Sains Malaysiana 49(2)(2020): 375-382

http://dx.doi.org/10.17576/jsm-2020-4902-15

The Effect of Intranasal Administration of ACTH Analogue Toward Neural Progenitor/Stem Cells Proliferation after Traumatic Brain Injury

(Kesan Administrasi Intranasal Analog ACTH terhadap Proliferasi Neural Progenitor/Sel Stem selepas Kecederaan Trauma Otak)

MICHAEL LUMINTANG LOE¹*, RR. SUZY INDHARTY¹, ANDRE MP SIAHAAN¹, STEVEN TANDEAN¹ & WIBI RIAWAN²

¹Department of Neurosurgery, Faculty of Medicine, Universitas Sumatera Utara/Haji Adam Malik General Hospital, Medan 20155, Indonesia

 ²Department of Biochemistry, Faculty of Medicine, University of Brawijaya, Malang 65145, Indonesia

Diserahkan: 7 September 2019/Diterima: 24 Oktober 2019

ABSTRACT

Traumatic brain injury (TBI) is a major health problem because of its high mortality and long-term disability worldwide. Neural progenitor/stem cells (NPSCs) that survive in certain parts of the brain, enable brain to produce new neurons and glia. ACTH_4-10Pro⁸-Gly⁹-Pro¹⁰ has a modulation effect on the expression and activation of the BDNF/TrkB system in the hippocampus area. The BDNF/TrkB pathway system is a potential therapeutic target toward NPSCs proliferation after TBI. Thirty male Sprague-Dawley rats were divided into three groups, i.e A=sham-operated controls; B=TBI; C=TBI+intranasal ACTH_4-10Pro⁸-Gly⁹-Pro¹⁰ administration. After 24 h, rats' brains were immunohistochemically processed, to observe the number of cells expressing mBDNF, TrkB, and SOX2 in the subgranular zone(SGZ) of the hippocampus dentate gyrus(DG). Data were analyzed with SPSS 17, ANOVA, Post Hoc Tukey HSD test, with p value < 0,05. Mean expression of BDNF group C=16.33 ± 2.83 increased significantly compared to group A=8.33 ± 1.32(p=0.0001) and group B=5.89 ±1.69(p=0.0001). Mean expression of TrkB group C=17.00 ± 1.58 increased significantly compared to group A=4.33 ± 1.73(p=0.0001) and group B=5.89 ± 2.47(p=0.0001), TrkB expression in group B increased insignificantly compared to group A (p= 0.234).  Mean expression of SOX2 in group C=12.56 ± 2.07 increased significantly compared to group B = 8.89 ±2.318(p=0.0001) and group A=4.89 ± 2.42(p=0.0001). ACTH_4-10Pro⁸-Gly⁹-Pro¹⁰ can increase the expression of BDNF and TrkB, and the proliferation of NPSCs in the subgranular zone (SGZ) of the hippocampus dentate gyrus (DG).

Keywords: ACTH; BDNF; neural stem cells; SOX2; TrkB; SEMAX^Ò; traumatic brain injury

ABSTRAK

Kecederaan trauma otak (TBI) adalah masalah kesihatan utama di seluruh dunia kerana kadar motaliti yang tinggi dan kecacatan jangka panjang. Neural progenitor/sel stem (NPSCs) yang bertahan pada bahagian tertentu otak, membolehkan otak menghasilkan sel neuron dan glia baru. ACTH_4-10Pro⁸-Gly⁹-Pro¹⁰ mempunyai kesan modulasi pada ekspresi dan pengaktifan sistem BDNF/TrkB di kawasan hipokampus. Sistem BDNF/TrkB merupakan sasaran terapeutik yang berpotensi ke arah proliferasi NPSC selepas TBI. Tiga puluh tikus Sprague-Dawley jantan dibahagikan kepada tiga kumpulan, iaitu A=kawalan negatif; B=TBI; C=TBI+ACTH_4-10Pro⁸-Gly⁹-Pro¹⁰ intranasal. Selepas 24 jam, otak tikus diproses secara imunohistokimia untuk melihat bilangan sel yang mengekspresikan mBDNF, TrkB, dan SOX2 pada subgranular zone(SGZ) daripada hipokampus dentat girus (DG). Data dianalisis dengan ujian SPSS 17, ANOVA, Post Hoc Tukey HSD, dengan nilai p <0.05. Ekspresi BDNF kumpulan C=16.33±2.83 meningkat secara signifikan berbanding kumpulan A=8.33±1.32(p=0.0001), dan kumpulan B=5.89 ±1.69(p=0.0001). Secara keseluruhan ekspresi TrkB kumpulan C =17.00 ±1.58 meningkat secara signifikan berbanding kumpulan A=4.33±1.73(p=0.0001) dan kumpulan B=5.89±2.47(p=0.0001), ekspresi TrkB pada kumpulan B meningkat tidak signifikan dibandingkan dengan kumpulan A (p= 0.234). Rata-rata ekspresi SOX2 kumpulan C=12.56±2.07 meningkat secara signifikan dibandingkan dengan kumpulan B=8.89±2.318(p=0.0001) dan kumpulan A=4.89±2.42(p=0.0001). ACTH_4-10Pro⁸-Gly⁹-Pro¹⁰ dapat meningkatkan ekspresi BDNF dan TrkB serta meningkatkan proliferasi NPSCs pada zon subgranulr (SGZ) daripada hipokampus dentat girus (DG).

