![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Department of Neurology, University of California, San Francisco and Department of Veterans Affairs Medical Center, San Francisco, California (S.W.S., J.P.B., C.M.A., R.A.S.); Departments of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Groton, Connecticut (J.L.T.); and Pharmacological Research 2, MedChem Research, Hepatic Biochemistry, Discovery Management, Novo Nordisk A/S, Maaloev, Denmark (K.F.)
Received for publication
October 14, 2006
Accepted
January 16, 2007.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
; Koizumi, 1974; Pfeiffer-Guglielmi et al., 2003). Utilization of astrocyte glycogen is accelerated both by neuronal activity (Swanson, 1992; Cruz and Dienel, 2002) and lack of energy substrate (Lewis et al., 1974; Choi et al., 2003). Studies using cell culture and optic nerve preparations demonstrate that elevated astrocyte glycogen can improve neuron survival and axon function during glucose deprivation (Swanson and Choi, 1993; Wender et al., 2000; Brown et al., 2005). In vitro studies have further suggested that lactate or pyruvate derived from astrocyte glycogen can be shuttled to neurons for oxidative metabolism (Dringen et al., 1993; Poitry-Yamate et al., 1995; Pellerin et al., 1998; Brown et al., 2005; Tekkok et al., 2005). Astrocyte glycogen may also serve to fuel energy-demanding functions of astrocytes themselves, such as glutamate uptake, that influence neuronal survival and function (Swanson, 1992; Dienel and Cruz, 2004).
Results of these in vitro studies have been difficult to verify in intact brain, largely because there has not been a useful way of manipulating brain glycogen content that does not affect other relevant aspects of brain metabolism. Astrocyte glycogen content is influenced by several neurotransmitters and neuropeptides, including vasoactive intestinal peptide, insulin, and noradrenalin (Nelson et al., 1968; Cambray-Deakin et al., 1988; Magistretti and Pellerin, 1997); however, these agents have many other actions on both neurons and glia, and most do not readily cross the blood-brain barrier. Brain glycogen can also be increased with barbiturates and other factors that decrease neuronal activity (Nelson et al., 1968; Phelps, 1972; Swanson, 1992), but this approach is similarly unsuitable for selectively targeting glycogen metabolism. Brain glycogen can also be modestly increased with hyperglycemia plus insulin (Nelson et al., 1968), but it is then difficult to distinguish between the effects of high circulating glucose concentrations and elevated brain glycogen.
In an effort to find a more selective way to increase brain glycogen stores, we used astrocyte cultures to screen several inhibitors of glycogen phosphorylase. One of these agents, CP-316,819, was found to cause astrocyte glycogen accumulation at physiological glucose concentrations but permit glycogen utilization when glucose levels fall. Using this compound in rats, we found that increased brain glycogen can sustain neuronal activity for long intervals during severe hypoglycemia.
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Glycogen Phosphorylase Inhibitors. CP-316,819 and 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) were prepared as described previously (Overkleeft et al., 1998; Yu et al., 2006). CP-316,819 was purified by chromatography on silica gel to greater than 98% purity, as assessed by HPLC analysis. MOR-14 was a kind gift from H. Fujiwara (Gifu University, Gifu, Japan). For cell culture studies, all compounds were prepared as 10x concentration stock solutions in water. For in vivo studies, CP-316,819 was dissolved 150 or 50 mg/ml in polyethylene glycol and then diluted 1:5 into physiological saline.
Primary Astrocyte Cultures. Confluent astrocyte cultures were prepared from forebrain cortices of Swiss-Webster mice as described previously (Swanson et al., 1989b) and used at 22 to 25 days in vitro. In brief, forebrain cortices were dissected from anesthetized 1-day-old pups, dissociated by incubation in papain/DNase, suspended in Eagle's minimal essential medium containing 10% fetal bovine serum (Hyclone, Ogden, UT) and 2 mM glutamine, and plated in 24-well tissue culture plates at approximately 5 x 104 cells/cm2. At confluence (12–14 days in vitro), the cells were incubated with 10 µM cytosine arabinoside for 48 h to prevent the proliferation of other cell types. This medium was replaced with minimal essential medium containing 5% fetal bovine serum and a total of 5 mM glucose. Medium was exchanged with fresh medium weekly and on the day before experiments.
