Concentration-dependent bimodal effect of specific 18 kDa Translocator Protein (TSPO) ligands on cell death processes induced by ammonium chloride: Potential implications for neuropathological effects due to hyperammonemia

CNS and Neurological Disorders - Drug Targets

Volumn 13, Issue 4, 2014, Pages 574-592

  Caballero, Beatriz ^a   Veenman, Leo ^a   Bode, Julia ^b   Leschiner, Svetlana ^a   Gavish, Moshe ^a  

^a TECHNION ISRAEL INSTITUTE OF TECHNOLOGY   (Israel)

^b UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

Author keywords

18 kDa Translocator Protein (TSPO); Ammonium chloride; Cell death; Cell swelling; Mitochondria; Neuropathology; Oxidative stress

Indexed keywords

AMMONIUM CHLORIDE; BENZODIAZEPINE RECEPTOR BLOCKING AGENT; CARDIOLIPIN; FIGN 1 27; LACTATE DEHYDROGENASE; N SEC BUTYL 1 (2 CHLOROPHENYL) N METHYL 3 ISOQUINOLINECARBOXAMIDE; PROTEIN; RO5 4864; TRANSLOCATOR PROTEIN; UNCLASSIFIED DRUG; 4 AMINOBUTYRIC ACID RECEPTOR; 4'-CHLORODIAZEPAM; BENZODIAZEPINE DERIVATIVE; GABAERGIC RECEPTOR AFFECTING AGENT; GLUTAMINE; INDOLEACETIC ACID DERIVATIVE; ISOQUINOLINE DERIVATIVE; LIGAND; N,N-DI-N-HEXYL-2-(4-FLUOROPHENYL)INDOLE-3-ACETAMIDE; NEUROPROTECTIVE AGENT; PROPIDIUM IODIDE; TSPO PROTEIN, HUMAN;

ARTICLE; CELL DEATH; CELL STRUCTURE; CELL SWELLING; CELL VIABILITY ASSAY; CHROMATIN CONDENSATION; CONTROLLED STUDY; CYTOTOXICITY ASSAY; DOSE RESPONSE; DRUG DOSE COMPARISON; GLIOBLASTOMA; HUMAN; HUMAN CELL; HYPERAMMONEMIA; LIPID OXIDATION; LIPID PEROXIDATION; MITOCHONDRIAL MEMBRANE POTENTIAL; NITROSYLATION; PHASE CONTRAST MICROSCOPY; REAL TIME POLYMERASE CHAIN REACTION; WESTERN BLOTTING; XTT ASSAY; CELL SHAPE; CHEMICALLY INDUCED; CHEMISTRY; DRUG EFFECTS; METABOLISM; MITOCHONDRION; PATHOPHYSIOLOGY; PHYSIOLOGY; TOXICITY; TUMOR CELL LINE;

AMMONIUM CHLORIDE; BENZODIAZEPINONES; CARDIOLIPINS; CELL DEATH; CELL LINE, TUMOR; CELL SHAPE; DOSE-RESPONSE RELATIONSHIP, DRUG; GABA AGENTS; GLUTAMINE; HUMANS; HYPERAMMONEMIA; INDOLEACETIC ACIDS; ISOQUINOLINES; L-LACTATE DEHYDROGENASE; LIGANDS; LIPID PEROXIDATION; MEMBRANE POTENTIAL, MITOCHONDRIAL; MITOCHONDRIA; NEUROPROTECTIVE AGENTS; PROPIDIUM; RECEPTORS, GABA;

EID: 84904512980     PISSN: 18715273     EISSN: 19963181     Source Type: Journal    
DOI: 10.2174/18715273113126660194     Document Type: Article

References (117)

