Authors
1 Department of Anatomical Science and Molecular Biology, Faculty of Medicine, Isfahan University of Medical Sciences; Anatomical Sciences Research Center, Kashan University of Medical Sciences, Kashan; Neuroscience Research Center, Shahid Beheshi University of Medical Sciences, Tehran, Iran
2 Neuroscience Research Center, Shahid Beheshi University of Medical Sciences, Tehran, Iran
3 Research Group on Health Psychology, University of Leuven, Belgium, Iran
4 Department of Physiology, Faculty of Medicine, Kashan University of Medical Sciences; Physiology Research Center, Kashan University of Medical Sciences, Kashan, Iran
5 Neuroscience Research Center, Shahid Beheshi University of Medical Sciences; Behavioural Science Research Center, Department of Psychiatry, Imam Hossein Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
Abstract
Background: Post-traumatic stress disorder (PTSD) is a stress-related psychosomatic disorder caused by occurrence of a traumatic event and the hippocampus volume of the patients with Post-traumatic stress disorder decreased. However, the mechanisms that cause such damage are not well-understood. The aim of this study is to detect the expression of apoptosis-related Bax, Bcl-2, Caspase-3 and Insulin-like growth Factor-I proteins in the hippocampus region in the Predatory stress rats.
Materials and Methods: A total of 70 male wistar rats were divided into Predatory stress groups of 1d, 2d, 3d, 7d, 14d, 30d and a normal control group (N = 10). Rats were subjected to 5 min of predatory stress and then exposed to the elevated plus-maze (EPM). Serum corticosterone and Insulin-like growth factor-1 level of Hippocampus were measured by ELISA technique. The expression of Bax, Bcl-2, and Caspase-3 were detected by western blotting.
Results: Rats spent significantly more time in closed arms of the elevated plus maze (EPM) than control group after exposure to stress. Serum levels of corticosterone significantly increased at 2d-3d. The expression of hippocampal IGF-1 was significantly up-regulated at 1d-2d after stress. Both Bax and the ratio of Bax/Bcl-2 significantly peaked at Predatory stress 2d-14d. Caspase3 was significantly active among 2d-30 compared to the normal control.
Conclusion: The activation of caspase-3 in the stress groups indicates that apoptosis may be one of the reasons inducing hippocampus atrophy and play roles in the pathogenesis of PTSD. Increase in hippocampus levels of IGF-1 during early PTSD might be involved in the early molecular inhibitory mechanism of apoptosis in PTSD.
Keywords
1. | Victor AM, Bernstein GA. Anxiety disorders and posttraumatic stress disorder update. Psychiatr Clin North Am 2009; 32:57-69. |
2. | Boscarino JA. Posttraumatic stress disorder and physical illness: Results from clinical and epidemiologic studies. Ann N Y Acad Sci 2004; 1032:141-53. |
3. | Bonne O, Brandes D, Gilboa A, Gomori JM, Shenton ME, Pitman RK, et al., Longitudinal MRI study of hippocampal volume in trauma survivors with PTSD. Am J Psychiatry 2001; 158:1248-51. |
4. | Sapolsky RM. Atrophy of the hippocampus in posttraumatic stress disorder: How and when?. Hippocampus 2001; 11:90-1. |
5. | Kitayama N, Vaccarino V, Kutner M, Weiss P, Bremner JD. Magnetic resonance imaging [MRI] measurement of hippocampal volume in posttraumatic stress disorder: A meta-analysis. J Affect Disord 2005; 88:79-86. |
6. | Blagosklonny MV. Apoptosis, proliferation, differentiation: In search of the order. Semin Cancer Biol 2003; 13:97-105. |
7. | Thornberry NA, Lazebnik Y. Caspases: Enemies within. Science 1998; 281:1312-6. |
8. | Guicciardi M, Gores G. Life and death by death receptors. FASEB J 2009; 23:1625-7. |
9. | Waldmeier PC, Tatton WG. Interrupting apoptosis in neurodegenerative disease: Potential for effective therapy? Drug Discov Today 2004;9:210-8. |
10. | Shishkina GT, Kalinina TS, Berezova IV, Bulygina VV, Dygalo NN. Resistance to the development of stress-induced behavioral despair in the forced swim test associated with elevated hippocampal Bcl-xl expression. Behav Brain Res 2010; 213:218-24. |
11. | Watanabe Y, Gould E, McEwen BS. Stress induces atrophy of pical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 1992; 588:341-5. |
12. | Bremner JD. Stress and brain atrophy. CNS Neural Disorder DR 2006; 5:503-12. |