Studies of Glycogen Content in Cultured Astrocytes. Incubations with the phosphorylase inhibitors were performed for 24 h in fresh cell culture medium. Drugs were added in 20-µl volumes of water into 400 µl of culture medium, with control wells receiving only the water vehicle. To assess glycogen utilization during substrate deficiency, cultures were placed in glucose-free medium (Earle's balanced salt solution) containing 0.01 µg/ml antimycin A for 60 min before cell harvest. Glycogen content was measured by the amyloglucosidase method (Swanson et al., 1989b). Duplicate wells from each 24-well plate were combined for each measurement, and three measurements from each astrocyte preparation were averaged for each data point (n).
Rat Brain Glycogen Determination. Male Sprague-Dawley rats (250–300 g) were obtained from Charles River (Wilmington, MA). Nonfasted rats were given i.p. injections of CP-316,819 at an initial dose of 150 mg/kg (5 ml/kg), with subsequent injections of 50 mg/kg (5 ml/kg) 12 and 16 h later. Controls received 5 ml/kg vehicle alone at the same dosing schedule. Two hours after the final injection, the rats were used for either brain glycogen determinations or hypoglycemia studies. For brain glycogen determinations, the rats were euthanized by high-energy (3 kW) focused microwave irradiation (Gerling Applied Engineering, Inc., Modesto, CA) (Swanson et al., 1990). Parietal cortex and hippocampus from both hemispheres was dissected free of underlying white matter and solubilized in 0.1 N NaOH/0.01% SDS for subsequent glycogen determinations by the amyloglucosidase method (Swanson et al., 1990). In some studies, the rats were decapitated 30 min before microwave injection to evaluate the ability of the increased brain glycogen to be utilized under ischemic, substrate-deficient conditions.
Hypoglycemia and Brain Histology. Nonfasted male Sprague-Dawley rats (250–300 g) were anesthetized with 1 to 3% isoflurane in a 75:25 mixture of nitrous oxide and oxygen (Air Liquide America, Houston, TX) and ventilated with a small animal respirator (Harvard Apparatus, South Natick, MA). A femoral artery line was placed for blood sampling and blood pressure monitoring. Hypoglycemia was induced with an i.p. injection of 30 U/kg insulin (1 ml/kg) (Suh et al., 2003). Blood glucose was measured with a YSI 2700 glucose analyzer (Yellow Springs, OH) at 30-min intervals, reduced to 15-min intervals as blood glucose approached 1 mM. Blood gases were measured at 1-h intervals using an I-STAT machine (I-STAT, Princeton, NJ), and ventilation was adjusted to keep PaCO2 between 35 and 45 mm Hg and PaO2 above 100 mm Hg. Blood pressure and electroencephalogram (EEG) were continuously monitored (BIOPAC Systems, Santa Barbara, CA). For EEG monitoring, two burr holes were made in the skull bilaterally over the parietal cortex, and two monopolar electrodes were placed beneath the dura. A reference needle was placed in the neck muscle. EEG isoelectricity was defined as EEG amplitude less than 25 µV for at least 30 s. A heating blanket/rectal probe servo-loop was used to maintain core temperature at 36.5 to 37.5°C.
