The effect of ACTH4-10Pro8Gly9Pro10 and HMG-CoA reductase inhibitor in moderate head injury: clinical outcome and serum Bcl-2 concentration
Background: An important component of brain tissue damage is apoptotic neuronal death. Bcl-2 is an anti-apoptotic protein, which inhibits the intrinsic pathway of apoptosis. ACTH4-10Pro8Gly9Pro10 and HMG-CoA reductase inhibitor are known for their neuroprotective effects. This study aimed to compare the effect of standard therapy, ACTH4-10Pro8Gly9Pro10, and HMG-CoA reductase inhibitor (simvastatin 40 mg/day) on serum Bcl-2 levels, clinical outcome, and reduction of hospital stay.
Methods: Sixty subjects with moderate head injury without any indication for surgery were taken consecutively and separated into three groups: standard treatment only (control group), standard treatment combined with ACTH4-10Pro8Gly9Pro10, and standard treatment combined with inhibitor of HMG-CoA reductase. Blood samples were taken on day-1 and day-5 from each subject for measurement of Bcl-2 concentration. Barthel Index and MMSE were measured at discharge and hospital length of stay was noted. Difference in mean was analyzed with one way ANOVA and correlation between Bcl-2 and clinical outcome was measured with Pearson correlation test.
Results: Bcl-2 serum levels on day-1 and day-5 were tespectively as follows: in control group were 1.39 ± 0.75 and 1.48 ± 0.77 ng/mL; in ACTH4-10Pro8Gly9Pro10 group 1.39 ± 0.70 and 3.70 ± 1.01 ng/mL which was significantly higher compared to other groups and associated with the shortest length of stay. In simvastatin group, 1.53 ± 0.55 and 2.17 ± 0.56 ng/mL. We found the length of stay in the ACTH4-10Pro8Gly9Pro10 group to be significantly shorter (p < 0.001). The correlation of clinical outcome (Barthel index and MMSE) with serum Bcl-2 levels was not significant.
Conclusion: ACTH4-10Pro8Gly9Pro10 significantly increased serum Bcl-2 concentration in head injury and associated with shorter length of stay. An increase of serum Bcl-2 concentration was also found in simvastatin group, but it was not significant. (Med J Indones. 2013;22:221-6. doi: 10.13181/mji.v22i4.604)
Faul M, Xu L, Wald MM, Coronado V. Traumatic brain injury in the United States: emergency department visits, hospitalizations and deaths 2002–2006. Atlanta, GA: CDC, National Center for Injury Prevention and Control; 2010.
Marshall LF. Head injury: recent past, present, and future. Neurosurgery. 2000;47(3):546-61. http://dx.doi.org/10.1097/00006123-200009000-00002
Yakovlev AG, Faden AI. Caspase-dependent apoptotic pathways in CNS injury. Mol Neurobiol. 2001;24(1-3):131-44. http://dx.doi.org/10.1385/MN:24:1-3:131
Hockenbery D, Nunez G, Milliman C, Schreiber RD, Korsmeyer SJ. Bcl-2 is an inner mitochondrial membrane protein that blocks programmed cell death. Nature. 1990;348(6299):334-6. http://dx.doi.org/10.1038/348334a0
Danial NN, Korsmeyer SJ. Cell death: critical control points. Cell. 2004;116(2):205-19. http://dx.doi.org/10.1016/S0092-8674(04)00046-7
Shacka JJ, Roth KA. Regulation of neuronal cell death and neurodegeneration by members of the Bcl-2 family: therapeutic implication. Curr Drug Targets CNS Neurol Disord. 2005;4(1):25-39. http://dx.doi.org/10.2174/1568007053005127
Clark RS, Chen J, Watkins SC, Kochanek PM, Chen M, Stetler RA, et al. Apoptosis-suppressor gene bcl-2 expression after traumatic brain injury in rats. J Neurosci. 1997;17(23):9172-82.
