Adaptive Role of Glial Cell Line-Derived Neurotrophic Factor in Cerebral Ischemia

The aim of the investigation was to study the effect of glial cell line-derived neurotrophic factor (GDNF) on animals` resistance to cerebral-ischemia-induced damage.

Materials and Methods. In vivo studies were carried out on C3H male mice weighing 18–40 g. Ischemia modeling was performed by bilateral irreversible occlusion of both carotid arteries. A neurological status as well as an orientative-exploratory behavior of experimental animals and their learning capability in the post-ischemic period were analyzed by using “Open field” and “Passive avoidance” tests. In addition, high-resolution respirometer Oxygraph-2k (Oroboros, Austria) was applied to study an oxygen uptake rate of brain mitochondria in ischemic conditions.

Results. GDNF application in bilateral occlusion of carotid arteries was found to contribute to the neurological status recovery. Moreover, it normalizes oxygen uptake rate of mitochondria in the post-ischemic period.

Conclusion. GDNF has a marked neuroprotective and antihypoxic effect under ischemia modeling in vivo.

1. Vedunova M.V., Shishkina T.V., Mishchenko T.A., Mitroshina E.V., Astrakhanova T.A., Pimashkin A.S., Mukhina I.V. Antihypoxic and neuroprotective effects of glial cell-derived neurotrophic factor (GDNF) in cultures of dissociated hippocampal cells under conditions of experimental hypoxia. Bull Exper Biol Med 2016; 161(1): 168–174, https://doi.org/10.1007/s10517-016-3369-3.
2. Shishkina T.V., Vedunova M.V., Mishchenko T.A., Mukhina I.V. The role of glial cell line-derived neurotrophic factor in the functioning of the nervous system (review). Sovremennye tehnologii v medicine 2015; 7(4): 211–220, https://doi.org/10.17691/stm2015.7.4.27.
3. Duarte E.P., Curcio M., Canzoniero L.M., Duarte C.B. Neuroprotection by GDNF in the ischemic brain. Growth Factors 2012; 30(4): 242–257, https://doi.org/10.3109/08977194.2012.691478.
4. Vedunova M.V., Mishchenko T.A., Mitroshina E.V., Mukhina I.V. TrkB-mediated neuroprotective and antihypoxic properties of brain-derived neurotrophic factor. Oxid Med Cell Longev 2015; 2015: 1–9, https://doi.org/10.1155/2015/453901.
5. Vasilyev I.A., Stupak V.V., Chernykh V.A., Zaidman A.M., Polovnikov E.V., Chernykh E.R., Shevela E.Y., Dergilev A.P. Experimental models of vascular lesions of the brain (literature review). Uspekhi sovremennogo estestvoznaniya 2015; 1(3): 366–369.
6. Kaya A.H., Erdogan H., Tasdemiroglu E. Searching evidences of stroke in animal models: a review of discrepancies. Turk Neurosurg 2016, https://doi.org/10.5137/1019-5149.jtn.15373-15.2.
7. Kumar A., Aakriti, Gupta V. A review on animal models of stroke: an update. Brain Res Bull 2016; 122: 35–44, https://doi.org/10.1016/j.brainresbull.2016.02.016.
8. Vedunova М.V., Sakharnova Т.А., Mitroshina E.V., Shishkina T.V., Astrakhanova T.A., Mukhina I.V. Antihypoxic and neuroprotective properties of BDNF and GDNF in vitro and in vivo under hypoxic conditions. Sovremennye tehnologii v medicine 2014; 6(4): 38–47.
9. Kul’chikov A.E., Makarenko A.N., Novikova Yu.L., Dobychina E.E. Sposob opredeleniya nevrologicheskogo defitsita u melkikh laboratornykh zhivotnykh pri porazhenii golovnogo mozga. A.s. 2327227 C2 [Neurologic impairment determination method in small laboratory animals with brain lesions. A.c. 2327227 С2]. 2008.