For studies of neuron survival, hypoglycemia was terminated with glucose infusion beginning 2 h after blood glucose had fallen to 1 mM. Glucose infusion was initiated with an injection of 0.2 ml of 50% glucose via the femoral vein, followed by continuous infusion of 1:1 solution of 50% glucose and Krebs-Henseleit buffer (1.5 ml/h for 3 h) and supplemented by 1 ml of 25% glucose by i.p. injection 1 h after beginning the i.v. glucose infusions. Rats were returned to their home cages after recovery, and brains were harvested 7 days later. Coronal 20-µm sections were prepared with a cryostat, and the sections were stained with hematoxylin and eosin to quantify neuron death in the designated vulnerable brain regions. Five coronal sections were analyzed from each animal, spaced 80 µm apart and spanning the hippocampus. A blinded observer counted the total number of eosinophilic neurons in each structure of interest, in both hemispheres, under a 20x microscope objective. Data from each animal were expressed as the mean number of degenerating neurons per section in the structure of interest.
Statistical Analysis. Data were analyzed using ANOVA with the Student-Newman-Keuls test where multiple groups were compared. All data are expressed as means ± S.E.M.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Yu et al., 2006), MOR-14 (Arai et al., 1998), DAB (Fosgerau et al., 2000), and methionine sulfoximine (MSO) (Sellinger and Weiler, 1963), each produced a dose-dependent increase in astrocyte glycogen content when added for 24 h to standard culture medium containing 5 mM glucose (Fig. 1A). To determine whether the elevated glycogen stores could then be used in the presence of these drugs, glycogen content was also measured after subsequent 60-min incubation in glucose-free medium that contained 10 µg/ml antimycin A to prevent oxidative metabolism of amino acids present in culture medium. The glycogenolysis normally induced by these substrate-free conditions was inhibited by MOR-14 and DAB but not by CP-316,819 or MSO (Fig. 1B).
|
MSO was used as a positive control in the cell culture studies because it has been shown previously to increase astrocyte glycogen content through an indirect inhibition of glycogenolysis (Swanson et al., 1989b); however, MSO is suboptimal as an agent for evaluating the effect of increased brain glycogen in vivo because it also causes seizures and inhibits glutamine synthetase (Sellinger and Weiler, 1963). CP-316,819 is an indole carboximide inhibitor of glycogen phosphorylase. In hepatocytes, this inhibitory effect is lost at low glucose concentrations (Martin et al., 1998), thereby allowing glycogen utilization when glucose levels are low. As shown in Fig. 1B, the inhibitory effect of CP-316,819 in astrocytes also required the presence of glucose, indicating a similar mode of action on the brain-specific isozyme of glycogen phosphorylase. For these reasons, we chose to use CP-316,819 to manipulate brain glycogen in vivo.
Similar to the results obtained in culture, CP-316,819 administered to rats at a total of 250 mg/kg in three divided doses produced an 88 ± 3% increase in brain glycogen content (Fig. 2). To confirm that this glycogen store can be used in the presence of CP-316,819, complete brain ischemia was induced by decapitation 30 min before microwave brain fixation. The increased brain glycogen store induced by CP-316,819 pretreatment was almost entirely depleted within the 30-min ischemic interval (Fig. 2).
|
). If astrocyte glycogen stores can substitute for circulating glucose as an energy substrate, then elevated brain glycogen stores should prolong the interval to isoelectric EEG during severe hypoglycemia. In the rat hypoglycemia model employed for these studies, EEG isoelectricity reproducibly occurs after an interval of 80 to 100 min after the blood glucose levels fall to 1 mM (Suh et al., 2003). This time interval was more than doubled in the group treated with CP-316,819, indicating a prolonged duration of neuronal activity (Fig. 3A).
|
In a second group of animals, we examined the effect of increased brain glycogen on neuronal survival after hypoglycemia. Rats were pretreated with CP-316,819 or with saline vehicle. Hypoglycemia was induced with insulin and reversed with glucose 120 min after the blood glucose level had fallen to 1 mM. Most rats in the saline-treated group, but none in the CP-316,819-treated group, exhibited isoelectric EEG intervals periods during this 120-min interval. Blood glucose levels in the two treatment groups were not significantly different at any time point during the hypoglycemic period (Fig. 3B). Rats in the saline-treated group showed substantial neuron death in each of the four vulnerable brain regions examined, whereas the CP-316,819-treated group showed negligible injury (Fig. 4), consistent with earlier studies demonstrating a tight link between duration of EEG isoelectricity and extent of neuron death (Auer et al., 1984). CP-316,819 administered less than 2 h prior to hypoglycemia had no significant effect on brain glycogen content and likewise had no significant effect on time to EEG isoelectricity or neuronal survival (data not shown).
