Potentiating Hemorrhage in a Periadolescent Rat Model of Closed-Head Traumatic Brain Injury Worsens Hyperexcitability but Not Behavioral Deficits.

Dounya Jalloul,Mouhamad Darwich,Nada Lawand,Leila Nasrallah,Firas Kobeissy,Kevin K W Wang,Makram Obeid,Rita Asdikian,Hala Darwish,Yasser Medlej,Nabil Karnib,Mariam Maawie,Helene Hajjar,Ronza Abdel Rassoul

doi:10.3390/ijms22126456

Abstract

Post-traumatic epilepsy (PTE) and neurocognitive deficits are devastating sequelae of head injuries that are common in adolescents. Investigating desperately needed treatments is hindered by the difficulties in inducing PTE in rodents and the lack of established immature rat models of pediatric PTE. Hemorrhage is a significant risk factor for PTE, but compared to humans, rats are less prone to bleeding because of their rapid blood coagulation system. In this study, we promoted bleeding in the controlled cortical impact (CCI) closed-head injury model with a 20 min pre-impact 600 IU/kg intraperitoneal heparin injection in postnatal day 35 (P35) periadolescent rats, given the preponderance of such injuries in this age group. Temporo-parietal CCI was performed post-heparin (HTBI group) or post-saline (TBI group). Controls were subjected to sham procedures following heparin or saline administration. Continuous long-term EEG monitoring was performed for 3 months post-CCI. Sensorimotor testing, the Morris water maze, and a modified active avoidance test were conducted between P80 and P100. Glial fibrillary acidic protein (GFAP) levels and neuronal damage were also assessed. Compared to TBI rats, HTBI rats had persistently higher EEG spiking and increased hippocampal GFAP levels (p < 0.05). No sensorimotor deficits were detected in any group. Compared to controls, both HTBI and TBI groups had a long-term hippocampal neuronal loss (p < 0.05), as well as contextual and visuospatial learning deficits (p < 0.05). The hippocampal astrogliosis and EEG spiking detected in all rats subjected to our hemorrhage-promoting procedure suggest the emergence of hyperexcitable networks and pave the way to a periadolescent PTE rat model.

Highlights

Traumatic brain injury (TBI) is common in adolescents and adults, with 300–400 cases per 100,000 individuals [1]
We modified the traditional cortical impact (CCI) model to induce a closed-head injury and increase TBI-associated hemorrhage with a single pre-impact heparin injection, which resulted in the potentiation of post-injury hyperexcitability
The promotion of hemorrhage in our novel modified CCI procedure was associated with persistent and significantly increased EEG discharges in the HTBI rats, as shown in Figure 3, suggesting the emergence of a potentially permanent abnormal network of hyperexcitability

Summary

Introduction

Traumatic brain injury (TBI) is common in adolescents and adults, with 300–400 cases per 100,000 individuals [1]. The incidence of PTE is as high as 53% following severe head injuries [4], and it accounts for up to 20% of all symptomatic epilepsies [5]. The adolescent population is one of the most affected age groups by TBI, and non-penetrating closed-head injuries [6]. PTE in the pediatric age group is often associated with severe neurocognitive disorders irrespective of injury severity [7,8]. Anti-seizure medications are transiently administered for one week following TBI to prevent early post-traumatic seizures in the first 7 days post-injury [9], but to date, there are no available neuroprotective treatment strategies that can prevent the later emergence of PTE and the often accompanying neurocognitive comorbidities. Investigating desperately needed novel preventive treatment strategies is hindered by the lack of well-established pediatric PTE models [10] and the very low rates of PTE emergence in current immature and adult animal models, with as little as 3–9% of experimental animals developing seizures [10,11,12]

Methods

Results

Conclusion