Th e eff ects of hypoglycemic and alcoholic coma on the blood-brain barrier permeability
Hatice Yorulmaz1*, Fatma Burcu Seker2, Baria Oztas3
1 Department of Physiotherapy and Rehabilitation, Halic University, Health Sciences, Kaptanpasa mah. Daruleceze cad. No 14, Okmeydanı, 34384, Istanbul, Turkey. 2 Department of Physiology, Yeditepe University, Faculty of Medicine, Inonu Mahallesi, Kayisdagi Caddesi, 26 Agustos Yerlesimi, 37455, Atasehir, Istanbul, Turkey. 3 Department of Physiology, Istanbul University, Istanbul Faculty of Medicine, Capa, Fatih, 34093, Istanbul, Turkey
Abstract
In this investigation, the eff ects of hypoglycemic coma and alcoholic coma on the blood-brain barrier (BBB) permeability have been compared. Female adult Wistar albino rats weighing - g were divided into three groups: Control group (n=), Alcoholic Coma Group (n=), and Hypoglycemic Coma group (n=). Th e animals went into coma approximately - hours after insulin administration and - minutes after alcohol administration. Evans blue (mL/kg) was injected intravenously as BBB tracer. It was observed that the alcoholic coma did not signifi cantly increase the BBB permeability in any of the brain regions when compared to control group. Changes in BBB permeability were signifi cantly increased by the hypoglycemic coma in comparison to the control group values (p<.). Our fi ndings suggest that hypoglycemic and alcoholic coma have diff erent eff ects on the BBB permeability depending on the energy metabolism. © Association of Basic Medical Sciences of FBIH. All rights reserved
KEY WORDS: blood-brain barrier, hypoglycemic coma, alcoholic coma.
INTRODUCTION tive eff ects on many structures and their functions including the cerebral capillary endothelial cells of the central nervous Brain tissue is protected by blood-brain barrier (BBB). It system [-]. While some studies have shown that acute is a specialized structure consisting of endothelial cells administrations of alcohol increased the BBB permeability, and tight junctions between them, a continuous basal others have suggested that it had no eff ect [-]. Th ere are lamina which surrounds these cells. The tight junctions gender related diff erences in the central nervous system, and are reinforced by the foot processes of the astrocytes []. acute and chronic administration of alcohol appears to aff ect Th ere are several reports investigating the eff ects of convul- the female brain much more than that of male [,]. Th e sions, acute hypertension, brain tumors, ischemia on the BBB reported brain morphological abnormalities could also occur permeability [-], however, only a few studies have exam- more precociously in alcoholic women than in men []. Es- ined eff ects of the state of coma [, ]. Hypoglycemic coma pecially social and environmental, physiological, genetic and leads to energy defi ciency due to a reduction in plasma glu- neurobiological ones have been demonstrated to contribute cose concentrations, ATP and other nucleoside triphosphates to the sex diff erence in response to alcohol intake, as well as []. Th e energy defi ciency with concomitant disruption of the development of alcoholic complications. A number of the ion homeostasis may cause dysfunctionality of both the neurotransmitters and growth factors may be partially in- neurons and the cerebral endothelial cells composing the volved in these diff erences between men and women []. BBB [-]. Increased BBB permeability causes vasogenic In the present study, we have comparatively inves- edema under pathological conditions. However, the changes tigated the effects of hypoglycemic coma and alco- in the BBB permeability during hypoglycemic coma have not holic coma on BBB permeability in the female rats. precisely been understood. It has been suggested that both acute and chronic administrations of alcohol have disrup- MATERIALS AND METHODS
* Corresponding author: Hatice Yorulmaz, Department of Animals and Procedure Physiotherapy and Rehabilitation, Halic University, Health Sciences, Istanbul, Turkey; Kaptanpasa mah. Daruleceze Th e procedures were in accordance with the Helsinki Dec- cad. No 14, Okmeydanı, Istanbul, 34384, Turkey; Telephone number: +90 212 2209696; Fax number: +90 212 526 49 17 laration . Th e female adult Wistar albino rats weighing e-mail: [email protected] - g were used in the experiments. The rats were di- Submitted 21 December 2010/ Accepted 27 January 2011 vided into three groups: . Control (n=), . Alcoholic Coma
