Biochemical mechanisms of development of neurological disorders in down syndrome: importance for medical rehabilitation

Authors:

Kolcheva Yulia Aleksandrovna – PhD in Medical sciences (Cand. Med. Sci.), Associate Professor of the Department of Pediatrics of the Institute of Additional Professional Education, Albrecht Federal Scientific and Educational Centre of Medkal and Social Expertise and Rehabilitation, 50 Bestuzhevskaya Street, 195067 St. Petersburg, Russian Federation; e-mail: j.kolcheva@mail.ru; https://orcid.org/0000-0003-0250-5478.

Adrianov Andrey Viktorovich – Grand PhD in Medical sciences (Dr. Med. Sci.), Associate Professor, Head of the Department of Pediatrics of the Institute of Additional Professional Education, Albrecht Federal Scientific and Educational Centre of Medical and Social Expertise and Rehabilitation, 50 Bestuzhevskaya Street, 195067 St. Petersburg, Russian Federation; e-mail: adrianov-av@mail.ru; https://orcid.org/0000-0001-8974-1160.

Annotation:

Introduction. Down syndrome is a fairly common genetic disease with multisystem involvement. In recent decades, there has been growing interest in the possible role of oxidative stress and inflammation, as well as the study of biochemical mechanisms in the development of neurological pathology in trisomy 21.

Aim. Identification of the correlation between the severity of dysfunction of mitochondrial enzymes, pro-inflammatory markers in children with Down syndrome and the level of cerebral deficit.

Materials and methods. 17 people (12 girls and 5 boys aged 5 to 8 years) with Down syndrome (complete trisomy of chromosome 21) were examined. The control group consisted of 14 children. All children underwent a detailed clinical and instrumental study with examination by a pediatrician, neurologist, child psychiatrist, neuropsychologist, electroencephalography, Dopplerography of brachiocephalic vessels, MRI of the brain, echocardiography, laboratory blood tests to determine the levels of coenzyme Q10, interleukin 6, interleukin 10, tumor necrosis factor alpha.

Results. We have identified a direct correlation between the severity of neurological deficits in children with Down syndrome and the level of coenzyme Q10, and also established relationships with the following indicators: interleukin 6, interleukin 10, tumor necrosis factor alpha.

Discussion. We have shown that with this pathology, a proxidant state and mitochondrial dysfunction develop, which have an adverse effect on the course of the most important metabolic processes, including the development and functioning of cerebral structures.
The direct correlation we identified between the severity of neurological deficits in children with Down syndrome and the level of coenzyme Q10 is consistent with the literature data, which indicate significantly lower values of coenzyme Q10 in children with Down syndrome. There are isolated publications indicating an imbalance of cytokines in Down syndrome, which is consistent with the results of our study. However, these results require larger studies to confirm this point of view.

Summary. The levels of interleukin 6, interleukin 10, and tumor necrosis factor in such children can be used as biomarkers reflecting the ongoing neurodegenerative process. Coenzyme Q10 in combination with antioxidants may play a positive role in alleviating neurological manifestations in Down syndrome in medical rehabilitation.

List of cited literature:

1. Coskun PE, Busciglio J. Oxidative Stress and Mitochondrial Dysfunction in Down’s Syndrome: Relevance to Aging and Dementia. Curr. Gerontol. Geriatr. 2012(1);1-7. DOI: 10.1155/2012/383170.

2. Ferrari M, Stagi S. Oxidative Stress in Down and Williams-Beuren Syndromes: An Overview. Molecules. 2021;26(11):3139. DOI: 10.3390/molecules26113139.

3. Helguera P, Seiglie J, Rodriguez J, Hanna M, et al. Adaptive Downregulation of Mitochondrial Function in Down Syndrome. Cell Metabolism. 2013(17):132-40. DOI: 10.1016/j.cmet.2012.12.005.

