SYSTEMS BIOLOGY-BASED DRUG DISCOVERY TO PROMOTE RECOVERY FROM TRAUMATIC BRAIN INJURY

NATALLIE KAJEVU; IVETTE BANUELOS‐CABRER; PEDRO ANDRADE; ANSSI LIPPONEN; MIKKO HILTUNEN; NOORA PUHAKKA; LUCIANA GAVERNET; LAUREANO SABATIER; TEEMU NATUNEN; ALAN TALEVI; ASLA PITKÄNEN

Simposio; The 38th Annual National Neurotrauma Symposium; 2021

More than 40% of traumatic brain injury (TBI) survivors develop long‐term health complications, including epilepsy. However, despite promising preclinical evidence, no treatments are available in clinic to improve post‐TBI recovery. Objective: To use perilesional transcriptomics data and molecular docking approach to identify drugs that mitigate TBI‐induced neuropathology. Hypothesis: Systems‐biology ‐derived discovery of compounds, promoting neuroprotection, alleviating inflammation and oxidative stress, and reducing seizure occurrence will identify treatments to promote post‐TBI recovery. Selected drugs were validated in vitro to assess their anti‐inflammatory and neuroprotective potential. Promising compounds [Trichostatin A (TSA) and FBA] were evaluated in vivo, using lateral fluid‐percussion injury in adult male Sprague‐Dawley rats. Drug or vehicle treatment was administered at 2 h and 24 h post‐TBI. Video‐electroencephalogram monitoring was continued for 2 wk post‐TBI. Mean number of seizures/rat during 0‐72 h post‐TBI was 9.7 ± 2.7 in vehicle, 9.0 ± 1.7 (p > 0.05 compared to vehicle) in TSA and 4.5 ± 0.9 (p  0.05) in TSA and 55 ± 5s (p > 0.05) in FBA treated rats. Some TSA and FBA treated animals had lower levels of plasma pNF‐H, a marker of axonal injury. Histologic analysis indicated that both in TSA and FBA groups 2/7 rats had small, 3/7 medium and 2/7 had large focal cortical lesions. FBA but not TSA reduced frequency of acute post‐TBI seizures. A subpopulation of animals showed reduced post‐TBI pNF‐H levels. Further quantitative studies with expanded animal cohort will show whether there is a link between milder post‐TBI seizure activity and extent of cortical lesion and plasma axonal injury marker levels.