1. Felipo V, Butterworth RF. Neurobiology of ammonia. Prog Neurobiol 2002; 67: 259-79.
2. Seiler N. Ammonia and Alzheimer's disease. Neurochem Int 2002; 41: 189-207.
3. Braissant O, McLin VA, Cudalbu C. Ammonia toxicity to the brain. J Inherit Metab Dis 2012; 36(4): 595-612.
4. Butterworth RF. Complications of cirrhosis III. Hepatic encephalopathy. J Hepatol 2000; 32: 171-80.
5. Butterworth RF. Pathogenesis of hepatic encephalopathy: update on molecular mechanisms. Ind J Gastroenterol 2003; 22(Suppl 2): S11-6.
6. Norenberg MD, Jayakumar AR, Rama Rao KV, Panickar KS. New concepts in the mechanism of ammonia-induced astrocyte swelling. Metab Brain Dis 2007; 22: 219-34.
7. Norenberg MD, Rama Rao KV, Jayakumar AR. Signaling factors in the mechanism of ammonia neurotoxicity. Metab Brain Dis 2009; 24: 103-17.
8. Swain M, Butterworth RF, Blei AT. Ammonia and related amino acids in the pathogenesis of brain edema in acute ischemic liver failure in rats. Hepatology 1992; 15: 449-53.
9. Girard G, Giguere JF, Butterworth RF. Region-selective reductions in activities of glutamine synthetase in rat brain following portacaval anastomosis. Metab Brain Dis 1993; 8: 207-15.
10. Matsui H, Ito H, Taniguchi Y, Takeda S, Takahashi R. Ammonium chloride and tunicamycin are novel toxins for dopaminergic neurons and induce Parkinson's disease-like phenotypes in medaka fish. J Neurochem 2010; 115: 1150-60.
11. Norenberg MD. The role of astrocytes in hepatic encephalopathy. Neurochem Pathol 1987; 6: 13-33.
12. Norenberg MD, Martinez-Hernandez A. Fine structural localization of glutamine synthetase in astrocytes of rat brain. Brain Res 1979; 161: 303-10.
13. Takahashi H, Koehler RC, Brusilow SW, Traystman RJ. Inhibition of brain glutamine accumulation prevents cerebral edema in hyperammonemic rats. Am J Physiol 1991; 261: H825-9.
14. Willard-Mack CL, Koehler RC, Hirata T, et al. Inhibition of glutamine synthetase reduces ammonia-induced astrocyte swelling in rat. Neuroscience 1996; 71: 589-99.
15. Jayakumar AR, Rao KV, Murthy Ch R, Norenberg MD. Glutamine in the mechanism of ammonia-induced astrocyte swelling. Neurochem Int 2006; 48: 623-8.
16. Jayakumar AR, Liu M, Moriyama M, et al. Na-K-Cl Cotransporter-1 in the mechanism of ammonia-induced astrocyte swelling. J Biol Chem 2008; 283: 33874-82.
17. Desjardins P, Du T, Jiang W, Peng L, Butterworth RF. Pathogenesis of hepatic encephalopathy and brain edema in acute liver failure: Role of glutamine redefined. Neurochem Int 2012; 60: 690-6.
18. Rama Rao KV, Norenberg MD. Brain energy metabolism and mitochondrial dysfunction in acute and chronic hepatic encephalopathy. Neurochem Int 2012; 60, 697-706.
19. Norenberg MD, Rama Rao KV, Jayakumar AR. Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr 2004; 36: 303-7.
20. Alvarez VM, Rama Rao KV, Brahmbhatt M, Norenberg MD. Interaction between cytokines and ammonia in the mitochondrial permeability transition in cultured astrocytes. J Neurosci Res 2011; 89: 2028-40.
21. Jayakumar AR, Rama Rao KV, Tong XY, Norenberg MD. Calcium in the mechanism of ammonia-induced astrocyte swelling. J Neurochem 2009; 109(Suppl 1): 252-7.
22. Rama Rao KV, Jayakumar AR, Norenberg MD. Role of oxidative stress in the ammonia-induced mitochondrial permeability transition in cultured astrocytes. Neurochemm Int 2005; 47: 31-8.
23. Rama Rao KV, Jayakumar AR, Tong X, Alvarez VM, Norenberg MD. Marked potentiation of cell swelling by cytokines in ammonia-sensitized cultured astrocytes. J Neuroinflamm 2010; 7: 66-73.
