Authors :
Presenting Author: Mariana Alves, PhD – 683 Hoes Lane West
Rebecca Kalmeijer, BSc – Research Assistant, Dept. Neurosurgery, 683 Hoes Lane West; Rogerio Da Rosa Gerbatin, PhD – Postdoctoral Researcher, Dept. Neurosurgery, Rutgers University; Denise Fedele, PhD – Sr. Lab Manager, Dept. Neurosurgery, Rutgers University; Kiran Toti, PhD – National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health – Molecular Recognition Section, Laboratory of Bioorganic Chemistry; Zhiwei Wen, PhD – Postdoctoral Researcher, Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Kenneth Jacobson, PhD – Molecular Recognition Section, Laboratory of Bioorganic Chemistry – National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Detlev Boison, Professor – Vice Chair of Research and Training, Dept. of Neurosurgery Professor, Dept. of Neurosurgery, Robert Wood Johnson Medical School Professor, Dept. of Neurosurgery, New Jersey Medical School Core Member, Brain Health Institute, Dept. Neurosurgery, Rutgers University
Rationale:
Traumatic Brain Injury (TBI) is a major cause of acquired epilepsies. Posttraumatic epilepsy (PTE) is a major unresolved health concern with a high rate of refractoriness to treatment. Therefore, there is an urgent need for the development of therapeutic strategies capable of preventing PTE and its progression.
Prior research from our lab demonstrated that epilepsy and its progression can be prevented by therapeutic adenosine (ADO) augmentation to the brain. Specifically, we demonstrated that the transient delivery of ADO to the brain via silk-based brain implants prevented epilepsy progression long term. In the brain ADO levels are primarily regulated by adenosine kinase (ADK), which is a well-established target for the prediction and prevention of epileptogenesis. However, the regulation of ADK expression after TBI, its role in the development of post-traumatic epilepsy (PTE), and the underlying mechanisms remain unclear and need to be investigated to form a mechanistic basis for future translational work. The goal of this study was to determine maladaptive ADK expression changes during epileptogenesis in a clinically relevant rodent model of PTE and to test whether ADK inhibitors can interfere with the epileptogenic process.
Methods:
TBI was performed using the controlled-cortical impact (CCI) model. Mice received a single left lateral impact with an electromagnetic CCI device allowing precisely-controlled cortical injuries. The parameters of the impact injury are a depth of 2.0 mm at a velocity of 5 m/s and 100 ms duration. Controls included a sham group and mice with a transgenic overexpression of ADK-L, the nuclear isoform of the enzyme, which plays a key epigenetic role in the epileptogenic process. Animals were transiently treated from 3 to 10 days after the CCI with either the non-selective ADK inhibitor 5-iodotubercidin (5-ITU), or with the novel ADK-L active inhibitor MRS4203. Kainic acid evoked seizures were quantified 4 weeks after the CCI via cortical EEG recordings.
Results:
We demonstrate progressive increases in ADK expression in conjunction with astrogliosis following CCI. In line with a role of ADK-L in promoting the epileptogenic process, mice overexpressing ADK-L presented an increase in brain excitability following a challenge with kainic acid 28 days post-CCI. An increase in the mortality rate was also observed in these mice when compared to CCI-wild-type mice. Importantly, CCI mice transiently treated with the ADK-L active inhibitor MRS4203 showed reduced brain excitability in the EEG total power 28 days post-CCI when compared to control mice or mice treated with the non-selective inhibitor 5-ITU.
Conclusions:
We conclude that CCI triggers ADK dysregulation similar to kainic acid induced epilepsy models, and that ADK-L is a potential target for the prevention of PTE.
Funding: H2020 Marie Skłodowska-Curie Actions Individual Fellowship (No. 101032321)
US Department of the Army, USAMRMC –
CDMRP - W81XWH2210638 - (PI: Boison)