Kata kunci: ACTH; BDNF; kecederaan trauma otak; sel stem neural; SEMAX^Ò; SOX2; TrkB

RUJUKAN

Agapova, T.Y., Agniullin, Y.V., Shadrina, M.I., Shram, S.I., Slominsky, P.A., Lymborska, S.A. & Myasoedov, N.F. 2007. Neurotrophin gene expression in rat brain under the action of semax, an analogue of ACTH_4-10. Neuroscience Letters 417(2): 201-205.

Atwal, J.K., Massie, B., Miller, F.D. & Kaplan, D.R. 2000. The TrkB-Shc site signals neuronal survival and local axon growth via MEK and P13-Kinase. Neuron 27(2): 265-277.

Cacialli, P., Palladino, A. & Lucini, C. 2018. Role of brain-derived neurotrophic factor during the regenerative response after traumatic brain injury in adult zebrafish. Neural Regeneration Research 13(6): 941-944.

Carney, N., Totten, A.M., O'Reilly, C., Ullman, J.S., Hawryluk, G.W.J., Bell, M.J., Bratton, S.L., Chesnut, R., Harris, O.A., Kissoon, N., Rubiano, A.M., Shutter, L., Tasker, R.C., Vavilala, M.S., Wilberger, J., Wright, D.W. & Ghajar, J. 2016. Guidelines for the Management of Severe Traumatic Brain Injury. 4th ed. New York: Brain Trauma Foundation. p. 244.

Centers for Disease Control and Prevention. 2015. Report to Congress on Traumatic Brain Injury in the United States: Epidemiology and Rehabilitation. Atlanta, GA: National Center for Injury Prevention and Control; Division of Unintentional Injury Prevention.

Conte, V., Raghupathi, R., Watson, D.J., Fujimoto, S., Royo, C., Marklund, N., Stocchetti, N. & McIntosh, T.K. 2009. TrkB gene transfer does not alter hippocampal neuronal loss and cognitive deficits following traumatic brain injury in mice. Restor. Neurol. Neurosci. 26(1): 45-56.

Dewan, M.C., Rattani, A., Gupta, S., Baticulon, R.E., Hung, Y-C., Punchak, M., Agrawal, A., Adeleye, A.O., Shrime, M.G., Rubiano, A.M. & Rosenfeld, J.V. 2018. Estimating the global incidence of traumatic brain injury. Journal of Neurosurgery 130(4): 1080-1097.

Dolotov, O.V., Karpenko, E.A., Inozemtseva, L.S., Seredenina, T.S., Levitskaya, N.G., Rozyczka, J., Dubynina, E.V., Novosadova, E.V., Andreeva, L.A., Alfeeva, L.Y., Kamensky, A.A., Grivennikov, I.A., Myasoedov, N.F. & Engele, J. 2006. Semax, an Analog of ACTH(4-10) with cognitive effects, regulates BDNF and TrkB Expression in the rat hippocampus. Brain Research 1117(1): 54-60.

Faigle, R. & Song, H.J. 2013. Signaling mechanisms regulating adult neural stem cells and neurogenesis. Biochimica et Biophysica Acta(BBA) - General Subjects 1830(2): 2435-2448. https://doi.org/10.1016/j.bbagen.2012.09.002.

