Neuroprotective Potential of Lithium Chloride in a Model of Traumatic Brain Injury
https://doi.org/10.15360/1813-9779-2025-5-2528
Abstract
Aim: to investigate the neuroprotective properties of lithium chloride in a rat model of open traumatic brain injury (OTBI).
Materials and Methods. An open traumatic brain injury (OTBI) model was induced using the D. M. Feeney method. The study included 40 male Wistar rats divided into four groups: sham-operated animals (sham, N=10); a OTBI control group (control, N=10); a group receiving lithium chloride at a dose of 1.5 mmol/kg after OTBI (OTBI + lithium 63 mg/kg, N=10); and a group receiving lithium chloride at a dose of 0.5 mmol/kg after OTBI (OTBI + lithium 21 mg/kg, N=10). Cognitive and neurological functions were assessed using the Morris water maze and the forelimb placing test. Brain lesion volume was assessed by magnetic resonance imaging (MRI) on day 14 post-injury.
Results. Lithium chloride at 63 mg/kg administered 60 minutes after OTBI reduced brain lesion volume by 41.5% compared to the control group (P=0.001), while the 21 mg/kg dose reduced lesion volume by 27.5% (P=0.001). Lithium chloride at 63 mg/kg improved cognitive performance by 71% compared to the control group (P=0.009); the 21 mg/kg dose resulted in a 65% improvement (P=0.010).
Conclusion. Lithium chloride at doses of 21 mg/kg and 63 mg/kg has neuroprotective properties, significantly reduces brain lesion volume (as confirmed by MRI), alleviates neurological deficits, and thereby improves cognitive function in animals after OTBI.
About the Authors
Denis T. SharikadzeRussian Federation
25 Petrovka Str., Bldg. 2, 107031 Moscow
Mikhail V. Gabitov
Russian Federation
25 Petrovka Str., Bldg. 2, 107031 Moscow
Ivan V. Redkin
Russian Federation
25 Petrovka Str., Bldg. 2, 107031 Moscow
Artem N. Kuzovlev
Russian Federation
25 Petrovka Str., Bldg. 2, 107031 Moscow
Viktor V. Moroz
Russian Federation
25 Petrovka Str., Bldg. 2, 107031 Moscow
References
1. Klyuchevsky V. V., Litvinov I. I. Practical traumatology: physician’s guide. Moscow: Practical medicine = Prakticheskaya Meditsina. 2020: 400. (in Russ.). ISBN 978-5-98811-610-3.
2. Kaur P., Sharma S. Recent advances in pathophysiology of traumatic brain injury. Curr. Neuropharmacol. 2018; 16 (8): 1224–1238. DOI: 10.2174/1570159X15666170613083606. PMID: 28606040.
3. Sabirov D. M., Rosstalnaya A. L., Makhmudov M. A. Epidemiological features of cranial injury traumatism. Bulletin of Emergency Medicine = Vestnik Ekstrennoy Meditsiny. 2019; 12 (2): 2–3. (in Russ.).
4. Akhanov G. Zh., Uteuliev E. S., Dyusembekov E. K., Nurbakyt A. N., Popova T. V. Clinical and epidemiological aspects of traumatic brain injury. Bulletin of the Kazakh National Medical University = Vestnik Kazakhskogo Natsionalnogo Meditsinskogo Universiteta. 2018; 3: 113–116.
5. Gaibov S. S.-Kh., Zakharchuk E. V., Vorobyev D. P. Epidemiology of traumatic brain injury in children under dynamic urbanization conditions. Russian Pediatric Journal = Rossiyskiy Pediatricheskiy Zhurnal. 2020; 23 (3): 178–182. (in Russ.). DOI: 10.18821/1560-9561-2020-23-3-178-182.
6. Rasskazova V. N., Kiku P. F., Bogdanova V. D., Volkova M. V., Palladova L. M., Sukhova A. V. Actual problems of childhood injuries and its prevention. Healthcare of the Russian Federation = Zdravookhrneniye Rossiskoy Federatsii. 2022; 66 (2): 138–144. (in Russ.). DOI: 10.47470/0044-197X-2022-66-2-138-144.