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TABLE 1. Values of arterial blood pressure, blood glucose levels and Evans (n=) and . Hypoglycemic Coma (n=) blue albumin extravasation, before and after coma. group. A cannulation was performed to the Rapoport criteria Mean Arterial animals under diethyl-ether anesthesia. Follow- Degree of BBB breakdown Pressure Experimental Blood Glucose n ing the injection of anesthesia through femoral Groups Levels (mg/dl) Before After vein, the femoral artery was catheterized to 0 +1+2+3 Coma Coma measure systemic arterial blood pressure. BBB Control permeability was determined using tracer Evans 89±3 - 8 - - - (n=8) blue (EB) (Sigma Cat no: E-) tracer ( mL/ kg, i.v.) []. Alcoholic coma was induced by in- Hypoglycemic Coma 89,5±3 85±7 21±2,5 3 2 3 4 jecting g/kg of ethyl alcohol intraperitoneally. (n=12) Th e rats went into coma - minutes after the Alcoholic alcohol administration []. Th e animals were Coma 88±5 87±10 131±43 14 4 - - (n=18) fasted for hours before the experiments but were allowed free access to water. To induce the hypoglycemic coma, IU/kg crystallin zinc insulin (Eli Lily Co, --) was administrated in- RESULTS traperitoneally under diethyl-ether anesthesia []. Th e rats went into coma approximately - hours later following insu- Th e values of blood pressure, blood glucose and the changes lin administration. Th e glucose oxidase method (Accu-Check in BBB permeability with respect to Rapoport criteria [] Advantage, Roche Diagnostics GmbH, Mannheim, Ger- are shown in Table . The baseline mean value of arterial many) was applied to blood samples drawn from the tails to blood pressure was .± mmHg for hypoglycemic coma determine the plasma glucose levels []. Th eir brains were group and was ±. mmHg for the alcoholic coma group. washed by . NaCl perfusion through the left ventricle No significant change was seen in arterial blood pressure minutes after the Evans Blue injection. Amount of Evans values of the rats after they went into hypoglycemic coma blue penetrating the tissue was evaluated macroscopically and alcoholic coma (± mmHg, ± mmHg). Plasma with respect to the Rapoport Criteria []. Staining of each glucose levels of the rats in alcoholic coma were found to hemisphere and of coronal sections by Evans blue was grad- be within the normal range (± mg/dl), whereas those ed as follows: Grade , no staining; Grade +, slight staining; of rats in hypoglycemic coma were ± . mg/dl (Table ). Grade +, moderate; and Grade +, marked and dark staining. It has been observed that the alcoholic coma did not increase After decapitation, the brain was quickly removed and dis- the BBB permeability signifi cantly in any of the brain regions sected into regions; left cerebral cortex, right cerebral cor- (p>.) when the Evans Blue concentrations in the regions tex, brain stem and cerebellum. Th e wet weights of the dis- of left hemisphere, right hemisphere, cerebellum and the sected regions were determined. Th en, each of the brain area brain stem (.±., .±., .±., .±. μg/mg was homogenized in tubes containing mL of N NaOH tissue respectively) of Alcoholic Coma Group were com- and mL of phosphate buff er (. g/L NaHPOHO, . pared with those of Control Group (.±., .±., g/L NaOH. ml of NaOH and ml of NaHPOHO .±., .±. μg/mg tissue respectively) (Figure ). were mixed and pH calibrated ,). Following the homog- enization, they were centrifuged at rpm for min at +°C. After centrifuging, each supernatant was transferred into spectrophotometer tubes and the absorbance values at nm wave length were read. Th e Evans blue values were calculated as mg Evans blue per gram brain tissue by using the obtained absorbance values, the regression equations and regression curves of the Evans blue absorbance-amount []. Statistical analysis The statistical analysis was made with SPSS (Statistical Package for Social Sciences . ver.). EB-albumin ex- travasation was expressed as mean±SEM. Data were com- pared among groups using one way analysis of variance FIGURE 1. Displaying quantitative measurements of EB dye con- (ANOVA) and subsequently Tukey’s test was performed tent (% mg) in the brain regions of the groups. *p<0.01 control vs. where ANOVA showed statistical significance (p<.). hypoglycemic coma
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Contrarily, increased BBB permeability was observed in of cemia damaged the endothelial ultrastructure of cerebral experimental animals that went into hypoglycemic coma arteries. Hsu and Hedley-Whyte [] have reported that (Table ). severe hypoglycemia in mice caused deletion in cerebral Evans Blue concentrations in the regions of left hemi- vessel walls. It has also been observed in our study that, the sphere, right hemisphere, cerebellum and the brain stem hypoglycemia coma signifi cantly increased the BBB perme- (.±., .±., .±., .±. μg/mg tissue re- ability in the left cortex, right cortex, cerebellum and brain spectively) of Hypoglycemic Coma Group were com- stem regions of the brain. In addition, lack of any signifi cant pared with those of Control Group (Figure ). It was de- change in arterial blood pressure in rats during the hypogly- termined that hypoglycemic coma increased the BBB cemic coma suggests that the blood pressure has no eff ect permeability signifi cantly in all of the brain regions (p<.). on the increased BBB permeability in case of hypoglycemia. It has been found that the glucose extraction in the cerebel- DISCUSSION lum is twice more than that of other parts of the brain [] so that the cerebellum conserves the cellular energy bet- Glucose is the main substrate the brain uses to generate ter than the cerebral cortex in case of hypoglycemic coma energy, which penetrates into the brain by facilitated diff u- [, ]. Th us, less BBB damage in the cerebellum has been sion through BBB []. Hypoglycemia due to the reduced reported in comparison to the other parts of the brain [, plasma glucose levels below normal