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
; Koizumi, 1974; Pfeiffer-Guglielmi et al., 2003). There is normally an ongoing utilization and resynthesis of brain glycogen (Watanabe and Passonneau, 1973), which is thought to provide a rapid coupling or buffering between local energy supply and demand during brain activity (Swanson, 1992; Shulman et al., 2001; Dienel and Cruz, 2004). Breakdown of glycogen is performed by glycogen phosphorylase in conjunction with glycogen debranching enzyme. Inhibitors that bind to the catalytic sites of these enzymes, such as the compounds DAB and MOR-14 used in the present study, cause glycogen accumulation and do not allow glycogen breakdown. A novel feature of CP-316,819 is that it acts at the indole inhibitor site of glycogen utilization in a manner that requires millimolar concentrations of glucose for optimal inhibitory activity (Martin et al., 1998). As a result, glycogen utilization is not inhibited during hypoglycemia. CP-316,819 and related compounds have been extensively evaluated as antihyperglycemic agents for type 2 diabetes because of their potential to limit hepatic production of glucose from glycogen without inducing hypoglycemia (Treadway et al., 2001). These studies have shown the drugs to be highly selective for glycogen phosphorylase.
In the present studies, rats treated with CP-316,819 showed an 88 ± 3% increase in brain glycogen and maintained neuronal activity for more than 90 min longer than untreated rats. The absolute increase in brain glycogen content was roughly 3 mM. This amount of glycogen would be expected to fuel brain metabolism for less than 15 min if it were the only energy supply available in the brain (Sokoloff et al., 1977). However, the flux of glucose from blood to brain is reduced, but not zero, during hypoglycemia, such that glycogen is not the sole energy source. There is, in addition, a compensatory reduction in the rate of glucose utilization and synaptic activity under hypoglycemic conditions (Suda et al., 1990). As a result, brain glycogen is consumed very gradually during hypoglycemia (Ratcheson et al., 1981; Choi et al., 2003). A quantitative analysis suggests that normal levels of astrocyte glycogen should be able to support brain metabolism for about 100 min of hypoglycemia (Gruetter, 2003). Our observation that near-doubling of brain glycogen content increases the time to EEG isoelectricity by 90 min is in good agreement with this estimate.
The findings of this study also suggest that pharmacological elevation of brain glycogen stores could be useful in forestalling hypoglycemic coma and brain injury in diabetic patients. Indole carboximides similar to CP-316,819 are currently under development as antihyperglycemic agents by virtue of their inhibitory effect on liver glycogenolysis (Treadway et al., 2001), although it remains to be established whether brain glycogen stores are affected at the doses currently used to target hepatic glycogen phosphorylase. Whether increased glycogen might similarly provide a buffer against energy failure in cerebral ischemia is less clear. Only glycolytic ATP production can occur under the anoxic conditions of ischemia; thus, much less ATP is generated per glycogen glucose moiety. Consequently, and in contrast to hypoglycemia, brain glycogen is consumed very rapidly (within 4 min) during complete ischemia (Lowry et al., 1964; Swanson et al., 1989a). Moreover, glycogen is metabolized to lactic acid under ischemic conditions, and the resulting acidosis may have deleterious effects that outweigh the beneficial effects of increased energy reserve (Yip et al., 1991).