7. Mira R. G., Lira M., Cerpa W. Traumatic brain injury: mechanisms of glial response. Front Physiol. 2021; 22 (12): 740939. DOI: 10.3389/fphys.2021.740939. PMID: 34744783.
8. Volkov E. V., Gandylyan K. S., Karpov S. M., Eliseeva E. V. Neurophysiological, cerebrovascular and immunological aspects of traumatic brain disease development in children with combined craniofacial trauma. Stavropol: StSMU. 2017: 107. (in Russ.). ISBN 978-5-89822-496-7.
9. Nemkova S. A. Modern approaches to the diagnosis and treatment of the consequences of traumatic brain injury in children and adolescents. S.S. Korsakov Journal of Neurology and Psychiatry = Zhurnal Nevrologii i Psikhiatrii imeni S. S. Korsakova. 2022; 122 (6): 20–29. (in Russ.). DOI: 10.17116/jnevro202212206120.
10. Pigolkin Yu. I., Dubrovin I. A., Leonov S. V., Gornostaev D. V. Traumatic brain injury. Mechanogenesis, morphology and forensic medical assessment. M. 2018: 231. (in Russ.). ISBN 978-5-534-12625-9.
11. Usachev D. Yu., Likhterman L. B., Kravchuk A. D., Okhlopkov V. A. Neurosurgery. National gidelines. Volume I. I. Traumatic brain injury. Moscow: FSAU «National Medical Research Center of Neurosurgery named after Academician N. N. Burdenko» of the Ministry of Health of the Russian Federation. 2022: 30–59. (in Russ.).
12. Baranich A. I., Sychev A. A., Savin I. A., Polupan A. A., Oshorov A. V., Potapov A. A. Coagulopathy associated in the acute phase of traumatic brain injury. General Reanimatology = Obshchaya Reanimatologiya. 2020; 16 (1): 27–34. (in Russ&Eng.). DOI: 10.15360/1813-9779-2020-1-27-34.
13. Poryadin G. V. Pathophysiology: general nosology and typical pathological processes. M. Medical Information Agency. 2022: 247. (in Russ.). ISBN 978-5-9986-0472-0.
14. Novitsky V. V., Kubatiev A. A., Puzyrev V. P., Urazova O. I. Pathophysiology: textbook. Moscow: GEOTAR-Media. 2022: 591. (in Russ.). ISBN 978-5-9704-6880-7.
15. Savvina I. A., Baratov B. I., Krasnenkova M. B. Pathophysiology and intensive care of severe traumatic brain injury: a textbook. St. Petersburg: Algiz. 2019: 52. ISBN: 978–5-6044213-1-4.
16. Berkowitz A. Clinical pathophysiology: it couldn’t be simpler. SPb: Dialect. 2021: 416. ISBN 978-5-907203-96-9.
17. Sussman E. S., Pendharkar A. V., Ho A. L., Ghajar J. Mild traumatic brain injury and concussion: terminology and classification. Handb Clin Neurol. 2018; 158: 21–24. DOI: 10.1016/B978-0-444-63954-7.00003-3. PMID: 30482349.
18. Belyaevsky A. D., Lebedeva E. A., Belousova M.Ye. Cytokines, oxidative stress and antioxidant defense in isolated and concomitant brain injury. General Reanimatology = Obshchaya Reanimatologiya. 2009; 5 (6): 36–39. (in Russ.&Eng.). DOI: 10.15360/1813-9779-2009-6-36.
19. Azevedo F. A. C., Andrade-Moraes C. H., Curado M. R., Oliveira-Pinto A. V., Guimarães D. M., Szczupak D., Gomes B. V., et al. Automatic isotropic fractionation for large-scale quantitative cell analysis of nervous tissue. J Neurosci Methods. 2013; 212 (1): 72–78. DOI: 10.1016/j.jneumeth.2012.09.015. PMID: 23017980.
20. Bartheld C. S., Bahney J., Herculano-Houzel S. J. The search for true numbers of neurons and glial cells in the human brain: a review of 150 years of cell counting. J Comp Neurol. 2016; 524 (18): 3865–3895. DOI: 10.1002/cne.24040. PMID: 27187682.
