rats

FAKHRUL ISLAM,* SUHAILA ZIA, IQBAL SAYEED, PARVINDER KAUR, and ABDULLAH SHAFIQUE AHMAD

Department of Medical Elementology and Toxicology,Neurotoxicology Laboratory, Jamia Hamdard (HamdardUniversity), Hamdard Nagar, New Delhi 110062, India

Received January 7, 2003; Revised April 3, 2003; Accepted May 1, 2003

ABSTRACT

The effects of various doses of sodium selenite (0.05, 0.1, and 0.2mg/kg body weight, ip) were studied on the content of phospholipids,cholesterol, esterified fatty acids (EFA), gangliosides, thiobarbituric acidreactive substance (TBARS), and sulfhydryl group in neuroendocrine cen-ters of male Wistar rats for 7 d. The lowest dose of Se (0.05 mg/kg) did notalter the above parameters significantly in neuroendocrine centers. Thecontent of phospholipids was depleted significantly in the pituitary anddepletion in the pineal was 80.22% with a 0.1-mg/kg dose of Se, but thisdose elevated its level significantly in the hypothalamus. Conversely, a 0.2-mg/kg dose of selenium elevated the level of phospholipids significantlyin the pituitary and hypothalamus, the elevation in the pineal was 70%.Selenium, 0.1 mg/kg, elevated the level of cholesterol in the pituitary butdepleted its level in the pineal (56.8%) and hypothalamus (13.60%). Sele-nium, 0.2 mg/kg, elevated the level of cholesterol significantly in the hypo-thalamus but its level was not significant in the pituitary and pineal. Thedepletion of esterified fatty acid in the pituitary and pineal with doses of0.1 and 0.2 mg/kg was significant in the pituitary, whereas its depletion inthe pineal was 85.4% and 69.26%, respectively. Selenium, 0.1 and 0.2mg/kg, depleted the level of gangliosides significantly and dose depend-ently in the pituitary but has elevated its level significantly and dosedependently in the hypothalamus. Its depletion in the pineal was 87.1%and 67.8% with the 0.1- and 0.2-mg/kg dose of selenium, respectively. Sele-

Biological Trace Element Research 71 Vol. 97, 2004

© Copyright 2004 by Humana Press Inc.All rights of any nature, whatsoever, reserved.0163-4984/04/9701–0071 $25.00

*Author to whom all correspondence and reprint requests should be addressed.

nium, 0.1 mg/kg, increased the content of TBARS significantly in neu-roendocrine centers and its elevation in the pineal was 703.8%. Selenium,0.2 mg/kg, elevated its level in the pituitary and it was 126.9% in thepineal, but this dose depleted its level significantly in the hypothalamus.The content of the sulfhydryl group with a 0.1-mg/kg dose of selenite wasdepleted significantly in neuroendocrine centers and it was 55.9% in thepineal. Selenium, 0.2 mg/kg, depleted the level of the sulfhydryl groupmore significantly in the pituitary and pineal, but its elevation in hypo-thalamus was significant.

Index Entries: Selenium; brain lipids; thiobarbituric acid reactivesubstance; sulfhydryl group; neuroendocrine centers.

INTRODUCTION

Lipids have been recognized as an essential constituent of all cells andare involved in numerous important biological processes. They are majorcomponents of all membranes, essential components of several crucialenzyme systems include a potent class of hormones, and have been impli-cated in the cellular transport of some compounds. Agranoff (1) has shownthat a number of trace lipids are known to be a cellular messenger in thebrain as in other tissues. Tayarani et al. (2) have reported that the brain tis-sue is known for its high content of polyunsaturated fatty acid, and aerobicmetabolism is a most vulnerable target for oxidative attack. Mammaliancell membranes consist of a lipid bilayer composed primarily of phospho-lipids and cholesterol.

Selenium is known to be a toxic substance if given in excess. Amongthe symptoms of intoxication, endocrine dysfunction, including growthreduction (3,4), and intrauterine absorption of fetuses and ovarian dys-function (5) have been reported. Moreover, selenium has been known toaccumulate in different parts of the endocrine system, such as the pituitary(6,7) and the pancreas (6). In the adrenal, selenium has been found to beaccumulated after exposure to sodium selenite as well as organoseleniumcompounds such as selenomethionine and cysteine (8,9). Selenium reactswith the thiol group in a 4 : 1 molar ratio to form selenotrisulfide, which isvery toxic and inhibits some enzymes (10). Selenium administered orallyto female Sprague–Dawley rats for 10 wk at 0.5–2.00 ppm significantlyenhanced natural killer activity. Delayed-type hypersensitivity responsewas suppressed at all doses. Further studies indicated that the effect of Seon blood glucose may be mediated through the adrenal and/or pituitary.The involvement of the pituitary in triggering the hyperglycemia as aresult of Se is established from the studies of the role of Se in developingembryology (7,11).