Failla, M.D., Conley, Y.P. & Wagner, A.K. 2016. Brain-derived neurotrophic factor (BDNF) in traumatic brain injury-related mortality: Interrelationships between genetics and acute systemic and central nervous system BDNF profiles. Neurorehabilitation and Neural Repair 30(1): 83-93.

Faried, A., Bachani, A.M., Sendjaja, A.N., Hung, Y.W. & Arifin, M.Z. 2017. Characteristics of moderate and severe traumatic brain injury of motorcycle crashes in Bandung, Indonesia. World Neurosurgery 100(4): 195-200. https://doi.org/10.1016/j.wneu.2016.12.133.

Gage, F.H. & Temple, S. 2013. Neural stem cells: Generating and regenerating the brain. Neuron 80(3): 588-601. https://doi.org/10.1016/j.neuron.2013.10.037.

Galgano, M., Toshkezi, G., Qiu, X.C., Russell, T., Chin, L. & Zhao, L-R. 2017. Traumatic brain injury: Current treatment strategies and future endeavors. Cell Transplantation 26(7): 1118-1130.

Gao, X. & Chen, J.H. 2009. Conditional knockout of brain-derived neurotrophic factor in the hippocampus increases death of adult-born immature neurons following traumatic brain injury. Journal of Neurotrauma 26(8): 1325-1335.

Girgis, F., Pace, J., Sweet, J. & Miller, J.P. 2016. Hippocampal neurophysiologic changes after mild traumatic brain injury and potential neuromodulation treatment approaches. Frontiers in Systems Neuroscience 10 (February). https://doi.org/10.3389/fnsys.2016.00008.

Gupta, V., You, Y., Gupta, V., Klistorner, A. & Graham, S. 2013. TrkB receptor signalling: Implications in neurodegenerative, psychiatric and proliferative disorders. International Journal of Molecular Sciences 14(5): 10122-10142.

Hicks, R.R., Zhang, L., Dhillon, H.S., Prasad, M.R. & Seroogy, K.B. 1998. Expression of TrkB MRNA is altered in rat hippocampus after experimental brain trauma. Molecular Brain Research 59(2): 264-268.

Jin, K.L., Sun, Y.J., Xie, L., Peel, A., Mao, X.O., Batteur, S. & Greenberg, D.A. 2003. Directed migration of neuronal precursors into the ischemic cerebral cortex and striatum. Molecular and Cellular Neuroscience 24(1): 171-189. https://doi.org/10.1016/S1044-7431(03)00159-3.

Kaplan, G.B., Vasterling, J.J. & Vedak, P.C. 2010. Brain-derived neurotrophic factor in traumatic brain injury, post-traumatic stress disorder, and their comorbid conditions: Role in pathogenesis and treatment. Behavioural Pharmacology 21(5-6): 427-437. https://doi.org/10.1097/FBP.0b013e32833d8bc9.

Koroleva, S.V. & Myasoedov, N.F. 2018. Semax as a universal drug for therapy and research. Biology Bulletin 45(6): 589-600. https://doi.org/10.1134/S1062359018060055.

Lindvall, O. & Kokaia, Z. 2015. Neurogenesis following stroke affecting the adult brain. Cold Spring Harb. Perspect. Biol. 7(11): a019034.

Loe, M.L. & Maliawan, S. 2019. Spontaneous recovery of medial prefrontal syndrome following giant olfactory groove meningioma resection: A case report. Bali Medical Journal 8(2): 287-291. https://doi.org/10.15562/bmj.v8i2.1454.

Medvedeva, E.V., Dmitrieva, V.G., Povarova, O.V., Limborska, S.A., Skvortsova, V.I., Myasoedov, F.N. & Dergunova, L.V. 2013. Effect of Semax and its C-Terminal fragment Pro-Gly-Pro on the expression of VEGF family genes and their receptors in experimental focal ischemia of the rat brain. Journal of Molecular Neuroscience 49(2): 328-333. https://doi.org/10.1007/s12031-012-9853-y.

Numakawa, T., Suzuki, S., Kumamaru, E., Adachi, N., Richards, M. & Kunugi, H. 2010. BDNF function and intracellular signaling in neurons. Histol. Histopathol. 25: 237-258.

