Clemastine Promotes Recovery of Neural Function and Suppresses Neuronal Apoptosis by Restoring Balance of Pro-inflammatory Mediators in an Experimental Model of Intracerebral Hemorrhage

Overview

Journal Int J Med Sci

Specialty General Medicine

Date 2021 Jan 13

PMID 33437198

Citations 6

Authors

Cheng Zhi

Shulian Zeng

Yuan Chen

Degui Liao

Miaoling Lai

Zhaotao Wang

Yezhong Wang

Shiyin Xiao

Affiliations

Soon will be listed here.

Abstract

Intracerebral hemorrhage (ICH) represents a common acute cerebrovascular event that imparts high rates of disability. The microglia-mediated inflammatory response is a critical factor in determining cerebral damage post-ICH. Clemastine (CLM) is a histamine receptor H1 (HRH1) antagonist that has been shown to modulate the inflammatory response. However, the effects of CLM on ICH and the underlying mechanism remain to be determined. This investigation reveals that CLM resulted in reduction of cerebral hematoma volume, decreased cerebral edema and lower rates of neuronal apoptosis as well as improved behavioral scores in an acute ICH murine model. CLM treatment was noted to decrease pro-inflammatory effectors and increased anti-inflammatory effectors post-ICH. In addition, CLM reduced the deleterious effects of activated microglia on neurons in a transwell co-culture system. Our findings show that CLM likely mediates its therapeutic effect through inhibition of microglia-induced inflammatory response and apoptosis, thereby enhancing restoration of neuronal function.

Citing Articles

Emerging therapeutic application of clemastine: a review of recent patents updates.

Soni S, Kaur G Naunyn Schmiedebergs Arch Pharmacol. 2025; .

PMID: 40055203 DOI: 10.1007/s00210-025-03978-3.

Neuroprotective Effect of Clemastine Improved Oligodendrocyte Proliferation through the MAPK/ERK Pathway in a Neonatal Hypoxia Ischemia Rat Model.

Bernis M, Hakvoort C, Nacarkucuk E, Burkard H, Bremer A, Zweyer M Int J Mol Sci. 2024; 25(15).

PMID: 39125778 PMC: 11311837. DOI: 10.3390/ijms25158204.

Effect of Clemastine on Neurophysiological Outcomes in an Ovine Model of Neonatal Hypoxic-Ischemic Encephalopathy.

Mike J, White Y, Hutchings R, Vento C, Ha J, Iranmahboub A Children (Basel). 2023; 10(11).

PMID: 38002819 PMC: 10670092. DOI: 10.3390/children10111728.

Insights on therapeutic potential of clemastine in neurological disorders.

Jiang S, Wang X, Cao T, Kang R, Huang L Front Mol Neurosci. 2023; 16:1279985.

PMID: 37840769 PMC: 10568021. DOI: 10.3389/fnmol.2023.1279985.

Comparing the efficacy in reducing brain injury of different neuroprotective agents following neonatal hypoxia-ischemia in newborn rats: a multi-drug randomized controlled screening trial.

Sabir H, Maes E, Zweyer M, Schleehuber Y, Imam F, Silverman J Sci Rep. 2023; 13(1):9467.

PMID: 37301929 PMC: 10257179. DOI: 10.1038/s41598-023-36653-9.

References

Khuman J, Zhang J, Park J, Carroll J, Donahue C, Whalen M . Low-level laser light therapy improves cognitive deficits and inhibits microglial activation after controlled cortical impact in mice. J Neurotrauma. 2011; 29(2):408-17. PMC: 3261787. DOI: 10.1089/neu.2010.1745. View

Burns J, Fisher J, Cervantes-Arslanian A . Recent Advances in the Acute Management of Intracerebral Hemorrhage. Neurosurg Clin N Am. 2018; 29(2):263-272. DOI: 10.1016/j.nec.2017.11.005. View

Tschoe C, Bushnell C, Duncan P, Alexander-Miller M, Wolfe S . Neuroinflammation after Intracerebral Hemorrhage and Potential Therapeutic Targets. J Stroke. 2020; 22(1):29-46. PMC: 7005353. DOI: 10.5853/jos.2019.02236. View

Garcia J, Wagner S, Liu K, Hu X . Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 1995; 26(4):627-34; discussion 635. DOI: 10.1161/01.str.26.4.627. View

Haller J, Wiss A, May C, Jones G, Smetana K . Acute Management of Hypertension Following Intracerebral Hemorrhage. Crit Care Nurs Q. 2019; 42(2):129-147. DOI: 10.1097/CNQ.0000000000000247. View

