The influence of acelysin and nimotop on the cellular response of the hippocampus during the dynamics of experimental subarachnoid hemorrhage

Authors

DOI:

https://doi.org/10.14739/2310-1237.2023.2.279845

Keywords:

subarachnoid hemorrhage, cerebral aneurysm rupture, GFAP, NeuN, CASP3

Abstract

Aim. Immunohistochemical study of rat hippocampal neurons and astrocytes at different time-points of experimental brain hemorrhage treated with acelysin and nimotop.

Materials and methods. Subarachnoid hemorrhage (SAH) was modeled according to R. V. Dudhani et al. using 35 Wistar rats which were divided into 7 groups. Animals of the 1st and 2nd groups, for 4 and 7 days respectively received acelysin at a dose of 15 mg/kg once a day; animals of the 3rd and 4th groups received nimodipine at a dose of 0.3 mg/kg every 8 hours for 4 and 7 days. In groups 5th and 6th (control), SAH was modeled without treatment with observation periods of 4 and 7 days, respectively. The 7th group consisted of intact animals. Hippocampal CA1 fields were studied immunohistochemically evaluating the expression of CASP3, NeuN, GFAP by the relative area of immunostaining in ImageJ.

Results. CASP3 expression in hippocampal neurons increases by 2.3 and 5.7 times on day 4 and by 1.8 and 3.9 times on day 7 of experimental SAH (groups 1–4) compared to intact group. GFAP expression increases in all observation groups compared to intact animals with the maximum values in the 5th group – by 8.14 times. The dynamics of NeuN expression in hippocampal neurons when using acelysin and nimotop corresponds to the inverse dynamics of CASP3 expression. The NeuN expression increases maximally on the 7th day of acelysin use and is equal to 91.76 % of the intact group values.

Conclusions. The experimental SAH is accompanied by a change in the expression of CASP3, NeuN in neurons and GFAP in astrocytes. The use of acelysin and nimotop leads to decrease in CASP3 expression in hippocampal neurons on the 4th day by 3.82 and 1.54 times compared to control group, and on the 7th day by 4.00 and 1.84 times, respectively, which reflects the positive effect of the therapy on the prevention of apoptotic death of hippocampal neurons. Compared with nimotop, the use of acelicine significantly increases the expression of NeuN on day 4 and 7 – by 1.84 and 1.95 times, respectively, which indicates a more pronounced neuroprotective effect of acelysin on hippocampal neurons in SAH. Increased GFAP expression reflects the dynamic reactive remodeling of astrocytes, while the use of acelysin and nimotop does not affect the reduction of GFAP levels on days 4 and 7 of SAH and their return to baseline values. The results of the present experimental study provide a theoretical justification of the feasibility of including metabolitotropic drugs in the basic therapy of SAH.

Author Biographies

O. Yu. Polkovnikov, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

MD, PhD, Associate Professor of the Department of Disaster Medicine, Military Medicine and Neurosurgery

S. I. Tertyshnyi, Zaporizhzhia State Medical and Pharmaceutical University, Ukraine

д-р мед. наук, професор, зав. каф. патологічної анатомії і судової медицини

References

Darkwah Oppong, M., Buffen, K., Pierscianek, D., Herten, A., Ahmadipour, Y., Dammann, P., Rauschenbach, L., Forsting, M., Sure, U., & Jabbarli, R. (2019). Secondary hemorrhagic complications in aneurysmal subarachnoid hemorrhage: when the impact hits hard. Journal of neurosurgery, 1-8. Advance online publication. https://doi.org/10.3171/2018.9.JNS182105

Weimer, J. M., Jones, S. E., & Frontera, J. A. (2017). Acute Cytotoxic and Vasogenic Edema after Subarachnoid Hemorrhage: A Quantitative MRI Study. AJNR. American journal of neuroradiology, 38(5), 928-934. https://doi.org/10.3174/ajnr.A5181

De Oliveira Manoel, A. L., Goffi, A., Marotta, T. R., Schweizer, T. A., Abrahamson, S., & Macdonald, R. L. (2016). The critical care management of poor-grade subarachnoid haemorrhage. Critical care, 20, 21. https://doi.org/10.1186/s13054-016-1193-9

Geraghty, J. R., & Testai, F. D. (2017). Delayed Cerebral Ischemia after Subarachnoid Hemorrhage: Beyond Vasospasm and Towards a Multifactorial Pathophysiology. Current atherosclerosis reports, 19(12), 50. https://doi.org/10.1007/s11883-017-0690-x