4. Zaki ME, El-Bassyouni HT, Tosson AM, Youness E, et al. Coenzyme Q10 and pro-inflammatory markers in children with Down syndrome: clinical and biochemical aspects. Journal Pediatry. 2017(93):100-4. DOI.org/10.1016/j.jped.2016.04.012.

5. Pallardo FV, Degan P, D’Ischia M, Kelly FJ, et al. Multiple evidence for an early age pro-oxidant state in Down Syndrome patients. Biogerontology. 2006(7):211-20. DOI: 10.1007/s10522-006-9002-5.

6. Barone E, Arena A, Head E, Butterfield DA, et al. Disturbance of redox homeostasis in Down Syndrome: Role of iron dysmetabolism. Free Radical Biology and Medicine. 2018( 114):84-93. DOI: 10.1016/j. freeradbiomed.2017.07.009.

7. Brooksbank BW, Balazs R. Superoxide Dismutase, Glutathione Peroxidase and Lipoperoxidation in Down’s Syndrome Fetal Brain. Developmental Brain Research. 1984(16):37-44. DOI: 10.1016/ s0140-6736(83)91427-7.

8. Busciglio J, Yankner BA. Apoptosis and increased generation of reactive oxygen species in Down’s Syndrome neurons in vitro. Nature Cell Biology. 1995(378):776-
9. DOI: 10.1038/378776a0.

9. Damiano S, Sozio C, La Rosa G, Guida, B, Faraonio R, Santillo M, Mondola P. Metabolism Regulation and Redox State: Insight into the Role of Superoxide Dismutase. International Journal of Molecular Sciences. 2020(21):6606. DOI: 10.3390/ijms21186606.

10. Epstein CJ, Avraham KB, Lovett M, Smith S, et al. Transgenic mice with increased Cu/Zn-superoxide dismutase activity: Animal model of dosage effects in Down syndrome. International Journal of Molecular Sciences. 1987(84):8044-48. DOI: 10.1073/ pnas.84.22.8044.

11. Pagano G, Talamanca AA, Castello G, Cordero MD, et al. Oxidative Stress and Mitochondrial Dysfunction across Broad-Ranging Pathologies: Toward Mitochondria-Targeted Clinical Strategies. Oxidative Medicine and Cellular Longevity. 2014(2014):1-27. DOI: 10.1155/2014/541230.

12. Piccoli C, Izzo A, Scrima R, Bonfiglio F, et al. Chronic pro- oxidative state and mitochondrial dysfunctions are more pronounced in fibroblasts from Down syndrome foeti with congenital heart defects. Human Molecular Genetics. 2012(22):1218-32. DOI: 10.1093/ hmg/dds529.

13. Pallardo FV, Lloret A, Lebel M, D’Ischia M, et al. Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome. Biogerontology. 2010(11): 401-19. DOI: 10.1007/ s10522-010-9269-4.

14. Izzo A, Mollo N, Nitti M, Paladino S, et al. Mitochondrial dysfunction in Down Syndrome: Molecular mechanisms and therapeutic targets. Journal of Molecular Medicine. 2018(24):1-8. DOI: 10.1186/ s10020-018-0004-y.

15. Ponomarenko GN. Fizicheskaya i reabilitatsionnaya meditsina: fundamental’nye osnovy i klinicheskaya praktika [Physical and rehabilitation medicine: fundamental principles and clinical practice]. Fizioterapiya, bal’neologiya i reabilitatsiya [Physiotherapy, balneology and rehabilitation]. 2016;15(6):284-9. DOI: 10.18821/1681-3456-2016-15-6-284-289. (In Russian).

16. Skirmont EI, Golubeva YB, Zimina EL, Lade AS, et al. Nekotorye aspekty ortopedicheskoj reabilitacii detej s cerebral’nym paralichom [Some aspects of orthopaedic rehabilitation for children with cerebral palsy]. Fizicheskaya i reabilitacionnaya medicina [Physical and Rehabilitation Medicine]. 2023;5(2):72-86. DOI: 10.26211/2658-4522-2023-5-2-72-86. (In Russian).