Cordonnier C, Demchuk A, Ziai W, Anderson C . Intracerebral haemorrhage: current approaches to acute management. Lancet. 2018; 392(10154):1257-1268. DOI: 10.1016/S0140-6736(18)31878-6. View

Lattanzi S, Cagnetti C, Provinciali L, Silvestrini M . How Should We Lower Blood Pressure after Cerebral Hemorrhage? A Systematic Review and Meta-Analysis. Cerebrovasc Dis. 2017; 43(5-6):207-213. DOI: 10.1159/000462986. View

Yang Y, Zhang Y, Wang Z, Wang S, Gao M, Xu R . Attenuation of Acute Phase Injury in Rat Intracranial Hemorrhage by Cerebrolysin that Inhibits Brain Edema and Inflammatory Response. Neurochem Res. 2015; 41(4):748-57. DOI: 10.1007/s11064-015-1745-4. View

Divani A, Liu X, Di Napoli M, Lattanzi S, Ziai W, James M . Blood Pressure Variability Predicts Poor In-Hospital Outcome in Spontaneous Intracerebral Hemorrhage. Stroke. 2019; 50(8):2023-2029. DOI: 10.1161/STROKEAHA.119.025514. View

10.

Ren H, Han R, Chen X, Liu X, Wan J, Wang L . Potential therapeutic targets for intracerebral hemorrhage-associated inflammation: An update. J Cereb Blood Flow Metab. 2020; 40(9):1752-1768. PMC: 7446569. DOI: 10.1177/0271678X20923551. View

11.

Hanley D, Thompson R, Rosenblum M, Yenokyan G, Lane K, McBee N . Efficacy and safety of minimally invasive surgery with thrombolysis in intracerebral haemorrhage evacuation (MISTIE III): a randomised, controlled, open-label, blinded endpoint phase 3 trial. Lancet. 2019; 393(10175):1021-1032. PMC: 6894906. DOI: 10.1016/S0140-6736(19)30195-3. View

12.

Thiex R, Tsirka S . Brain edema after intracerebral hemorrhage: mechanisms, treatment options, management strategies, and operative indications. Neurosurg Focus. 2007; 22(5):E6. DOI: 10.3171/foc.2007.22.5.7. View

13.

Babu R, Bagley J, Di C, Friedman A, Adamson C . Thrombin and hemin as central factors in the mechanisms of intracerebral hemorrhage-induced secondary brain injury and as potential targets for intervention. Neurosurg Focus. 2012; 32(4):E8. DOI: 10.3171/2012.1.FOCUS11366. View

14.

Yuan X, Juan Z, Zhang R, Sun X, Yan R, Yue F . Clemastine Fumarate Protects Against Myocardial Ischemia Reperfusion Injury by Activating the TLR4/PI3K/Akt Signaling Pathway. Front Pharmacol. 2020; 11:28. PMC: 7025565. DOI: 10.3389/fphar.2020.00028. View

15.

Patrizz A, Doran S, Chauhan A, Ahnstedt H, Roy-OReilly M, Lai Y . EMMPRIN/CD147 plays a detrimental role in clinical and experimental ischemic stroke. Aging (Albany NY). 2020; 12(6):5121-5139. PMC: 7138568. DOI: 10.18632/aging.102935. View

16.

Zhou Y, Wang Y, Wang J, Stetler R, Yang Q . Inflammation in intracerebral hemorrhage: from mechanisms to clinical translation. Prog Neurobiol. 2013; 115:25-44. DOI: 10.1016/j.pneurobio.2013.11.003. View

17.

Cree B, Niu J, Hoi K, Zhao C, Caganap S, Henry R . Clemastine rescues myelination defects and promotes functional recovery in hypoxic brain injury. Brain. 2017; 141(1):85-98. PMC: 6394402. DOI: 10.1093/brain/awx312. View

18.

Ducruet A, Zacharia B, Hickman Z, Grobelny B, Yeh M, Sosunov S . The complement cascade as a therapeutic target in intracerebral hemorrhage. Exp Neurol. 2009; 219(2):398-403. PMC: 3731062. DOI: 10.1016/j.expneurol.2009.07.018. View

19.

Wang J . Preclinical and clinical research on inflammation after intracerebral hemorrhage. Prog Neurobiol. 2010; 92(4):463-77. PMC: 2991407. DOI: 10.1016/j.pneurobio.2010.08.001. View

20.

van Asch C, Luitse M, Rinkel G, van der Tweel I, Algra A, Klijn C . Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010; 9(2):167-76. DOI: 10.1016/S1474-4422(09)70340-0. View