10. Garcia J.H. Early reperfusion as a rationale of therapy in ischemic stroke. Rev Neurol 1995; 23(123): 1067–1073.
11. Kuster G.W., Baruzzi A.C., Pacheco Ede P., Domingues R.B., Pieruccetti M., Giacon L.M., Garcia J.C., Furlan V., Massaro A.R. Early reperfusion therapy in acute ischemic stroke after recent myocardial infarction. Arq Neuropsiquiatr 2016; 74(8): 690–691, https://doi.org/10.1590/0004-282x20160099.
12. Manukhina E.B., Terekhina O.L., Belkina L.M., Abramochkin D.V., Budanova O.P., Mashina S.Yu., Smirin B.V., Yakunina E.B., Downey H.F. Vasoprotective effect of adaptation to hypoxia in myocardial ischemia and reperfusion injury. Patologicheskaya fiziologiya i eksperimental’naya terapiya 2013; 4: 26–31.
13. Onken M., Berger S., Kristian T. Simple model of forebrain ischemia in mouse. J Neurosci Methods 2012; 204(2): 254–261, https://doi.org/10.1016/j.jneumeth.2011.11.022.
14. Tang Y., Wang L., Wang J., Lin X., Wang Y., Jin K., Yang G.Y. Ischemia-induced angiogenesis is attenuated in aged rats. Aging Dis 2016; 7(4): 326, https://doi.org/10.14336/ad.2015.1125.
15. Pshennikova M.G., Bakhtina L.Yu., Budanova O.P., Malyshev I.Yu. Effect of adaptation to not damaging stress influences on resistance to acute stress in rats August line and Wistar population. Patogenez 2014; 12(4): 31–34.
16. Watanabe A., Sasaki T., Yukami T., Kanki H., Sakaguchi M., Takemori H., Kitagawa K., Mochizuki H. Serine racemase inhibition induces nitric oxide-mediated neurovascular protection during cerebral ischemia. Neuroscience 2016; 339: 139–149, https://doi.org/10.1016/j.neuroscience.2016.09.036.
17. Sheldon R.A., Sadjadi R., Lam M., Fitzgerald R., Ferriero D.M. Alteration in downstream hypoxia gene signaling in neonatal glutathione peroxidase overexpressing mouse brain after hypoxia-ischemia. Dev Neurosci 2015; 37(4–5): 398–406, https://doi.org/10.1159/000375369.
18. Kitagawa K., Matsumoto M., Yang G., Mabuchi T., Yagita Y., Hori M., Yanagihara T. Cerebral ischemia after bilateral carotid artery occlusion and intraluminal suture occlusion in mice: evaluation of the patency of the posterior communicating artery. J Cereb Blood Flow Metab 1998; 18(5): 570–579, https://doi.org/10.1097/00004647-199805000-00012.
19. Yang G., Kitagawa K., Ohtsuki T., Kuwabara K., Mabuchi T., Yagita Y., Takazawa K., Tanaka S., Yanagihara T., Hori M., Matsumoto M. Regional difference of neuronal vulnerability in the murine hippocampus after transient forebrain ischemia. Brain Res 2000; 870(1–2): 195–198, https://doi.org/10.1016/s0006-8993(00)02319-2.
20. Wellons J.C. 3rd, Sheng H., Laskowitz D.T., Mackensen G.B., Pearlstein R.D., Warner D.S. A comparison of strain-related susceptibility in two murine recovery models of global cerebral ischemia. Brain Res 2000; 868(1): 14–21, https://doi.org/10.1016/s0006-8993(00)02216-2.
21. Soria F.N., Pérez-Samartín A., Martin A., Gona K.B., Llop J., Szczupak B., Chara J.C., Matute C., Domercq M. Extrasynaptic glutamate release through cystine/glutamate antiporter contributes to ischemic damage. J Clin Invest 2014; 124(8): 3645–3655, https://doi.org/10.1172/jci71886.