13. | Davila D, Piriz J, Trejo JL, Nunez A, Torres-Aleman I. Insulin and insulin-like growth factor I signalling in neurons. Front Biosci 2007; 12:3194-202. |
14. | Llorens-Martín M, Torres-Alemán I, Trejo JL. Mechanisms mediating brain plasticity: IGF1 and adult hippocampal neurogenesis. Neuroscientist 2009; 15:134-48. |
15. | Aberg D. Role of the growth hormone/insulin-like growth factor 1 axis in neurogenesis. Endocr Dev 2010; 17:63-76. |
16. | Bitar MS. Insulin and glucocorticoid-dependent suppression of the IGF-I system in diabetic wounds. Surgery 2000; 127:687-95. |
17. | D'Ercole AJ, Ye P, O'Kusky JR. Mutant mouse models of insulin-like growth factor actions in the central nervous system. Neuropeptides 2002; 36:209-20. |
18. | Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, et al., Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol 1999; 19:7203-15. |
19. | McCarthy NJ, Whyte MK, Gilbert CS, Evan GI. Inhibition of Ced-3/ICE-related proteases does not prevent cell death induced by oncogenes, DNA damage, or the Bcl-2 homologue Bak. J Cell Biol 1997; 136:215-27. |
20. | Haunstetter A, Izumo S. Apoptosis: Basic mechanisms and implications for cardiovascular disease. Circ Res 1998; 82:1111-29. |
21. | Dietrich MO, Muller A, Bolos M, Carro E, Perry ML, Portela LV. Western style diet impairs entrance of blood-borne insulin-like growth factor-1 into the brain. Neuromol Med 2007; 9:324-30. |
22. | Bateman JM, McNeill H. Insulin/IGF signalling in neurogenesis. Cell Mol Life Sci 2006; 63:1701-5. |
23. | Adamec RE, Stark-Adamec C, Livingston KE. The development of predatory aggression and defense in the domestic cat (Felis catus). II. Development of aggression and defense in the first 164 days of life. Behav Neural Biol 1980; 30:410-34. |
24. | Adamec RE, Stark-Adamec C, Livingston KE. The development of predatory aggression and defense in the domestic cat (Felis catus). I. Effects of early experience on adult patterns of aggression and defense. Behav Neural Biol 1980; 38:389-409. |
25. | Cohen H, Zohar J, Matar MA, Zeev K, Loewenthal U, Richter-Levin G. Setting apart the affected: the use of behavioral criteria in animal models of post traumatic stress disorder. Neuropsychopharmacol 2004; 29:1962-70. |
26. | Pellow S, Chopin P, File SE, Briley M. Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Meth 1985; 14:149-67. |
27. | Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 1976; 72:248-54. |
28. | Fink G. Stress controversies: Post-traumatic stress disorder, hippocampal volume,gastroduodenal ulceration. J Neuroendocrinol 2011; 23:107-17. |
29. | Zhang L, Zhou R, Li X, Ursano RJ, Li H. Stress-induced change of mitochondria membrane potential regulated by genomic and non-genomic GR signaling: A possible mechanism for hippocampus atrophy in PTSD. Med Hypotheses 2006; 66:1205-8. |
30. | Cohen H, Kozlovsky N, Alona C, Matar MA, Joseph Z. Animal model for PTSD: From clinical concept to translational research. Neuropharmacol 2012; 62:715-24. |
31. | Adamec RE, Burton P, Shallow T, Budgell J. Unilateral block of NMDA receptors in the amygdala prevents predator stress-induced lasting increases in anxiety-like behavior and unconditioned startle--effective hemisphere depends on the behavior. Physiol Behav 1999;65:739-51. |
32. | Li X, Han F, Liu D, Shi Y. Changes of Bax, Bcl-2 and apoptosis in hippocampus in the rat model of post-traumatic stress disorder. Neurol Res 2010; 32:579-86. |
33. | Li XM, Han F, Liu JD, Shi Y. Single-prolonged stress induced mitochondrial-dependent apoptosis in hippocampus in the rat model of post-traumatic stress disorder. J Chem Neuroanat 2010; 40:248-55. |
34. | Lee E, Son H. Adult hippocampal neurogenesis and related neurotrophic factors. BMB Rep 2009; 42:239-44. |
35. | Bitar MS. Insulin and glucocorticoid-dependent suppression of the IGF-I system in diabetic wounds. Surgery 2000; 127:687-95. |
36. | Zhang W, Ghetti B, Lee WH. Decreased IGF-I gene expression during the apoptosis of Purkinje cells in pcd mice. Brain Res Dev Brain Res 1997; 98:164-76. |
37. | Ishii DN. Implication of insulin-like growth factors in the pathogenesis of diabetic neuropathy. Brain Res Rev 1995; 20:47-67. |
38. | Anderson MF, Aberg MA, Nilsson M, Eriksson PS. Insulin-like growth factor-I and neurogenesis in the adult mammalian brain. Brain. Res Dev Brain Res 2002; 134:115-22. |