24. Reddy PV, Rama Rao KV, Norenberg MD. Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes. J Neurosci Res 2009; 87: 2677-85.
25. Sinke AP, Jayakumar AR, Panickar KS, et al. NFkappaB in the mechanism of ammonia-induced astrocyte swelling in culture. J Neurochem 2008; 106: 2302-11.
26. Panickar KS, Jayakumar AR, Rao KV, Norenberg MD. Ammoniainduced activation of p53 in cultured astrocytes: role in cell swelling and glutamate uptake. Neurochem Int 2009; 55: 98-105.
27. Hawkins RA, Jessy J. Hyperammonaemia does not impair brain function in the absence of net glutamine synthesis. Biochemistry 1991; 277(Pt 3): 697-703.
28. Rama Rao KV, Jayakumar AR, Norenberg MD. Induction of the mitochondrial permeability transition in cultured astrocytes by glutamine. Neurochem Int 2003; 43: 517-23.
29. Rama Rao KV, Jayakumar AR, Norenberg MD. Glutamine in the pathogenesis of acute hepatic encephalopathy. Neurochem Int 2012; 62: 575-80.
30. Albrecht J, Dolinska M, Hilgier W, Lipkowski AW, Nowacki J. Modulation of glutamine uptake and phosphate-activated glutaminase activity in rat brain mitochondria by amino acids and their synthetic analogues. Neurochem Int 2000; 36: 341-7.
31. Albrecht J, Norenberg MD. Glutamine: a Trojan horse in ammonia neurotoxicity. Hepatology 2006; 44: 788-94.
32. Itzhak Y, Norenberg MD. Ammonia-induced upregulation of peripheral-type benzodiazepine receptors in cultured astrocytes labeled with [3H]PK 11195. Neurosci Lett 1994; 177: 35-8.
33. Norenberg MD, Itzhak Y, Bender AS. The peripheral benzodiazepine receptor and neurosteroids in hepatic encephalopathy. Adv Exp Med Biol 1997; 420: 95-111.
34. Butterworth RF. The astrocytic (peripheral-type) benzodiazepine receptor: role in the pathogenesis of portal-systemic encephalopathy. Neurochem Int 2000; 36: 411-6.
35. Desjardins P, Butterworth RF. The peripheral-type benzodiazepine (omega 3) receptor in hyperammonemic disorders. Neurochem Int 2002; 41: 109-14.
36. Belanger M, Desjardins P, Chatauret N, Rose C, Butterworth RF. Mild hypothermia prevents brain edema and attenuates upregulation of the astrocytic benzodiazepine receptor in experimental acute liver failure. J Hepatol 2005; 42: 694-9.
37. Braestrup C, Squires RF. Specific benzodiazepine receptors in rat brain characterized by high-affinity (3H) diazepam binding. Proc Natl Acad Sci USA 1977; 74: 3805-9.
38. Gavish M, Bachman I, Shoukrun R, et al. Enigma of the peripheral benzodiazepine receptor. Pharmacol Rev 1999; 51: 629-50.
39. Papadopoulos V, Baraldi M, Guilarte TR, et al. Translocator protein (18kDa): new nomenclature for the peripheral-type benzodiazepine receptor based on its structure and molecular function. Trends Pharmacol Sci 2006; 27: 402-9.
40. Kugler W, Veenman L, Shandalov Y, et al. Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glioblastoma cells exposed to erucylphosphohomocholine. Cell Oncol 2008; 30: 435-50.
41. Zeno S, Zaaroor M, Leschiner S, Veenman L, Gavish M. CoCl(2) induces apoptosis via the 18 kDa translocator protein in U118MG human glioblastoma cells. Biochemistry 2009; 48: 4652-61.
42. Avital A, Richter-Levin G, Leschiner S, et al. Acute and repeated swim stress effects on peripheral benzodiazepine receptors in the rat hippocampus, adrenal, and kidney. Neuropsychopharmacology 2001; 25: 669-78.