It remains to be established, at the cellular level, how increased astrocyte glycogen stores preserve neuronal function during hypoglycemia. Several lines of evidence suggest that glycogenolysis in astrocytes can serve to produce and supply neighboring neurons with metabolic intermediates, notably lactate (Dringen et al., 1993; Swanson and Choi, 1993; Poitry-Yamate et al., 1995; Pellerin et al., 1998; Wender et al., 2000; Brown et al., 2005; Tekkok et al., 2005). Moreover, studies in astrocyte cultures suggest that lactate derived from glycogen is preferentially exported from the cells (Sickmann et al., 2005). Together, these observations suggest that lactate generated from astrocyte glycogen can be shuttled to neurons as an energy substrate to supplement the reduced supply of glucose available to the brain during hypoglycemia. However, it is also possible that glycogenolysis in astrocytes serves to fuel astrocyte functions that more indirectly support brain activity (Dienel and Cruz, 2004). One important and energetically demanding astrocyte function is the uptake of neurotransmitter glutamate (Anderson and Swanson, 2000), and failure of glutamate uptake leads to neuronal depolarization, EEG isoelectricity, and neuronal death in hypoglycemia and other conditions. Thus, glycogen support of astrocyte metabolism, neuronal metabolism, or both could be important in prolonging neuronal activity and limiting neuronal death during hypoglycemia. Manipulation of brain glycogen content by the methods presented here may provide an approach for discriminating between these potential effects of astrocyte glycogen on neuronal and astrocyte metabolism in vivo.
|
Footnotes |
|---|
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: CP-316,819, [R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide; DAB, 1,4-dideoxy-1,4-imino-D-arabinitol; MOR-14, N-methyl-1-deoxynojirimycin; EEG, electroencephalogram; MSO, methionine sulfoximine.
Address correspondence to: Dr. Raymond A. Swanson, Neurology Service (127), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. E-mail: raymond.swanson{at}ucsf.edu
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Anderson CM and Swanson RA (2000) Astrocyte glutamate transport: review of properties, regulation, and physiological functions. Glia 32: 1–14.[CrossRef][Medline]
Arai M, Minatoguchi S, Takemura G, Uno Y, Kariya T, Takatsu H, Fujiwara T, Higashioka M, Yoshikuni Y, and Fujiwara H (1998) N-Methyl-1-deoxynojirimycin (MOR-14), an alpha-glucosidase inhibitor, markedly reduced infarct size in rabbit hearts. Circulation 97: 1290–1297.
Auer RN, Olsson Y, and Siesjo BK (1984) Hypoglycemic brain injury in the rat: correlation of density of brain damage with the EEG isoelectric time: a quantitative study. Diabetes 33: 1090–1098.[Abstract]
Brown AM, Sickmann HM, Fosgerau K, Lund TM, Schousboe A, Waagepetersen HS, and Ransom BR (2005) Astrocyte glycogen metabolism is required for neural activity during aglycemia or intense stimulation in mouse white matter. J Neurosci Res 79: 74–80.[CrossRef][Medline]
Cambray-Deakin M, Pearce B, Morrow C, and Murphy S (1988) Effects of neurotransmitters on astrocyte glycogen stores in vitro. J Neurochem 51: 1852–1857.[CrossRef][Medline]
Choi IY, Seaquist ER, and Gruetter R (2003) Effect of hypoglycemia on brain glycogen metabolism in vivo. J Neurosci Res 72: 25–32.[CrossRef][Medline]
Cruz NF and Dienel GA (2002) High glycogen levels in brains of rats with minimal environmental stimuli: implications for metabolic contributions of working astrocytes. J Cereb Blood Flow Metab 22: 1476–1489.[CrossRef][Medline]
Dienel GA and Cruz NF (2004) Nutrition during brain activation: does cell-to-cell lactate shuttling contribute significantly to sweet and sour food for thought? Neurochem Int 45: 321–351.[CrossRef][Medline]
Dringen R, Gebhardt R, and Hamprecht B (1993) Glycogen in astrocytes: possible function as lactate supply for neighboring cells. Brain Res 623: 208–214.[CrossRef][Medline]
Fosgerau K, Westergaard N, Quistorff B, Grunnet N, Kristiansen M, and Lundgren K (2000) Kinetic and functional characterization of 1,4-dideoxy-1, 4-imino-D-arabinitol: a potent inhibitor of glycogen phosphorylase with anti-hyperglyceamic effect in ob/ob mice. Arch Biochem Biophys 380: 274–284.[CrossRef][Medline]
Gruetter R (2003) Glycogen: the forgotten cerebral energy store. J Neurosci Res 74: 179–183.[CrossRef][Medline]
Koizumi J (1974) Glycogen in the central nervous system. Prog Histochem Cytochem 6: 1–37.[Medline]
Lewis LD, Ljunggren B, Ratcheson RA, and Siesjo BK (1974) Cerebral energy state in insulin-induced hypoglycemia, related to blood glucose and to EEG. J Neurochem 23: 673–679.[CrossRef][Medline]
Lowry OH, Passonneau JV, Hasselberger FH, and Schultz DW (1964) Effect of ischemia on known substrates and cofactors of the glycolytic pathway in brain. J Biol Chem 239: 18–30.