O’Dell, D.M., Raghupathi, R., Crino, P.B., Eberwine, J.H. & McIntosh, T.K. 2000. Traumatic brain injury alters the molecular fingerprint of TUNEL-positive cortical neurons in vivo: A single-cell analysis. The Journal of Neuroscience: The Official Journal of the Society for Neuroscience 20(13): 4821-4828.

Poduslo, J.F. & Curran, G.L. 1996. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Molecular Brain Research 36(2): 280-286.

Prins, M., Greco, T., Alexander, D. & Giza, C.C. 2013. The pathophysiology of traumatic brain injury at a glance. Disease Models & Mechanisms 6(6): 1307-1315.

Rabinowitz, A.R. & Levin, H.S. 2014. Cognitive sequelae of traumatic brain injury. The Psychiatric Clinics of North America 37(1): 1-11.

Rolfe, A. & Sun, D. 2015. Stem cell therapy in brain trauma: Implications for repair and regeneration of injured brain in experimental TBI models. In Brain Neurotrauma: Molecular, Neuropsychological, and Rehabilitation Aspects, edited by Kobeissy, F.H. Boca Raton: CRC Press/Taylor & Francis.

Sandhir, R., Onyszchuk, G. & Berman, N.E.J. 2008. Exacerbated glial response in the aged mouse hippocampus following controlled cortical impact injury. Experimental Neurology 213(2): 372-380.

Seo, D.E., Shin, S.D., Song, K.J., Ro, Y.S., Hong, K.J. & Park, J.H. 2018. Effect of hypoxia on mortality and disability in traumatic brain injury according to shock status: A cross-sectional analysis. The American Journal of Emergency Medicine 12: S0735675718309847. https://doi.org/10.1016/j.ajem.2018.12.022.

Sun, D. 2014. The potential of endogenous neurogenesis for brain repair and regeneration following traumatic brain injury. Neural Regeneration Research 9(7): 688-692.

Urrea, C., Castellanos, D.A., Sagen, J., Tsoulfas, P., Bramlett, H.M. & Dietrich, W.D. 2006. Widespread cellular proliferation and focal neurogenesis after traumatic brain injury in the rat. Res. Neurology and Neuroscience 25: 65-76.

Wolf, J.A., Johnson, B.N., Johnson, V.E., Putt, M.E., Browne, K.D., Mietus, C.J., Brown, D.P., Wofford, K.L., Smith, D.H., Grady, M.S., Cohen, A.S. & Cullen, D.K. 2017. Concussion induces hippocampal circuitry disruption in swine. Journal of Neurotrauma 34(14): 2303-2314. https://doi.org/10.1089/neu.2016.4848.

Zhang, C-L., Zou, Y.H., He, W.M., Gage, F.H. & Evans, R.M. 2008. A role for adult TLX-positive neural stem cells in learning and behaviour. Nature 451(7181): 1004-1007. https://doi.org/10.1038/nature06562.

Zhang, Y.H., Xian, X.C. & Nicol, G.D. 2008. Brain-derived neurotrophic factor enhances the excitability of rat sensory neurons through activation of the P75 neurotrophin receptor and the sphingomyelin pathway. The Journal of Physiology 586(13): 3113-3127. https://doi.org/10.1113/jphysiol.2008.152439.

Zheng, W.M., ZhuGe, Q.C., Zhong, M., Chen, G.R., Shao, B., Wang, H., Mao, X.O., Xie, L., & Jin, K.L. 2013. Neurogenesis in adult human brain after traumatic brain injury. Journal of Neurotrauma 30(22): 1872-1880. https://doi.org/10.1089/neu.2010.1579.

Zuccato, C., Marullo, M., Vitali, B., Tarditi, A., Mariotti, C., Valenza, M., Lahiri, N., Wild, E.J., Sassone, J., Ciammola, A., Bachoud-Lèvi, A.C., Tabrizi, S.J., Di Donato, S. & Cattaneo, E. 2011. Brain-derived neurotrophic factor in patients with Huntington’s Disease. PLoS ONE 6(8): e22966. https://doi.org/10.1371/journal.pone.0022966.

*Pengarang untuk surat-menyurat; email: dr.michael.lumintang@gmail.com