43. Shargorodsky L, Veenman L, Caballero B, et al. The nitric oxide donor sodium nitroprusside requires the 18 kDa Translocator Protein to induce cell death. Apoptosis 2012; 17: 647-65.
44. Anholt RR, Pedersen PL, De Souza EB, Snyder SH. The peripheral-type benzodiazepine receptor. Localization to the mitochondrial outer membrane. J Biol Chem 1986; 261: 576-83.
45. McEnery MW, Snowman AM, Trifiletti RR, Snyder SH. Isolation of the mitochondrial benzodiazepine receptor: association with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci USA 1992; 89: 3170-4.
46. Papadopoulos V, Lecanu L. Translocator protein (18 kDa) TSPO: an emerging therapeutic target in neurotrauma. Exp Neurol 2009; 219: 53-7.
47. Papadopoulos V, Lecanu L, Brown RC, Han Z, Yao ZX. Peripheral-type benzodiazepine receptor in neurosteroid biosynthesis, neuropathology and neurological disorders. Neuroscience 2006; 138: 749-56.
48. Veenman L, Alten J, Linnemannstons K, et al. Potential involvement of F0F1-ATP(synth)ase and reactive oxygen species in apoptosis induction by the antineoplastic agent erucyl phosphohomocholine in glioblastoma cell lines: a mechanism for induction of apoptosis via the 18 kDa mitochondrial translocator protein. Apoptosis 2010; 15: 753-68.
49. Veenman L, Papadopoulos V, Gavish M. Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response. Curr Pharm Des 2007; 13: 2385-405.
50. Veenman L, Shandalov Y, Gavish M. VDAC activation by the 18 kDa translocator protein (TSPO), implications for apoptosis. J Bioenerg Biomembr 2008; 40: 199-205.
51. Veiga S, Carrero P, Pernia O, Azcoitia I, Garcia-Segura LM. Translocator protein 18 kDa is involved in the regulation of reactive gliosis. Glia 2007; 55: 1426-36.
52. Cosenza-Nashat M, Zhao ML, Suh HS, et al. Expression of the translocator protein of 18 kDa by microglia, macrophages and astrocytes based on immunohistochemical localization in abnormal human brain. Neuropathol Appl Neurobiol 2009; 35: 306-28.
53. Levin E, Premkumar A, Veenman L, et al. The peripheral-type benzodiazepine receptor and tumorigenicity: isoquinoline binding protein (IBP) antisense knockdown in the C6 glioma cell line. Biochemistry 2005; 44: 9924-35.
54. Shoukrun R, Veenman L, Shandalov Y, et al. The 18-kDa translocator protein, formerly known as the peripheral-type benzodiazepine receptor, confers proapoptotic and antineoplastic effects in a human colorectal cancer cell line. Pharmacogenet Genom 2008; 18: 977-88.
55. Bode J, Veenman L, Caballero B, et al. The 18 kDa translocator protein influences angiogenesis, as well as aggressiveness, adhesion, migration, and proliferation of glioblastoma cells. Pharmacogenet Genom 2012; 22: 538-50.
56. Veenman L, Gavish M. The Role of 18 kDa Mitochondrial Translocator Protein (TSPO) in Programmed Cell Death, and Effects of Steroids on TSPO Expression. Curr Mol Med 2012; 12: 398-412.
57. Veenman L, Bode J, Gaitner M, et al. Effects of 18-kDa translocator protein knockdown on gene expression of glutamate receptors, transporters, and metabolism, and on cell viability affected by glutamate. Pharmacogenet Genom 2012; 22: 606-19.
58. Gregoire M, Hernandez-Verdun D, Bouteille M. Visualization of chromatin distribution in living PTO cells by Hoechst 33342 fluorescent staining. Exp Cell Res 1984; 152: 38-46.
59. Perazzo JC, Tallis S, Delfante A, et al. Hepatic encephalopathy: An approach to its multiple pathophysiological features. World J Hepatol 2012; 4: 50-65.