21. Zarzhetsky Yu.V., Volkov A. V. Some problems of the pathogenesis and therapy of terminal and postresuscitation conditions (experimental studies). General Reanimatology = Obshchaya Reanimatologiya. 2012; 8 (4): 55–58. (in Russ.&Eng.). DOI: 10.15360/1813-9779-2012-4-55.
22. Moroz V. V., Silachev D. N., Plotnikov E.Yu., Zorova L. D., Pevzner I. B., Grebenchikov O. A., Likhvantsev V. V. Mechanisms of cell damage and protection in ischemia/reperfusion and experimental rationale for the use of lithium-based preparations in anesthesiology. General Reanimatology = Obshchaya Reanimatologiya 2013; 9 (1): 63–66. (in Russ.&Eng.). DOI: 10.15360/1813-9779-2013-1-63.
23. Grebenchikov O. A., Cherpakov R. A., Evseyev A. K., Ershov A. V., Kuzovlev A. N., Lonchinsky P. A., Petrikov S. S., et al. Lithium chloride effect on mortality and neurological deficits in the model of ischemic stroke in rats. Russian Sklifosovsky Journal «Emergency Medical Care» = Zhurnal im. N.V. Sklifosovskogo «Neotlozhnaya Meditsinskaya Pomoshch». 2021; 10 (4): 676–686. (in Russ.). DOI: 10.23934/2223-9022-2021-10-4-676-686b.
24. Grebenchikov O. A., Lobanov A. V., Shaikhutdinova E. R., Kuzovlev A. N., Yershov A. V. Cardioprotective properties of lithium chloride on a model of myocardial infarction in rats. Pathology of Blood Circulation and Cardiac Surgery = Patologiya Krovoobrashcheniya i Kardiokhirurgiya. 2019; 23 (2): 43–49. (in Russ.). DOI: 10.21688/1681-3472-2019-2-43-49.
25. Junde Z., Tingting L., Lu Z., Shan C., Dan Y., Yizhen Z. Lithium chloride promotes neural functional recovery after local cerebral ischaemia injury in rats through Wnt signalling pathway activation. Folia Morphol (Warsz). 2023; 82 (3): 519–532. DOI: 10.5603/FM.a2022.0068. PMID: 35916382.
26. Pan H.-Y., Valapala M. Regulation of autophagy by the glycogen synthase kinase-3 (GSK-3) signaling pathway. Int J Mol Sci. 2022; 23 (3): 1709. DOI: 10.3390/ijms23031709. PMID: 35163631.
27. Lu K.-T., Cheng N.-C., Wu, C.-Y. Yang Y.-L. NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade. Crit Care Med. 2008; 36 (3): 917–922. DOI: 10.1097/ccm.0b013e31816590c4. PMID: 18431281.
28. Xiao Y., Fan M., Jin W., Li W.A., Jia Y., Dong Y., Jiang X., et al. Lithium chloride ameliorated spatial cognitive impairment through activating mTOR phosphorylation and inhibiting excessive autophagy in the repeated cerebral ischemia-reperfusion mouse model. Exper Ther Med. 2020; 20 (5): 109. DOI: 10.3892/etm.2020.9237. PMID: 32989388.
29. Chen B., Zhang M., Ji M., Zhang D., Chen B., Gong W., Li X., et al. The neuroprotective mechanism of lithium after ischaemic stroke. Commun Biol. 2022; 5 (1): 105. DOI: 10.1038/s42003-022-03051-2. PMID: 35115638.
30. Barbisan F., Azzolin V. F., Teixeira C. F. Mastella M. H., Ribeiro E. E., do Prado-Lima P. A. S., Praia R. S., et al. Xanthine-catechin mixture enhances lithium-induced anti-inflammatory response in activated macrophages in vitro. Biomed Res Int. 2017; 2017: 4151594. DOI: 10.1155/2017/4151594. PMID: 29250539.
31. Mastella M. H., Roggia I., Turra B. O., Bonotto N. C. A., Teixeira C. F., Pulcinelli D. L. F., Meira G. M., et al. The protective effect of lithium against rotenone may be evolutionarily conserved: evidence from eisenia fetida, a primitive animal with a ganglionic brain. Neurochem Res. 2023; 48 (12): 3538–3559. DOI: 10.1007/s11064-023-04001-y. PMID: 37526866.