In rats, the brain has a higher metabolic priority for selenium than anyother tissue (12–16). There is now considerable evidence that the pineal isinvolved in the control of the secretory function of the hypothalamo-

72 Islam et al.

Biological Trace Element Research Vol. 97, 2004

neurohypophysial complex, and selenium at a very low concentration hasbeen reported to inhibit the glucocorticoid hormone receptors binding(17), and has initiated our interest to study the role of selenium in neu-roendocrine centers of rats.

MATERIALS AND METHODS

Chemicals

Sodium selenite, 1-amino-2-naphthol-4-sulfonic acid (ANSA), andthiobarbituric acid (TBA) were purchased from Sigma–Aldrich ForeignHolding Chemical Co., India. Other chemicals were of analytical grade.

Animals

Male Wistar rats, 180–200 g, of Jamia Hamdard Central AnimalHouse were used in this study. Animals were housed in an air-condi-tioned room and had free access to a commercial pellet diet (HindustanLever Ltd., Bombay, India) and water ad libitum. The animals weredivided into 4 groups, each having 16 animals. Group I received salineand served as the control. Groups II–IV received an ip injection of sele-nium selenite, 0.05, 0.1, and 0.2 mg/kg/d, for 7 d, respectively. For thelipids profile, eight animals from each group were used; the rest of theanimals were used for the estimation of TBARS and the –SH group. Ond 8, overnight fasted animals were killed by cervical dislocation andbrains were taken out immediately and neuroendocrine centers (i.e.,hypothalamus, pituitaries, and pineals) were dissected out. The pineal ofeight animals in each group were pooled and expressed as a single read-ing of each group. Each part was processed for the extraction of lipidsaccording to the method of Folch et al. (18) as modified by us (19) forsmall brain tissues. Phosphorus was estimated as described by Marinetti(20); EFA was estimated according to the method of Stern and Shapiro(21); gangliosides were estimated according to our own method (22);cholesterol was estimated by the method of Henly (23). TBARS wasdetermined according to the method of Utley (24) as modified by us forsmall brain tissue (25). The method of Ellman (26) was used for the esti-mation of the sulfhydryl group as modified by Sedlak and Lindsay (27).Protein was estimated by the method of Lowry (28).

Statistical Analysis

The statistical analysis of data was done using the Student’s t-test. Thesignificance of results was ascertained at p < 0.05. All of the data are pre-sented as means ± standard error (SE) of the means.

Se and Lipid Peroxidation in Rat Brain 73


RESULTS

Table 1 shows the effect of various doses of sodium selenite on thelevel of phospholipids in neuroendocrine centers of the rat. The pituitaryhas shown a significant inhibition of phospholipids with doses of 0.1 and0.2 mg/kg sodium selenite, but the elevation of the phospholipid levelwith 0.05 mg/kg sodium selenite was not significant. An inhibition of80.2% in phospholipids was noted in the pineal gland with 0.1 mg/kgsodium selenite; however, the inhibition of phospholipids was 8.0% and70.0% with 0.05 and 0.2 mg/kg sodium selenite, respectively. The effect ofvarious doses of sodium selenite on the level of phospholipids in hypo-thalamus was dose dependent. The significant elevation was observedwith 0.1 and 0.2 mg/kg of sodium selenite.

Table 2 shows the alteration of various doses of sodium selenite on thecontent of cholesterol in neuroendocrine centers of rats. Sodium selenitedoses (0.05 and 0.1 mg/kg) elevated the level of cholesterol in pituitary andit was significant with the 0.1-mg/kg dose, but its level in the pituitary withthe 0.2-mg/kg dose of sodium selenite was nonsignificantly inhibited. In thepineal, the inhibition of the content of cholesterol was 56.8% and 17.7% withthe doses of 0.1 and 0.2 mg/kg of sodium selenite, respectively. On the otherhand, the 0.05-mg/kg dose of sodium selenite elevated the level of choles-terol. In the hypothalamus, the level of cholesterol was significantly elevatedwith the 0.2-mg/kg sodium selenite dose. The other doses of sodium selen-ite inhibited the cholesterol level in the hypothalamus nonsignificantly.

Table 3 shows the effect of various doses of sodium selenite on thelevel of EFA in the neuroendocrine centers of rats. The control group hasshown a very high content of EFA in the pineal gland, followed by thepituitary, but its content was lower in the hypothalamus. A significant

74 Islam et al.


Table 1Effects of Graded Doses of Sodium Selenite on the Level of Phospholipids

in Neuroendocrine Centers of the Rat

Note: Values are expressed as mg/g fresh tissue; mean ± S.E. of eight animals. Valuesin parentheses show the percent increase (+) or decrease (–) with respect to control.