60. Friis MB, Friborg CR, Schneider L, et al. Cell shrinkage as a signal to apoptosis in NIH 3T3 fibroblasts. J Physiol 2005; 567: 427-43.
61. Bortner CD, Cidlowski JA. Cell shrinkage and monovalent cation fluxes: role in apoptosis. Arch Biochem Biophys 2007; 462: 176-88.
62. Knight SA, Dancis A. Reduction of 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide inner salt (XTT) is dependent on CaFRE10 ferric reductase for Candida albicans grown in unbuffered media. Microbiology 2006; 152: 2301-8.
63. Petrosillo G, Ruggiero FM, Paradies G. Role of reactive oxygen species and cardiolipin in the release of cytochrome c from mitochondria. FASEB J 2003; 17: 2202-8.
64. Gonzalvez F, Gottlieb E. Cardiolipin: setting the beat of apoptosis. Apoptosis 2007; 12: 877-85.
65. Gunter TE, Pfeiffer DR. Mechanisms by which mitochondria transport calcium. Am J Physiol 1990; 258: C755-86.
66. Pfaffl MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res 2001; 29: e45.
67. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of proteindye binding. Anal Biochem 1976; 72: 248-54.
68. Veenman L, Levin E, Weisinger G, et al. Peripheral-type benzodiazepine receptor density and in vitro tumorigenicity of glioma cell lines. Biochem Pharmacol 2004; 68: 689-98.
69. Fares F, Gavish M. Characterization of peripheral benzodiazepine binding sites in human term placenta. Biochem Pharmacol 1986; 35: 227-30.
70. Awad M, Gavish M. Peripheral-type benzodiazepine receptors in human cerebral cortex, kidney, and colon. Life Sci 1991; 49: 1155-61.
71. Albrecht J, Zielinska M, Norenberg MD. Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal. Biochem Pharmacol 2010; 80: 1303-8.
72. Jalan R, Olde Damink SW, Hayes PC, Deutz NE, Lee A. Pathogenesis of intracranial hypertension in acute liver failure: inflammation, ammonia and cerebral blood flow. J Hepatol 2004; 41: 613-20.
73. Yang CZ, Li HL, Zhou Y, et al. A new specialization in astrocytes: glutamate-and ammonia-induced nuclear size changes. J Neurosci Res 2011; 89: 2041-51.
74. Haghighat N, McCandless DW, Geraminegad P. Responses in primary astrocytes and C6-glioma cells to ammonium chloride and dibutyryl cyclic-AMP. Neurochem Res 2000; 25: 277-84.
75. Haghighat N, Oblinger MM, McCandless DW. Cytoprotective effect of estrogen on ammonium chloride-treated C6-glioma cells. Neurochem Res 2004; 29: 1359-64.
76. Bustamante J, Lores-Arnaiz S, Tallis S, et al. Mitochondrial dysfunction as a mediator of hippocampal apoptosis in a model of hepatic encephalopathy. Mol Cell Biochem 2011; 354: 231-40.
77. Klejman A, Wegrzynowicz M, Szatmari EM, et al. Mechanisms of ammonia-induced cell death in rat cortical neurons: roles of NMDA receptors and glutathione. Neurochem Int 2005; 47: 51-7.
78. Svoboda N, Zierler S, Kerschbaum HH. cAMP mediates ammoniainduced programmed cell death in the microglial cell line BV-2. Eur J Neurosci 2007; 25: 2285-95.
79. Suzuki H, Yanaka A, Shibahara T, et al. Ammonia-induced apoptosis is accelerated at higher pH in gastric surface mucous cells. Am J Physiol Gastrointest Liver Physiol 2002; 283: G986-95.
80. Ducis I, Norenberg LO, Norenberg MD. Effect of ammonium chloride on the astrocyte benzodiazepine receptor. Brain Res 1989; 493: 362-5.
81. Lavoie J, Layrargues GP, Butterworth RF. Increased densities of peripheral-type benzodiazepine receptors in brain autopsy samples from cirrhotic patients with hepatic encephalopathy. Hepatology 1990; 11: 874-8.