Magistretti PJ and Pellerin L (1997) Regulation by neurotransmitters of glial energy metabolism. Adv Exp Med Biol 429: 137–143.[Medline]
Martin WH, Hoover DJ, Armento SJ, Stock IA, McPherson RK, Danley DE, Stevenson RW, Barrett EJ, and Treadway JL (1998) Discovery of a human liver glycogen phosphorylase inhibitor that lowers blood glucose in vivo. Proc Natl Acad Sci USA 95: 1776–1781.
Nelson SR, Schulz DW, Passonneau JV, and Lowry OH (1968) Control of glycogen levels in brain. J Neurochem 15: 1271–1279.[CrossRef][Medline]
Overkleeft HS, Renkema GH, Neele J, Vianello P, Hung IO, Strijland A, van der Burg AM, Koomen GJ, Pandit UK, and Aerts JM (1998) Generation of specific deoxynojirimycin-type inhibitors of the non-lysosomal glucosylceramidase. J Biol Chem 273: 26522–26527.
Pellerin L, Pellegri G, Bittar PG, Charnay Y, Bouras C, Martin JL, Stella N, and Magistretti PJ (1998) Evidence supporting the existence of an activity-dependent astrocyte-neuron lactate shuttle. Dev Neurosci 20: 291–299.[CrossRef][Medline]
Pfeiffer-Guglielmi B, Fleckenstein B, Jung G, and Hamprecht B (2003) Immunocytochemical localization of glycogen phosphorylase isozymes in rat nervous tissues by using isozyme-specific antibodies. J Neurochem 85: 73–81.[Medline]
Phelps CH (1972) Barbiturate-induced glycogen accumulation in brain: an electron microscopic study. Brain Res 39: 225–234.[CrossRef][Medline]
Poitry-Yamate CL, Poitry S, and Tsacopoulos M (1995) Lactate released by Muller glial cells is metabolized by photoreceptors from mammalian retina. J Neurosci 15: 5179–5191.[Abstract]
Ratcheson RA, Blank AC, and Ferrendelli JA (1981) Regionally selective metabolic effects of hypoglycemia in brain. J Neurochem 36: 1952–1958.[CrossRef][Medline]
Sellinger OZ and Weiler P Jr (1963) The nature of the inhibition in vitro of cerebral glutamine synthetase by the convulsant, methionine sulfoximine. Biochem Pharmacol 12: 989–1000.[CrossRef][Medline]
Shulman RG, Hyder F, and Rothman DL (2001) Cerebral energetics and the glycogen shunt: neurochemical basis of functional imaging. Proc Natl Acad Sci USA 98: 6417–6422.
