Systems Biology-Based Drug Discovery To Promote Recovery From Traumatic Brain Injury

KAJEVU NATALIE; BANUELOS-CABRERA IVETTE; ANDRADE PEDRO; LIPPONEN ANSSI; HILTUNEN MIKKO; PUHAKKA NOORA; GAVERNET LUCIANA; SABATIER LAUREANO; NATUNEN TEEMU ; TALEVI ALAN; PITKANEN ASLA

Simposio; 38th Annual National Neurotrauma Symposium; 2021

More than 40% of traumatic brain injury (TBI) survivors develop longtermhealth complications, including epilepsy. However, despite promisingpreclinical evidence, no treatments are available in clinic to improvepost-TBI recovery. Objective: To use perilesional transcriptomics dataand molecular docking approach to identify drugs that mitigate TBIinducedneuropathology. Hypothesis: Systems-biology -derived discoveryof compounds, promoting neuroprotection, alleviating inflammationand oxidative stress, and reducing seizure occurrence will identify treatmentsto promote post-TBI recovery. Selected drugs were validatedin vitro to assess their anti-inflammatory and neuroprotective potential.Promising compounds [Trichostatin A (TSA) and FBA] were evaluatedin 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 2wk post-TBI. Mean number of seizures/rat during 0-72 h post-TBI was9.7– 2.7 in vehicle, 9.0– 1.7 (p> 0.05 compared to vehicle) in TSA and4.5– 0.9 (p < 0.05) in FBAtreated rats.Mean seizure durationwas 61– 5 sin vehicle, 65– 4s (p> 0.05) in TSA and 55– 5s (p > 0.05) in FBA treatedrats. Some TSA and FBA treated animals had lower levels of plasmapNF-H, a marker of axonal injury. Histologic analysis indicated that bothin TSA and FBA groups 2/7 rats had small, 3/7 mediumand 2/7 had largefocal cortical lesions. FBA but not TSA reduced frequency of acute post-TBI seizures.Asubpopulation of animals showed reduced post-TBI pNFHlevels. Further quantitative studies with expanded animal cohort willshow whether there is a link between milder post-TBI seizure activity andextent of cortical lesion and plasma axonal injury marker levels.