82. Panickar KS, Jayakumar AR, Rama Rao KV, Norenberg MD. Downregulation of the 18-kDa translocator protein: effects on the ammonia-induced mitochondrial permeability transition and cell swelling in cultured astrocytes. Glia 2007; 55: 1720-7.
83. Rao VL, Qureshi IA, Butterworth RF. Increased densities of binding sites for the peripheral-type benzodiazepine receptor ligand [3H]PK 11195 in congenital ornithine transcarbamylase-deficient sparse fur mouse. Pediatr Res 1993; 34: 777-80.
84. Itzhak Y, Roig-Cantisano A, Dombro RS, Norenberg MD. Acute liver failure and hyperammonemia increase peripheral-type benzodiazepine receptor binding and pregnenolone synthesis in mouse brain. Brain Res 1995; 705: 345-8.
85. Desjardins P, Bandeira P, Raghavendra Rao VL, Ledoux S, Butterworth RF. Increased expression of the peripheral-type benzodiazepine receptor-isoquinoline carboxamide binding protein mRNA in brain following portacaval anastomosis. Brain Res 1997; 758: 255-8.
86. Bodega G, Suarez I, Lopez-Fernandez LA, et al. Possible implication of ciliary neurotrophic factor (CNTF) and betasynuclein in the ammonia effect on cultured rat astroglial cells: a study using DNA and protein microarrays. Neurochem Int 2006; 48: 729-38.
87. Broaddus WC, Bennett JP Jr. Peripheral-type benzodiazepine receptors in human glioblastomas: pharmacologic characterization and photoaffinity labeling of ligand recognition site. Brain Res 1990; 518: 199-208.
88. Veenman L, Leschiner S, Spanier I, et al. PK 11195 attenuates kainic acid-induced seizures and alterations in peripheral-type benzodiazepine receptor (PBR) protein components in the rat brain. J Neurochem 2002; 80: 917-27.
89. Le Fur G, Vaucher N, Perrier ML, et al. Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195; by thermodynamic studies. Life Sci 1983; 33: 449-57.
90. Awad M, Gavish M. Species differences and heterogeneity of solubilized peripheral-type benzodiazepine binding sites. Biochem Pharmacol 1989; 38: 3843-9.
91. Awad M, Gavish M. Solubilization of peripheral-type benzodiazepine binding sites from cat cerebral cortex. J Neurochem 1989; 52: 1880-5.
92. Scarf AM, Kassiou M. The translocator protein. J Nucl Med 2011; 52: 677-80.
93. Strohmeier R, Roller M, Sanger N, Knecht R, Kuhl H. Modulation of tamoxifen-induced apoptosis by peripheral benzodiazepine receptor ligands in breast cancer cells. Biochem Pharmacol 2002; 64: 99-107.
94. Chelli B, Lena A, Vanacore R, et al. Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential depolarization and apoptosis induction in rat C6 glioma cells. Biochem Pharmacol 2004; 68: 125-34.
95. Hirsch T, Decaudin D, Susin SA, et al. PK11195; a ligand of the mitochondrial benzodiazepine receptor, facilitates the induction of apoptosis and reverses Bcl-2-mediated cytoprotection. Exp Cell Res 1998; 241: 426-34.
96. Bono F, Lamarche I, Prabonnaud V, Le Fur G, Herbert JM. Peripheral benzodiazepine receptor agonists exhibit potent antiapoptotic activities. Biochem Biophys Res Commun 1999; 265: 457-61.
97. Gonzalez-Polo RA, Carvalho G, Braun T, et al. PK11195 potently sensitizes to apoptosis induction independently from the peripheral benzodiazepin receptor. Oncogene 2005; 24: 7503-13.
98. Jorda EG, Jimenez A, Verdaguer E, et al. Evidence in favour of a role for peripheral-type benzodiazepine receptor ligands in amplification of neuronal apoptosis. Apoptosis 2005; 10: 91-104.