* p < 0.01; **p<0.001 compared to control.

inhibition of EFA was observed with 0.1 and 0.2 mg/kg sodium selenite inthe pituitary. The inhibition by 0.05 mg/kg sodium selenite was not sig-nificant (29.07%). The inhibition of EFA in the pineal was not dose depend-ent and it was maximum with the 0.1-mg/kg dose of sodium selenite(85.4%). A nonsignificant alteration with various doses of sodium selenitewas observed in the hypothalamus.

Table 4 shows the effect of various doses of sodium selenite on thelevel of gangliosides in the neuroendocrine centers of rats. A dose-depend-ent inhibition on its level was observed in the pituitary. The depletion was



Table 2Effects of Graded Doses of Sodium Selenite on the Level of Cholesterol


Note: Values are expressed as mg/g fresh tissue; mean ± S.E. of eight animals. Valuesin parentheses show the percent increase (+) or decrease (–) with respect to control.

*p < 0.02; **p < 0.01 compared to control.

Table 3Effects of Graded Doses of Sodium Selenite on the Level

of Esterified Fatty Acid in Neuroendocrine Centers of the Rat

Note: Values are expressed as mg/g fresh tissue; mean ± S.E. of eight animals. Values inparentheses show the percent increase (+) or decrease (–) with respect to control.

*p < 0.001, compared to control.

significant with 0.1 and 0.2 mg/kg of sodium selenite. Also, an inhibitionof gangliosides was observed with various doses of sodium selenite in thepineal. The inhibition was maximum with 0.1 mg/kg sodium selenite(87.1%); however, 0.2 and 0.05 mg/kg sodium selenite showed 67.8% and17.8% inhibition, respectively. In the hypothalamus, 0.1 and 0.2 mg/kg ofsodium selenite elevated the level of gangliosides significantly, but it wasdepleted 13.3% with 0.05 mg/kg sodium selenite.

Figure 1 shows the effect of sodium selenite (0.05, 0.1, and 0.2 mg/kg)on TBARS in neuroendocrine centers. Sodium selenite, 0.1 mg/kg, elevatedthe level of TBARS drastically and it was maximum in the pineal (703.8%),followed by the pituitary (205.5%) and hypothalamus (33.3%). On the otherhand, the 0.05-mg/kg dose depleted the level of TBARS in the hypothala-mus (8.33%) and pineal (9.7%) but elevated its level in the pituitary (8.1%).The elevation with the high dose of sodium selenite (0.2 mg/kg) was sig-nificant in the pituitary and hypothalamus and it was 126.9% in the pineal.

Figure 2 shows the effect of sodium selenite (0.05, 0.1 and 0.2 mg/kg)on sulfhydryl group in the neuroendocrine centers of rats. Its level wasinhibited significantly with doses of 0.1 and 0.2 mg/kg sodium selenite inthe pituitary and pineal; however, the alteration by 0.05 mg/kg sodiumselenite in neuroendocrine centers was not significant. On the other hand,the 0.2-mg/kg dose of sodium selenite elevated the level of thiol group inthe hypothalamus.

DISCUSSION

Lipids are essential components of all the cellular structures in thebrain. Myelin sheath and neurophil of gray matter account for much of the

76 Islam et al.


Table 4Effects of Graded Doses of Sodium Selenite on the Level of Gangliosides


Note: Values are expressed as mg/g fresh tissue; mean ± S.E. of eight animals. Values inparentheses show the percent increase (+) or decrease (–) with respect to control.

*p < 0.02; **p < 0.01; ***p<0.001, compared to control.

total lipids content of brain tissue (29). It is well known that distinctregional differences occur in the lipid content of the mammalian brain. Theeffect of various doses of sodium selenite on the level of phospholipids,cholesterol, esterified fatty acids, gangliosides, TBARS, and sulfhydrylgroup was studied in neuroendocrine centers of rats. To date, no report onlipid levels in neuroendocrine centers is available. Therefore, the data inthe control group are the first report on the above-mentioned lipid param-eters in neuroendocrine centers and the effect of selenium thereon. Weobserved that the level of phospholipids, cholesterol, EFA, and ganglio-sides in control group was maximum in the pineal, followed by pituitaryand hypothalamus, and the level of TBARS in pituitary was 10 times lessthan its level in the hypothalamus. The low content of TBARS in the pitu-itary indicates the presence of hormone/hormones which is/are a potentantioxidant and protects the pituitary from oxidative stress.