Kerr, N., Lee, S. W., Perez-Barcena, J., Crespi, C., Ibañez, J., Bullock, M. R., Dietrich, W. D., Keane, R. W., & de Rivero Vaccari, J. P. (2018). Inflammasome proteins as biomarkers of traumatic brain injury. PloS one, 13(12), e0210128. https://doi.org/10.1371/journal.pone.0210128

Rodríguez-Rodríguez, A., Egea-Guerrero, J. J., Ruiz de Azúa-López, Z., & Murillo-Cabezas, F. (2014). Biomarkers of vasospasm development and outcome in aneurysmal subarachnoid hemorrhage. Journal of the neurological sciences, 341(1-2), 119-127. https://doi.org/10.1016/j.jns.2014.04.020

Subarachnoid haemorrhage caused by a ruptured aneurysm: diagnosis and management, NICE guideline NG228. (2022, November 23). https://www.nice.org.uk/guidance/ng228

Ditz, C., Machner, B., Schacht, H., Neumann, A., Schramm, P., Tronnier, V. M., & Küchler, J. (2021). Effects of post-interventional antiplatelet therapy on angiographic vasospasm, delayed cerebral ischemia, and clinical outcome after aneurysmal subarachnoid hemorrhage: a single-center experience. Neurosurgical review, 44(5), 2899-2912. https://doi.org/10.1007/s10143-021-01477-6

Belenichev, I. F., Bak, P. G., Popazova, O. O., Bukhtiyarova, N. V., & Yadlovsky, O. Yu. (2022). Nitric oxide-dependent mechanism of endothelial dysfunction formation is a promising target link for pharmacological management. Biopolymers and Cell, 38(3), 145-157. http://dx.doi.org/10.7124/bc.000A79

Enriquez-Marulanda, A., Salem, M. M., Ravindran, K., Ascanio, L. C., Maragkos, G. A., Gomez-Paz, S., Alturki, A. Y., Ogilvy, C. S., Thomas, A. J., & Moore, J. (2019). Effect of Premorbid Antiplatelet Medication Use on Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage: A Propensity Score-matched Study. Cureus, 11(9), e5603. https://doi.org/10.7759/cureus.5603

Wallace, A. N., Kayan, Y., Almandoz, J. E. D., Mulder, M., Milner, A. A., Scholz, J. M., Stiernagle, K., Contestabile, E., & Tipps, M. E. (2020). Dual antiplatelet therapy does not improve outcomes after aneurysmal subarachnoid hemorrhage compared with aspirin monotherapy. Clinical neurology and neurosurgery, 195, 106038. https://doi.org/10.1016/j.clineuro.2020.106038

Yang, S., Liu, T., Wu, Y., Xu, N., Xia, L., & Yu, X. (2021). The Role of Aspirin in the Management of Intracranial Aneurysms: A Systematic Review and Meta-Analyses. Frontiers in neurology, 12, 646613. https://doi.org/10.3389/fneur.2021.646613

Dudhani, R. V., Kyle, M., Dedeo, C., Riordan, M., & Deshaies, E. M. (2013). A low mortality rat model to assess delayed cerebral vasospasm after experimental subarachnoid hemorrhage. Journal of visualized experiments : JoVE, (71), e4157. https://doi.org/10.3791/4157

Zhang, B., Zhang, H. X., Shi, S. T., Bai, Y. L., Zhe, X., Zhang, S. J., & Li, Y. J. (2019). Interleukin-11 treatment protected against cerebral ischemia/reperfusion injury. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 115, 108816. https://doi.org/10.1016/j.biopha.2019.108816

Teertam, S. K., & Phanithi, P. B. (2022). Up-regulation of Sirtuin-1/autophagy signaling in human cerebral ischemia: possible role in caspase-3 mediated apoptosis. Heliyon, 8(12), e12278. https://doi.org/10.1016/j.heliyon.2022.e12278

Li, R., Zhao, M., Yao, D., Zhou, X., Lenahan, C., Wang, L., Ou, Y., & He, Y. (2022). The role of the astrocyte in subarachnoid hemorrhage and its therapeutic implications. Frontiers in immunology, 13, 1008795. https://doi.org/10.3389/fimmu.2022.1008795

Evans, D., Flood, R., Davies, O., Wareham, J., & Mortimer, A. (2021). Impact of Intravenous Aspirin Administration on Ventriculostomy-Associated Hemorrhage in Coiled Acute Subarachnoid Hemorrhage Patients. Neurointervention, 16(2), 141-148. https://doi.org/10.5469/neuroint.2021.00150