99. Bender AS, Norenberg MD. Effect of benzodiazepines and neurosteroids on ammonia-induced swelling in cultured astrocytes. J Neurosci Res 1998; 54: 673-80.
100. Garnier M, Boujrad N, Oke BO, et al. Papadopoulos V. Diazepam binding inhibitor is a paracrine/autocrine regulator of Leydig cell proliferation and steroidogenesis: action via peripheral-type benzodiazepine receptor and independent mechanisms. Endocrinology 1993; 132: 444-58.
101. Alexander BE, Roller E, Klotz U. Characterization of peripheraltype benzodiazepine binding sites on human lymphocytes and lymphoma cell lines and their role in cell growth. Biochem Pharmacol 1992; 44: 269-74.
102. Zisterer DM, Hance N, Campiani G, et al. Antiproliferative action of pyrrolobenzoxazepine derivatives in cultured cells: absence of correlation with binding to the peripheral-type benzodiazepine binding site. Biochem Pharmacol 1998; 55: 397-403.
103. Costa B, Salvetti A, Rossi L, et al. Peripheral benzodiazepine receptor: characterization in human T-lymphoma Jurkat cells. Mol Pharmacol 2006; 69: 37-44.
104. Sakai M, Ferraz-de-Paula V, Pinheiro ML, et al. Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo. Eur J Pharmacol 2010; 626: 131-8.
105. Owen DR, Howell OW, Tang SP, et al. Two binding sites for [3H]PBR28 in human brain: implications for TSPO PET imaging of neuroinflammation. J Cereb Blood Flow Metab 2010; 30: 1608-18.
106. Owen DR, Gunn RN, Rabiner EA, et al. Mixed-affinity binding in humans with 18-kDa translocator protein ligands. J Nucl Med 2011; 52: 24-32.
107. Decaudin D, Castedo M, Nemati F, et al. Peripheral benzodiazepine receptor ligands reverse apoptosis resistance of cancer cells in vitro and in vivo. Cancer Res 2002; 62: 1388-93.
108. Rama Rao KV, Jayakumar AR, Norenberg MD. Differential response of glutamine in cultured neurons and astrocytes. J Neurosci Res 2005; 79: 193-9.
109. Jayakumar AR, Rama Rao KV, Schousboe A, Norenberg MD. Glutamine-induced free radical production in cultured astrocytes. Glia 2004; 46: 296-301.
110. Dolinska M, Hilgier W, Albrecht J. Ammonia stimulates glutamine uptake to the cerebral non-synaptic mitochondria of the rat. Neurosci Lett 1996; 213: 45-8.
111. Hawkins RA, Jessy J, Mans AM, De Joseph MR. Effect of reducing brain glutamine synthesis on metabolic symptoms of hepatic encephalopathy. J Neurochem 1993; 60: 1000-6.
112. Murthy CR, Rama Rao KV, Bai G, Norenberg MD. Ammoniainduced production of free radicals in primary cultures of rat astrocytes. J Neurosci Res 2001; 66: 282-8.
113. Pichili VB, Rao KV, Jayakumar AR, Norenberg MD. Inhibition of glutamine transport into mitochondria protects astrocytes from ammonia toxicity. Glia 2007; 55: 801-9.
114. Bai G, Rama Rao KV, Murthy CR, et al. Ammonia induces the mitochondrial permeability transition in primary cultures of rat astrocytes. J Neurosci Res 2001; 66: 981-91.
115. Svoboda N, Kerschbaum HH. L-Glutamine-induced apoptosis in microglia is mediated by mitochondrial dysfunction. Eur J Neurosci 2009; 30: 196-206.
116. Jayakumar AR, Panickar KS, Murthy Ch R, Norenberg MD. Oxidative stress and mitogen-activated protein kinase phosphorylation mediate ammonia-induced cell swelling and glutamate uptake inhibition in cultured astrocytes. J Neurosci 2006; 26: 4774-84.
117. Sonnewald U, Westergaard N, Jones P, et al. Metabolism of [U-13C5] glutamine in cultured astrocytes studied by NMR spectroscopy: first evidence of astrocytic pyruvate recycling. J Neurochem 1996; 67: 2566-72.