The effect of clopidogrel and aspirin on the severity of traumatic brain injury in a rat model

Firas Kobeissy; Khalil Mallah; Kazem Zibara; Fatima Dakroub; Zeinab Dalloul; Mohammad Nasser; Leila Nasrallah; Zahraa Mallah; Ghewa A El-Achkar; Naify Ramadan; Wael Mohamed; Stefania Mondello; Hala Darwish; Eva Hamade; Aida Habib

doi:10.1016/j.neuint.2022.105301

The effect of clopidogrel and aspirin on the severity of traumatic brain injury in a rat model

Neurochem Int. 2022 Mar:154:105301. doi: 10.1016/j.neuint.2022.105301. Epub 2022 Feb 2.

Authors

Firas Kobeissy¹, Khalil Mallah², Kazem Zibara³, Fatima Dakroub⁴, Zeinab Dalloul⁵, Mohammad Nasser⁴, Leila Nasrallah⁵, Zahraa Mallah⁴, Ghewa A El-Achkar⁵, Naify Ramadan⁵, Wael Mohamed⁶, Stefania Mondello⁷, Hala Darwish⁸, Eva Hamade⁹, Aida Habib¹⁰

Affiliations

¹ Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon. Electronic address: firasko@gmail.com.
² Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Department of Microbiology and Immunology, Medical University of South Carolina, 173 Ashley Avenue, BSB 204, MSC 504, Charleston, SC, 29425, USA.
³ ER045, Laboratory of Stem Cells, DSST, PRASE, Lebanese University, Beirut, Lebanon; Department of Biology, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
⁴ Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Molecular Biology and Cancer Immunology Laboratory, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon.
⁵ Department of Biochemistry and Molecular Genetics, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
⁶ Clinical Pharmacology Department, Menoufia Medical School, Menoufia University, AlMinufya, Egypt; Basic Medical Science Department, Kulliyyah of Medicine, International Islamic University Malaysia, Kuantan, Pahang, Malaysia.
⁷ Department of Neurosciences, University of Messina, Messina, Italy.
⁸ Nehme and Therese Tohme Multiple Sclerosis Center, Faculty of Medicine, American University of Beirut Medical Center, Lebanon; Hariri School of Nursing, American University of Beirut, Lebanon.
⁹ Molecular Biology and Cancer Immunology Laboratory, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon; Department of Biochemistry, Faculty of Sciences-I, Lebanese University, Beirut, Lebanon. Electronic address: eva.hamade@ul.edu.lb.
¹⁰ Department of Basic Medical Sciences, College of Medicine, QU Health, Qatar University, Doha, Qatar. Electronic address: aida.habib@qu.edu.qa.

PMID: 35121011
DOI: 10.1016/j.neuint.2022.105301

Abstract

Traumatic Brain Injury (TBI) is one of the leading causes of death and disability worldwide. Aspirin (ASA) and clopidogrel (CLOP) are antiplatelet agents that inhibit platelet aggregation. They are implicated in worsening the intracerebral haemorrhage (ICH) risk post-TBI. However, antiplatelet drugs may also exert a neuroprotective effect post-injury. We determined the impact of ASA and CLOP treatment, alone or in combination, on ICH and brain damage in an experimental rat TBI model. We assessed changes in platelet aggregation and measured serum thromboxane by enzyme immune assay. We also explored a panel of brain damage and apoptosis biomarkers by immunoblotting. Rats were treated with ASA and/or CLOP for 48 h prior to TBI and sacrificed 48 h post-injury. In rats treated with antiplatelet agents prior to TBI, platelet aggregation was completely inhibited, and serum thromboxane was significantly decreased, compared to the TBI group without treatment. TBI increases UCHL-1 and GFAP, but decreases hexokinase expression compared to the non-injured controls. All groups treated with antiplatelet drugs prior to TBI had decreased UCH-L1 and GFAP serum levels compared to the TBI untreated group. Furthermore, the ASA and CLOP single treatments increased the hexokinase serum levels. We confirmed that αII-spectrin cleavage increased post-TBI, with the highest cleavage detected in CLOP-treated rats. Aspirin and/or CLOP treatment prior to TBI is a double-edged sword that exerts a dual effect post-injury. On one hand, ASA and CLOP single treatments increase the post-TBI ICH risk, with a further detrimental effect from the ASA + CLOP treatment. On the other hand, ASA and/or CLOP treatments are neuroprotective and result in a favourable profile of TBI injury markers. The ICH risk and the neuroprotection benefits from antiplatelet therapy should be weighed against each other to ameliorate the management of TBI patients.

Keywords: Aspirin; Clopidogrel; Controlled cortical impact; Intracerebral haemorrhage; Neuroprotection; Traumatic brain injury.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Aspirin / pharmacology
Aspirin / therapeutic use
Brain Injuries* / drug therapy
Brain Injuries, Traumatic* / drug therapy
Clopidogrel / pharmacology
Humans
Platelet Aggregation Inhibitors / pharmacology
Platelet Aggregation Inhibitors / therapeutic use
Rats

Substances

Platelet Aggregation Inhibitors
Clopidogrel
Aspirin