Abstract：Objective To observe the changes in anxiety-like behavior among rats in the recovery stage after hypoxic-ischemic brain damage (HIBD) during the perinatal period and to investigate the effect of insulin-like growth factor 1 (IGF-1) on the long-term anxiety-like behavior and its action mechanism among rats with HIBD. Methods Ninety neonatal rats (7 days old) were randomly and equally divided into normal control, HIBD, and HIBD+IGF-1 groups. A neonatal rat model of HIBD was established by Rice method in the HIBD and HIBD+IGF-1 groups. The rats in the HIBD+IGF-1 group were intraperitoneally injected with IGF-1 (0.2 mg/kg) immediately after HIBD, and the other two groups were intraperitoneally injected with an equal volume of normal saline. The anxiety-like behavior was evaluated by elevated plus-maze test on postnatal days 21 and 28. The expression of tyrosine hydroxylase (TH) in the substantia nigra was measured by immunohistochemistry on postnatal days 14, 21, and 28. Results On postnatal days 21 and 28, the open-arm time (OAT) and percentage of OAT for the HIBD and HIBD+IGF-1 groups were significantly lower than those for the normal control group (P<0.05), but there were no significant differences between the HIBD and HIBD+IGF-1 groups (P>0.05); the percentage of open arm entry showed no significant difference between the three groups (P>0.05). On postnatal day 14, there were no significant differences in percentage of TH immunostaining-positive area between the three groups (P>0.05). On postnatal days 21 and 28, the HIBD and HIBD+IGF-1 groups had significantly lower percentages of TH immunostaining-positive area than the normal control group (P<0.05), but there was no significant difference between the HIBD and HIBD+IGF-1 groups (P>0.05). Conclusions HIBD in the perinatal period may cause the changes in anxiety-like behavior in adolescent rats, which may be related to decreased expression of TH in the substantia nigra. Neonatally given IGF-1 cannot improve the long-term anxiety-like behavior in rats after HIBD, and it does not affect TH expression in the substantia nigra. IGF-1 may not regulate the changes in longterm anxiety-like behavior in adolescent rats.
TANG Qin,LIU Fu-Rong,LUO Ya-Li et al. Effect of IGF-1 on long-term anxiety-like behavior in rats after hypoxic-ischemic brain damage[J]. CJCP, 2014, 16(3): 295-300.
Northington FJ, Chavez-Valdez R, Martin LJ. Neuronal cell death in neonatal hypoxia-ischemia[J]. Ann Neurol, 2011, 69(5): 743-758.
[3]
Bona E, Johansson BB, Hagberg H. Sensorimotor function and neuropathology five to six weeks after hypoxia-ischemia in sevenday-old-rats[J]. Pediatr Res, 1997, 42(5): 678-683.
[4]
Van Handel M, Swaab H, de Vries LS, et al. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review[J]. Eur J Pediatr, 2007, 166(7): 645-654.
[5]
Ming-Yan H, Luo YL, Zhang XC, et al. Hypoxic-ischemic injury decreases anxiety-like behavior in rats when associated with loss of tyrosine-hydroxylase immunoreactive neurons of the substantia nigra[J]. Braz J Med Biol Res, 2012, 45(1): 13-19.
[6]
Yan XB, Wang SS, Hou HL, et al. Lithium improves the behavioral disorder in rats subjected to transient global cerebral ischemia[J]. Bhave Brain Res, 2007, 177(2): 282-289.
Li M, Chiu JF, Gagne J, et al. Age-related differences in insulinlike growth factor-1 receptor signaling regulates Akt/FOXO3a and ERK/Fos pathways in vascular smooth muscle cells[J]. Cell Physiol, 2008, 217(2): 377-387.
[9]
Aguado F, Rodrigo J, Cacicedo L, et al. Distribution of insulinlike growth factor-1 receptor mRNA in rat brain. Regulation in the hypothalamoneurohypophysial system[J]. Mol Endocrinol, 1993, 11(2): 231-239.
[10]
Wang JM, Hayashi T, Zhang WR, et al. Reduction of ischemic brain injury by topical application of insulin-like growth factor-1 after transient middle cerebral artery occlusion in rats[J]. Brain Res, 2000, 859(2): 381-385.
[11]
Brywe KG, Mallard C, Gustavsson M, et al. IGF-1 neuroprotection in the immature brain after hypoxia-ischem ia, involvement of Akt and GSK3beta?[J]. Eur J Neurosci, 2005, 21(6): 1489-1502.
[12]
Bakos J, Duncko R, Makatsori A, et al. Prenatal immune challenge affects growth, behavior, and brain dopamine in offspring[J]. Ann N Y Acad Sci, 2004, 1018: 281-287.
[13]
Winter B, Juckel G, Voktorov I, et al. Anxious and hyperactive phenotype following brief ischemic episodes in mice[J]. Biol Psychiatry, 2005, 57(10): 1166-1175.
[14]
Fan LW, Lin S, Pang Y, et al. Minocycline attenuates hypoxiaischemia-induced neurological dysfunction and brain injury in the juvenile rat[J]. Eur J Neurosci, 2006, 24(2): 341-350.
[15]
Thomas Tayra J, Kameda M, Yasuhara T, et al. The neuroprotective and neurorescue effects of carbamylated erythropoietin Fc fusion protein (CEPO-Fc) in a rat model of Parkinson's disease[J]. Brain Res, 2013, 1502: 55-70.
[16]
Tatton W, Greenwood C, Salo PT, et al. Transmitter synthesis increases in substantia nigra neurons of the aged mouse[J]. Neurosci Left, 1991, 131(1): 179-182.
[17]
Lin S, Fan LW, Rhodes PG, et al. Intranasal administration of IGF-1 attenuates hypoxic-ischemic brain injury in neonatal rats[J]. Exp Neurol, 2009, 217(2): 361-370.
[18]
Zhu DN, Jia YJ, Wang J, et al. Human insulin-like growth factor 1-transfected umbilical cord blood neural stem cell transplantation improves hypoxic-ischemic brain injury[J]. Neural Regen Res, 2011, 6(19): 1445-1451.