32. Araldi E., Jutzeler C. R., Ristow M. Lithium treatment extends human lifespan: findings from the UK Biobank. Aging (Albany N. Y.). 2023; 15 (2): 421–440. DOI: 10.18632/aging.206118. PMID: 36640269.
33. Zhu Z.-F., Wang Q.-G., Han B.-J., William C. P. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull. 2010; 83 (5): 272–277. DOI: 10.1016/j.brainresbull.2010.07.008. PMID: 20638460.
34. Dash P. K., Johnson D., Clark J., Orsi S. A., Zhang M., Zhao J., Grill R. J., et al. Involvement of the glycogen synthase kinase-3 signaling pathway in TBI pathology and neurocognitive outcome. PLoS One. 2011; 6 (9): e24648.
35. Yu F., Zhang Y., Chuang D.-M. Lithium reduces BACE1 overexpression, β amyloid accumulation, and spatial learning deficits in mice with traumatic brain injury. J Neurotrauma. 2012; 29 (13): 2342–2351. DOI: 10.1089/neu.2012.2449. PMID: 18589444.
36. Carlson S. W., Dixon C. E. Lithium improves dopamine neurotransmission and increases dopaminergic protein abundance in the striatum after traumatic brain injury. J Neurotrauma. 2018; 35 (23): 2827–2836. DOI: 10.1089/neu.2017.5509. PMID: 29699444.
37. Delangre E., Pommier G., Tolu S., Uzan B., Bailbe D., Movassat J. Lithium treatment mitigates the diabetogenic effects of chronic cortico-therapy. Biomed Pharmacother. 2023; 164: 114895. DOI: 10.1016/j.biopha.2023.114895. PMID: 37224758.
38. Li B., Wang W., Huang Y., Han L., Li J., Zheng N., Wu Z., et al. Lithium treatment promotes the activation of primordial follicles through PI3K/Akt signaling. Biol Reprod. 2022; 107 (4): 1059–1071. DOI: 10.1093/biolre/ioac150. PMID: 35871551.
39. Cherpakov R. A., Grebenchikov O. A. Effect of lithium chloride concentration on its neuroprotective properties in ischemic stroke in rats. General Reanimatology = Obshchaya Reanimatologiya. 2021; 17 (5): 101–110. (in Russ.&Eng.). DOI: 10.15360/1813-9779-2021-5-101-110.
40. Feeney D. M., Boyeson M. G., Linn R. T., Murray H. M., Dail W. G. Responses to cortical injury: I. Methodology and local effects of contusions in the rat. Brain Res. 1981; 211 (1): 67–77. DOI: 10.1016/0006-8993(81)90067-6. PMID: 7225844.
41. Jolkkonen J., Puurunen K., Rantakömi S., Härkönen A., Haapalinna A., Sivenius J. Behavioral effects of the α2-adrenoceptor antagonist, atipamezole, after focal cerebral ischemia in rats. Eur J Pharmacol. 2000; 400 (2–3): 211–219. DOI: 10.1016/s0014-2999(00)00409-x. PMID: 10988336.
42. Morris R. G. M. Spatial localization does not require the presence of local cues. Learning and Motivation. 1981; 12 (2): 239–260. DOI: 10.1016/0023-9690(81)90020-5.
43. Yu F., Wang Z., Tchantchou F., Chiu C.-T., Zhang Y., Chuang D.-M. Lithium ameliorates neurodegeneration, suppresses neuroinflammation, and improves behavioral performance in a mouse model of traumatic brain injury. J Neurotrauma. 2012; 29 (2): 362–374. DOI: 10.1089/neu.2011.1942. PMID: 21895523.
44. Zhu Z.-F., Wang Q.-G., Han B.-J., William C. P. Neuroprotective effect and cognitive outcome of chronic lithium on traumatic brain injury in mice. Brain Res Bull. 2010; 83 (5): 272–277. DOI: 10.1016/j.brainresbull.2010.07.008. PMID: 20638460.
Supplementary files
Review
For citations:
Sharikadze D.T., Gabitov M.V., Redkin I.V., Kuzovlev A.N., Moroz V.V. Neuroprotective Potential of Lithium Chloride in a Model of Traumatic Brain Injury. General Reanimatology. (In Russ.) https://doi.org/10.15360/1813-9779-2025-5-2528