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Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury.
Behav Brain Res. 2018 03 15; 340:1-13.BB

Abstract

Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs). Among the proposed drugs is docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibiting neuroprotective properties. In this study, we utilized an innovative intervention of neonatal NSCs transplantation in combination with DHA injections in order to ameliorate brain damage and promote functional recovery in an experimental model of TBI. Thus, NSCs derived from the subventricular zone of neonatal pups were cultured into neurospheres and transplanted in the cortex of an experimentally controlled cortical impact mouse model of TBI. The effect of NSC transplantation was assessed alone and/or in combination with DHA administration. Motor deficits were evaluated using pole climbing and rotarod tests. Using immunohistochemistry, the effect of transplanted NSCs and DHA treatment was used to assess astrocytic (Glial fibrillary acidic protein, GFAP) and microglial (ionized calcium binding adaptor molecule-1, IBA-1) activity. In addition, we quantified neuroblasts (doublecortin; DCX) and dopaminergic neurons (tyrosine hydroxylase; TH) expression levels. Combined NSC transplantation and DHA injections significantly attenuated TBI-induced motor function deficits (pole climbing test), promoted neurogenesis, coupled with an increase in glial reactivity at the cortical site of injury. In addition, the number of tyrosine hydroxylase positive neurons was found to increase markedly in the ventral tegmental area and substantia nigra in the combination therapy group. Immunoblotting analysis indicated that DHA+NSCs treated animals showed decreased levels of 38kDa GFAP-BDP (breakdown product) and 145kDa αII-spectrin SBDP indicative of attenuated calpain/caspase activation. These data demonstrate that prior treatment with DHA may be a desirable strategy to improve the therapeutic efficacy of NSC transplantation in TBI.

Authors+Show Affiliations

Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon.ER045, Laboratory of Stem Cells, DSST, Lebanese University, Beirut, Lebanon; Department of Biology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon.Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon; American University of Beirut Medical Center Special Kids Clinic, Neurogenetics Program and Division of Pediatric Neurology, Departments of Pediatrics and Adolescent Medicine, Beirut, Lebanon.Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, A.O.U. "Policlinico G. Martino", Via Consolare Valeria, Messina, 98125, Italy.Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. Electronic address: wa12@aub.edu.lb.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon. Electronic address: js61@aub.edu.lb.Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon, Lebanon; Department of Psychiatry, Center for Neuroproteomics and Biomarkers Research, University of Florida, Gainesville, FL, USA. Electronic address: Firasko@gmail.com.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

29126932

Citation

Ghazale, Hussein, et al. "Docosahexaenoic Acid (DHA) Enhances the Therapeutic Potential of Neonatal Neural Stem Cell Transplantation post-Traumatic Brain Injury." Behavioural Brain Research, vol. 340, 2018, pp. 1-13.
Ghazale H, Ramadan N, Mantash S, et al. Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury. Behav Brain Res. 2018;340:1-13.
Ghazale, H., Ramadan, N., Mantash, S., Zibara, K., El-Sitt, S., Darwish, H., Chamaa, F., Boustany, R. M., Mondello, S., Abou-Kheir, W., Soueid, J., & Kobeissy, F. (2018). Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury. Behavioural Brain Research, 340, 1-13. https://doi.org/10.1016/j.bbr.2017.11.007
Ghazale H, et al. Docosahexaenoic Acid (DHA) Enhances the Therapeutic Potential of Neonatal Neural Stem Cell Transplantation post-Traumatic Brain Injury. Behav Brain Res. 2018 03 15;340:1-13. PubMed PMID: 29126932.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Docosahexaenoic acid (DHA) enhances the therapeutic potential of neonatal neural stem cell transplantation post-Traumatic brain injury. AU - Ghazale,Hussein, AU - Ramadan,Naify, AU - Mantash,Sara, AU - Zibara,Kazem, AU - El-Sitt,Sally, AU - Darwish,Hala, AU - Chamaa,Farah, AU - Boustany,Rose Mary, AU - Mondello,Stefania, AU - Abou-Kheir,Wassim, AU - Soueid,Jihane, AU - Kobeissy,Firas, Y1 - 2017/11/07/ PY - 2016/08/29/received PY - 2017/10/27/revised PY - 2017/11/06/accepted PY - 2017/11/12/pubmed PY - 2018/9/5/medline PY - 2017/11/12/entrez KW - Docosahexaenoic acid KW - Motor function KW - Neural stem cells KW - Neurogenesis KW - Reactive gliosis KW - Traumatic brain injury SP - 1 EP - 13 JF - Behavioural brain research JO - Behav. Brain Res. VL - 340 N2 - Traumatic Brain Injury (TBI) is a major cause of death and disability worldwide with 1.5 million people inflicted yearly. Several neurotherapeutic interventions have been proposed including drug administration as well as cellular therapy involving neural stem cells (NSCs). Among the proposed drugs is docosahexaenoic acid (DHA), a polyunsaturated fatty acid, exhibiting neuroprotective properties. In this study, we utilized an innovative intervention of neonatal NSCs transplantation in combination with DHA injections in order to ameliorate brain damage and promote functional recovery in an experimental model of TBI. Thus, NSCs derived from the subventricular zone of neonatal pups were cultured into neurospheres and transplanted in the cortex of an experimentally controlled cortical impact mouse model of TBI. The effect of NSC transplantation was assessed alone and/or in combination with DHA administration. Motor deficits were evaluated using pole climbing and rotarod tests. Using immunohistochemistry, the effect of transplanted NSCs and DHA treatment was used to assess astrocytic (Glial fibrillary acidic protein, GFAP) and microglial (ionized calcium binding adaptor molecule-1, IBA-1) activity. In addition, we quantified neuroblasts (doublecortin; DCX) and dopaminergic neurons (tyrosine hydroxylase; TH) expression levels. Combined NSC transplantation and DHA injections significantly attenuated TBI-induced motor function deficits (pole climbing test), promoted neurogenesis, coupled with an increase in glial reactivity at the cortical site of injury. In addition, the number of tyrosine hydroxylase positive neurons was found to increase markedly in the ventral tegmental area and substantia nigra in the combination therapy group. Immunoblotting analysis indicated that DHA+NSCs treated animals showed decreased levels of 38kDa GFAP-BDP (breakdown product) and 145kDa αII-spectrin SBDP indicative of attenuated calpain/caspase activation. These data demonstrate that prior treatment with DHA may be a desirable strategy to improve the therapeutic efficacy of NSC transplantation in TBI. SN - 1872-7549 UR - https://www.unboundmedicine.com/medline/citation/29126932/Docosahexaenoic_acid__DHA__enhances_the_therapeutic_potential_of_neonatal_neural_stem_cell_transplantation_post_Traumatic_brain_injury_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0166-4328(17)31810-7 DB - PRIME DP - Unbound Medicine ER -