Huang, W. Y., Saver, J. L., Wu, Y. L., Lin, C. J., Lee, M., & Ovbiagele, B. (2019). Frequency of Intracranial Hemorrhage With Low-Dose Aspirin in Individuals Without Symptomatic Cardiovascular Disease: A Systematic Review and Meta-analysis. JAMA neurology, 76(8), 906-914. https://doi.org/10.1001/jamaneurol.2019.1120

Can, A., Rudy, R. F., Castro, V. M., Yu, S., Dligach, D., Finan, S., Gainer, V., Shadick, N. A., Savova, G., Murphy, S., Cai, T., Weiss, S. T., & Du, R. (2018). Association between aspirin dose and subarachnoid hemorrhage from saccular aneurysms: A case-control study. Neurology, 91(12), e1175-e1181. https://doi.org/10.1212/WNL.0000000000006200

Phan, K., Moore, J. M., Griessenauer, C. J., Ogilvy, C. S., & Thomas, A. J. (2017). Aspirin and Risk of Subarachnoid Hemorrhage: Systematic Review and Meta-Analysis. Stroke, 48(5), 1210-1217. https://doi.org/10.1161/STROKEAHA.116.015674

Dasenbrock, H. H., Yan, S. C., Gross, B. A., Guttieres, D., Gormley, W. B., Frerichs, K. U., Ali Aziz-Sultan, M., & Du, R. (2017). The impact of aspirin and anticoagulant usage on outcomes after aneurysmal subarachnoid hemorrhage: a Nationwide Inpatient Sample analysis. Journal of neurosurgery, 126(2), 537-547. https://doi.org/10.3171/2015.12.JNS151107

Ditz, C., Machner, B., Schacht, H., Neumann, A., Schramm, P., Tronnier, V. M., & Küchler, J. (2021). Effects of post-interventional antiplatelet therapy on angiographic vasospasm, delayed cerebral ischemia, and clinical outcome after aneurysmal subarachnoid hemorrhage: a single-center experience. Neurosurgical review, 44(5), 2899-2912. https://doi.org/10.1007/s10143-021-01477-6

Shulyatnikova, T. V., & Tumanskiy, V. O. (2021). Immunohistochemical analysis of GFAP expression in the experimental sepsis-associated encephalopathy. Pathologia. 18(3), 295-302. https://doi.org/10.14739/2310-1237.2021.3.240033

Gyldenholm, T., Hvas, C. L., Hvas, A. M., & Hviid, C. V. B. (2022). Serum glial fibrillary acidic protein (GFAP) predicts outcome after intracerebral and subarachnoid hemorrhage. Neurological sciences, 43(10), 6011-6019. https://doi.org/10.1007/s10072-022-06274-7

Cenik, Y., Baydin, A., Çakmak, E., Fidan, M., Aydin, K., Tuncel, Ö. K., & Aslan, K. (2021). The Effect of Biomarkers and Optic Nerve Sheath Diameter in Determining Mortality in non-Traumatic Subarachnoid Hemorrhage. Clinical neurology and neurosurgery, 207, 106813. https://doi.org/10.1016/j.clineuro.2021.106813

Chung, C. L., Huang, Y. H., Lin, C. J., Chong, Y. B., Wu, S. C., Chai, C. Y., Tsai, H. P., & Kwan, A. L. (2022). Therapeutic Effect of Mitochondrial Division Inhibitor-1 (Mdivi-1) on Hyperglycemia-Exacerbated Early and Delayed Brain Injuries after Experimental Subarachnoid Hemorrhage. International journal of molecular sciences, 23(13), 6924. https://doi.org/10.3390/ijms23136924

Kwon, H. S., & Koh, S. H. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Translational neurodegeneration, 9(1), 42. https://doi.org/10.1186/s40035-020-00221-2

Belenichev, I. F., Aliyeva, O. G., Popazova, O. O., & Bukhtiyarova, N. V. (2023). Involvement of heat shock proteins HSP70 in the mechanisms of endogenous neuroprotection: the prospect of using HSP70 modulators. Frontiers in cellular neuroscience, 17, 1131683. https://doi.org/10.3389/fncel.2023.1131683

Downloads

Published

2023-08-30

How to Cite

1.
Polkovnikov OY, Tertyshnyi SI. The influence of acelysin and nimotop on the cellular response of the hippocampus during the dynamics of experimental subarachnoid hemorrhage. Pathologia [Internet]. 2023Aug.30 [cited 2024Nov.25];20(2):147-53. Available from: http://pat.zsmu.edu.ua/article/view/279845

Issue

Section

Original research