Phospholipids and cholesterol may be considered as a backbone oflipids, functioning as structural elements and governing the rigidity andflexibility, the permeability to water and nonelectrolytes, and possibly



Fig. 1. Effect of sodium selenite (0.05, 0.1, and 0.2 mg/kg body weight, ip) onthe content of TBARS in the neuroendocrine centers of the rat. Values are mean ±SE of eight animals. *p<0.02; **p<0.01 as compared to the control animals.

mediation in the uphill transport of ions. Phospholipids occur in substan-tial amount in both white and gray matter. The percentage inhibition in thecontent of phospholipids was maximum in the pineal than other regions ofthe neuroendocrine centers. Because no report of Se on the phospholipidslevels in pineal is available at present, it can be postulated that melatoninmay bind with Se to form a selenomelatonin, as in the case of selenotrisul-fide (10), and alter the level of phospholipids in the pineal gland. The pitu-itary secretes a number of hormones. The alteration of hormones may alterthe level of phospholipids (19). No Se data on the level of phospholipids inthe pituitary is available. It may be supposed that Se directly or indirectlyhas altered the content of phospholipids either by stimulating/inhibitingthe level of pituitary hormones, by binding with the hormone/hormonesand making selenohormone, which may be responsible for the elevation ofthe phospholipids level, or by altering the receptor site of hormones as inthe case of glucocorticoid receptor, which has been reported to be inhibitedby selenium (17). This supports our finding that Se may have also alteredthe receptor-binding site of the neuroendocrine hormones, which maycause an alteration of the level of lipids in these areas.

78 Islam et al.


Fig. 2. Effect of sodium selenite (0.05, 0.1, and 0.2 mg/kg body weight, ip) onthe sulfhydryl groups in the neuroendocrine centers of rat. Values are mean ± SEof eight animals. *p<0.02; **p<0.01 as compared to the control animals.

Our data suggest that the effect of two doses (0.1 and 0.2 mg/kg) ofsodium selenite on the content of phospholipids was reciprocal in neuroen-docrine centers, except in the hypothalamus (see Table 1). The alteration ofphospholipids with the 0.1- and 0.2-mg/kg dose of Se in neuroendocrinecenters of the present study supports our recent finding of Se on phospho-lipids in circadian rhythm centers of rat (16). Most of the esterified fattyacids are polyunsaturated fatty acid and some are in the free form, but mostof them are part of phospholipids, monoglycerides, diglycerides, andtriglycerides. The phospholipids are synthesized from fatty acids. Thedepleted level of EFA in the pituitary and pineal may also be a cause of thedepletion of phospholipids in these regions with the 0.1-mg/kg dose of Se.

Gangliosides are glycosphingolipids, constituents of the cellularplasma membrane. They are believed to play an important role in theinteractions of cells with the extracellular microenvironment (30). Clinicaltrials using injection of gangliosides have recently been designed to boostrecovery after spinal cord injury (31). Gangliosides are also used as thera-peutic agents in patients in clinical trials (31–33). The high concentration ofgangliosides in the central nervous system has led to the widely held viewthat these molecules may play an important role in differentiation of neu-ronal cells (34). The data presented in Table 4 show that the level of gan-gliosides was inhibited significantly in the pituitary and pineal with 0.1-and 0.2-mg/kg doses of sodium selenite, but these doses have elevated thelevel significantly in the hypothalamus. The opposite findings of the gan-gliosides level in the pituitary, pineal, and hypothalamus indicate a signif-icant role of their hormones in the regions, because the melatonin has beenreported to have a circadian rhythm activity, whereas the pituitary andhypothalamus hormones have no such effect.

We have observed that the Se stimulated the formation of TBARS inneuroendocrine centers and it was more effective in the pineal where theelevated TBARS was 703.8% with the 0.1-mg/kg sodium selenite dose and205.5% in the pituitary. These findings indicate that Se directly or indi-rectly plays some role in altering either the level of melatonin or the recep-tor-binding site of melatonin or produces a more toxic substance thatenhances the level of TBARS in these centers. Acute ip administration of Se(1.3 and 3.8 mg/kg) significantly increased the plasma adrenocorticotropichormone, β-endorphin, and corticosterone levels. An increase in β-endor-phin levels in the hypothalamic area in animals kept in short day coincidewith the early increase in pineal melatonin content during the dark phase,support our finding that Se may enhance the level of these hormones,which, in turn, acts on TBARS and the –SH group.

ACKNOWLEDGMENT

One of the authors, Suhaila Zia, is very thankful to the HamdardNational Foundation, New Delhi, for providing financial assistance.



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