Chen J, Simon RP, Nagayama T, Zhu R, Loeffert JE, Watkins SC, et al. Suppression of endogenous bcl-2 expression by antisense treatment exacerbates ischemic neuronal death. J Cereb Blood Flow Metab. 2000;20(7):1033-9. http://dx.doi.org/10.1097/00004647-200007000-00002
Skvortsova VI, Gusev EI, Efremova NM, Gubskaya OB, Zhuravleva EY, Myasoedov NF. Effects of neuropeptide Semax (ACTH 4-10) in acute ischemic stroke. European Journal of Neurology. 2002;9 Suppl 2:164.
Balduini W, Mazzoni E, Carloni S, De Simoni MG, Perego C, Sironi L, et al. Prophylactic but not delayed administration of simvastatin protects against long-lasting cognitive and morphological consequences of neonatal hypoxic-ischemic brain injury, reduces interleukin-1beta and tumor necrosis factor-alpha mRNA induction, and does. Stroke. 2003;34(8):2007-12.
Vaughan CJ, Delanty N, Basson CT. Do statins afford neuroprotection in patients with cerebral ischaemia and stroke? CNS Drugs. 2001;15(8):589-96. http://dx.doi.org/10.2165/00023210-200115080-00002
Jick H, Zornberg GL, Jick SS, Seshadri S, Drachman DA. Statins and the risk of dementia. Lancet. 2000;356(9242):1627-31. http://dx.doi.org/10.1016/S0140-6736(00)03155-X
Zacco A, Togo J, Spence K, Ellis A, Lloyd D, Furlong S, et al. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors protect cortical neurons from excitotoxicity. J Neurosci. 2000;23(11):104-11.
Johnson-Anuna LN, Eckert GP, Keller JH, Igbavboa U, Franke C, Fechner T, et al. Chronic administration of statins alters multiple gene expression patterns in mouse cerebral cortex. J Pharmacol Exp Ther. 2000;312(2):786-93. http://dx.doi.org/10.1124/jpet.104.075028
Kraus JF, McArthur DL. Epidemiology of head injury. In: Cooper PR, editor. Head injury. Baltimore: Williams & Wilkins; 2003. p. 1-26.
Bruns J, Hauser WA. The epidemiology of traumatic brain injury: a review. Epilepsia. 2003;44 Suppl 10:2-10. http://dx.doi.org/10.1046/j.1528-1157.44.s10.3.x
Uzan M, Erman H, Tanriverdi T, Sanus GZ, Kafadar A, Uzun H. Evaluation of apoptosis in cerebrospinal fluid of patients with severe head injury. Acta Neurochir (Wien). 2006;148(11):1157-64. http://dx.doi.org/10.1007/s00701-006-0887-1
Wagner AK, McCullough EH, Niyonkuru C, Ozawa H, Loucks TL, Dobos JA, et al. Acute serum hormone levels: characterization and prognosis after severe traumatic brain injury. J Neurotrauma. 2011;28(6):871-88. http://dx.doi.org/10.1089/neu.2010.1586
Johson-Anuna LN, Eckert GP, Franke C, Igbavboa U, Muller WE, Wood WG. Simvastatin protects neuron from cytotoxicity by up-regulating Bcl-2 m-RNA and protein. J Neurochem. 2007;101(1):77-86. http://dx.doi.org/10.1111/j.1471-4159.2006.04375.x
Franke C, Nöldner M, Abdel-Kader R, Johnson-Anuna LN, Wood G, Müller WE, et al. Bcl-2 upregulation and neuroprotection in guinea pig brain following chronic simvastatin treatment. Neurobiol Dis. 2007;25(2):438-45. http://dx.doi.org/10.1016/j.nbd.2006.10.004
Clark RS, Kochanek PM, Adelson PD, Bell M, Carcillo J, Chen M, et al. Increases in bcl-2 protein in cerebrospinal fluid and evidence for programmed cell death in infants and children after severe traumatic brain injury. J Pediatr. 2000;137(2):197-204. http://dx.doi.org/10.1067/mpd.2000.106903
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