Sickmann HM, Schousboe A, Fosgerau K, and Waagepetersen HS (2005) Compartmentation of lactate originating from glycogen and glucose in cultured astrocytes. Neurochem Res 30: 1295–1304.[CrossRef][Medline]
Sokoloff L, Reivich M, Kennedy C, Des Rosiers MH, Patlak CS, Pettigrew KD, Sakurada O, and Shinohara M (1977) The [14C]deoxyglucose method for the measurement of local cerebral glucose utilization: theory, procedure, and normal values in the conscious and anesthetized albino rat. J Neurochem 28: 897–916.[Medline]
Suda S, Shinohara M, Miyaoka M, Lucignani G, Kennedy C, and Sokoloff L (1990) The lumped constant of the deoxyglucose method in hypoglycemia: effects of moderate hypoglycemia on local cerebral glucose utilization in the rat. J Cereb Blood Flow Metab 10: 499–509.[Medline]
Suh SW, Aoyama K, Chen Y, Garnier P, Matsumori Y, Gum E, Liu J, and Swanson RA (2003) Hypoglycemic neuronal death and cognitive impairment are prevented by poly(ADP-ribose) polymerase inhibitors administered after hypoglycemia. J Neurosci 23: 10681–10690.
Swanson RA (1992) Physiologic coupling of glial glycogen metabolism to neuronal activity in brain. Can J Physiol Pharmacol 70: S138–144.
Swanson RA and Choi DW (1993) Glial glycogen stores affect neuronal survival during glucose deprivation in vitro. J Cereb Blood Flow Metab 13: 162–169.[Medline]
Swanson RA, Sagar SM, and Sharp FR (1989a) Regional brain glycogen stores and metabolism during complete global ischaemia. Neurol Res 11: 24–28.[Medline]
Swanson RA, Shiraishi K, Morton MT, and Sharp FR (1990) Methionine sulfoximine reduces cortical infarct size in rats after middle cerebral artery occlusion. Stroke 21: 322–327.
Swanson RA, Yu AC, Sharp FR, and Chan PH (1989b) Regulation of glycogen content in primary astrocyte culture: effects of glucose analogues, phenobarbital, and methionine sulfoximine. J Neurochem 52: 1359–1365.[CrossRef][Medline]
Tekkok SB, Brown AM, Westenbroek R, Pellerin L, and Ransom BR (2005) Transfer of glycogen-derived lactate from astrocytes to axons via specific monocarboxylate transporters supports mouse optic nerve activity. J Neurosci Res 81: 644–652.[CrossRef][Medline]
Treadway JL, Mendys P, and Hoover DJ (2001) Glycogen phosphorylase inhibitors for treatment of type 2 diabetes mellitus. Expert Opin Investig Drugs 10: 439–454.[CrossRef][Medline]
Watanabe H and Passonneau JV (1973) Factors affecting the turnover of cerebral glycogen and limit dextrin in vivo. J Neurochem 20: 1543–1554.[CrossRef][Medline]
Wender R, Brown AM, Fern R, Swanson RA, Farrell K, and Ransom BR (2000) Astrocytic glycogen influences axon function and survival during glucose deprivation in central white matter. J Neurosci 20: 6804–6810.
Yip PK, He YY, Hsu CY, Garg N, Marangos P, and Hogan EL (1991) Effect of plasma glucose on infarct size in focal cerebral ischemia-reperfusion. Neurology 41: 899–905.
Yu LJ, Chen Y, Treadway JL, McPherson RK, McCoid SC, Gibbs EM, and Hoover DJ (2006) Establishment of correlation between in vitro enzyme binding potency and in vivo pharmacological activity: application to liver glycogen phosphorylase a inhibitors. J Pharmacol Exp Ther 317: 1230–1237.
This article has been cited by other articles:
|
|
 |
|
  G. Oz, A. Kumar, J. P. Rao, C. T. Kodl, L. Chow, L. E. Eberly, and E. R. Seaquist Human Brain Glycogen Metabolism During and After Hypoglycemia Diabetes, September 1, 2009; 58(9): 1978 - 1985. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