22. Beckmann N. High resolution magnetic resonance angiography non-invasively reveals mouse strain differences in the cerebrovascular anatomy in vivo. Magn Reson Med 2000; 44(2): 252–258, https://doi.org/10.1002/1522-2594(200008)44:2252::aid-mrm123.0.co;2-g.
23. Zhen G., Doré S. Optimized protocol to reduce variable outcomes for the bilateral common carotid artery occlusion model in mice. J Neurosci Methods 2007; 166(1): 73–80, https://doi.org/10.1016/j.jneumeth.2007.06.029.
24. Hermann D.M., Zechariah A., Kaltwasser B., Bosche B., Caglayan A.B., Kilic E., Doeppner T.R. Sustained neurological recovery induced by resveratrol is associated with angioneurogenesis rather than neuroprotection after focal cerebral ischemia. Neurobiol Dis 2015; 83: 16–25, https://doi.org/10.1016/j.nbd.2015.08.018.
25. Katsuragi S., Ikeda T., Ikenoue T. A strategy to treat neonatal hypoxic encephalopathy using glial cell line-derived neurotrophic factor. No To Hattatsu 2011; 43(4): 265–272.
26. Cheng H., Fu Y.-S., Guo J.-W. Ability of GDNF to diminish free radical production leads to protection against kainate-induced excitotoxicity in hippocampus. Hippocampus 2004; 14(1): 77–86, https://doi.org/10.1002/hipo.10145.
27. Wang E., Gao J., Yang Q., Parsley M.O., Dunn T.J., Zhang L., DeWitt D.S., Denner L., Prough D.S., Wu P. Molecular mechanisms underlying effects of neural stem cells against traumatic axonal injury. J Neurotrauma 2012; 29(2): 295–312, https://doi.org/10.1089/neu.2011.2043.
28. Liao Y., Zhong D., Kang M., Yao S., Zhang Y., Yu.Y. Transplantation of neural stem cells induced by all-trans-retinoic acid combined with glial cell line derived neurotrophic factor and chondroitinase abc for repairing spinal cord injury of rats. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2015; 29(8): 1009–1015.
29. Chao M.V. Intercellular networks underlying developmental decisions. Neuron 2016; 91(5): 947–949, https://doi.org/10.1016/j.neuron.2016.08.025.
30. Costantini F., Shakya R. GDNF/Ret signaling and the development of the kidney. BioEssays 2006; 28(2): 117–127, https://doi.org/10.1002/bies.20357.
31. Shang J., Deguchi K., Yamashita T., Ohta Y., Zhang H., Morimoto N., Liu N., Zhang X., Tian F., Matsuura T., Funakoshi H., Nakamura T., Abe K. Antiapoptotic and antiautophagic effects of glial cell line-derived neurotrophic factor and hepatocyte growth factor after transient middle cerebral artery occlusion in rats. J Neurosci Res 2010; 88(10): 2197–2206, https://doi.org/10.1002/jnr.22373.
32. Yamashita T., Abe K. Recent progress in therapeutic strategies for ischemic stroke. Cell Transplantation 2016; 25(5): 893–898, https://doi.org/10.3727/096368916x690548.
33. Szydlowska K., Tymianski M. Calcium, ischemia and excitotoxicity. Cell Calcium 2010; 47(2): 122–129, https://doi.org/10.1016/j.ceca.2010.01.003.

Mitroshina Е.V., Abogessimengane B.Zh., Urazov М.D., Hamraoui I., Mishchenko Т.А., Astrakhanova Т.А., Shchelchkova N.А., Lapshin R.D., Shishkina Т.V., Belousova I.I., Mukhina I.V., Vedunova М.V. Adaptive Role of Glial Cell Line-Derived Neurotrophic Factor in Cerebral Ischemia. Sovremennye tehnologii v medicine 2017; 9(1): 68, https://doi.org/10.17691/stm2017.9.1.08