range leads to brain ]. Similarly, we found less Evans blue-albumin extravasa- dysfunctionalities []. Hypoglycemia is a relatively com- tion in the cerebellum when compared to the cerebral cortex. mon condition primarily aff ecting diabetic patients treated Alcohol is a soluble substance in both water and oil and can with insulin or other hypoglycemic drugs and insulinoma easily penetrate the lipid membranes of all the cells in the patients. Hypoglycemic eff ects on the CNS include various body. Thus, alcohol can penetrate the BBB easily []. Al- symptoms such as irritability and lack of concentration, dis- cohol could affect the blood flow of the brain, brain glu- ruption of cognitive functions, convulsions and unconscious- cose metabolism, synthesis and catabolism of various neu- ness. Even a single hypoglycemic episode with convulsions rotransmitters [-], and also aff ects many structures and and/or coma may, if prolonged and severe enough, cause functions including the capillary endothelial cells in central permanent degenerative alterations in the cerebral cortex nervous system []. In alcoholics, also many physiologi- []. Th ese symptoms of hypoglycemia suggest the presence cal dysfunctions occur beside the structural changes in the of increased intracranial pressure and cerebral edema []. brain []. However, the eff ects of acute alcohol administra- In a hypoglycemic coma, neurons and especially cerebral tion on BBB permeability are controversial, there are stud- endothelial cells composing the BBB may face energy fail- ies suggesting that alcohol has no eff ect on BBB permeabil- ure []. Endothelial cells of brain capillaries diff er than the ity beside the studies indicating that alcohol has increased others with their relatively higher metabolism []. Th e ce- the BBB permeability against the various tracers [-]. rebral capillary endothelial cells have mitochondria in large Rossner et al. [], have demonstrated that ethanol quantities [] and contain comparatively -fold more (- g/kg i.v.) increased Evans blue permeability of BBB in Na+-K+-ATPase enzymes than the umbilical endothelial a short term. Similarly, Eriksson et al. [] have adminis- cells []. Hypoglycemia causes the dysfunctionality of active tered ethanol ( g/kg i.p.) and have observed increased Na+-K+-ATPases in cerebral endothelial cell membranes due BBB permeability in rats. However, Hillbom and Tervo to the energy defi ciency. Due to this dysfunctionality, potas- [] have observed no increase in BBB permeability after sium ions exit and ions like sodium and calcium penetrate administration of ethanol ( g/kg i.p.) in rats. Eff ects of into the cerebral endothelial cells and the cytotoxic edema ethanol on BBB permeability have also been studied by us- occurring as a result of these changes. Thus, it may cause ing C-sucrose tracer in rats []. They have found that swelling of the endothelial cells and the tight connections BBB permeability did not increase when they have adminis- between them may detach. Th e vasogenic edema, occurring tered acutely ethanol as g/kg i.p. Gulati et al. [], us- as a result of the elevated amount of albumin due to the in- ing sodium fl uorescent as tracer, have injected ethyl alcohol creased permeability, may be responsible for dysfunctional- of , , and as , mg/kg i.v. and consequently ity of neurons in case of hypoglycemia []. Finally, it can not found that the BBB permeability has increased signifi cantly. be excluded that hypoglycemia has detrimental eff ects on They suggested a correlation between alcohol concentra- mitochondria at the level of the axon, aff ecting energy pro- tion and BBB permeability, and the ethyl alcohol of has duction in the axon itself, in the associated Schwann cells, increased the permeability more than the concentrations of in the local blood vessels and/or in the perineurial sheath and . However, no change in BBB permeability in rats []. Sekimoto et al. [] have demonstrated that hypogly- has also been reported following administration of etha-
BOSNIAN JOURNAL OF BASIC MEDICAL SCIENCES 2011; 11 (2): 110-112 HATICE YORULMAZ ET AL.: THE EFFECTS OF HYPOGLYCEMIC AND ALCOHOLIC COMA ON THE BLOODBRAIN BARRIER PERMEABILITY
nol as g/kg i.p. []. In the present study, ethanol admin- ACKNOWLEDGEMENT istered at the coma dose ( g/kg) slightly increased the BBB permeability in only four animals. Th is discrepancy may be Th e authors would like to thank to Professor Bayram Yilmaz attributed to the sex of the animals, concentration and ad- of Yeditepe University, Medical School, Department of Phys- ministration pattern of alcohol and the diff erence between iology in Istanbul for reading and improving the language of the tracers used for the investigation of BBB permeability. the manuscript. The effect mechanism of alcohol on BBB permeability could have been clarified. In contrast to our findings, Ha- REFERENCES orah et al. [] have shown that the alcohol caused de- [] Chaudhuri JD. Blood brain barrier and infection. Med Sci Monit formation of integrity of BBB by causing the increase in ; (): -. reactive oxygen types, activation of myosin light chain ki- [] Bolwig TG, Hertz MM, Westergaard E. 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