The doctoral dissertation in the field of Neuroscience will be examined at the Faculty of Health Sciences. The public examination will be streamed online.
What is the topic of your doctoral research? Why is it important to study the topic?
Traumatic brain injury (TBI) is one of the leading causes of injury related death and disability globally. TBI is an alteration in brain function caused by an external force to the brain resulting in a primary injury. After the primary injury, a cascade of secondary molecular modifications occurs and can persist for weeks to even years after TBI. These secondary modifications lead to chronic TBI-induced pathology resulting in lifelong neurological disorders. Particularly TBI increases the risk of epileptogenesis which is a chronic and continuous process that leads to post traumatic epilepsy. To date no treatments can effectively halt or mitigate the secondary events which occur after TBI. The main aim of this preclinical study is to identify treatments that can be repurposed to improve recovery after TBI.
What are the key findings or observations of your doctoral research?
We hypothesised that treatments which prevent the major hallmarks of TBI in vitro, such as cell death, neuroinflammation and oxidative stress will have favourable disease modifying effect and promote both structural and functional recovery after lateral fluid percussion-induced-TBI (LFPI-TBI) in rats. Three approaches were used to identify drugs that could be repurposed to treat post-TBI secondary pathology: A pathology centric approach, a systems biology-based approach and computer-aided drug discovery. An antioxidant duotherapy treatment identified through the pathology centric approach had a favourable neuroprotective effect in vitro. The antioxidant treatment increased cortical expression of NRF2 and had a mild effect on the beam walking test after TBI in rats. Trichostatin A (TSA), a histone deacetylace inhibitor identified through the system biology-based approach had a strong neuroprotective effect in vitro. In vivo, TSA had a promising effect in reducing cortical lesion area and plasma phosphorylated neurofilament heavy (pNF-H) after TBI in rats. Combining TSA with a potent antiseizure drug – Levetiracetam (LEV) did not enhance the antiseizure effect of LEV.
Finally, FBA, a compound discovered through computer-aided drug discovery (CADD), had a promising neuroprotective effect in vitro. FBA also reduced cortical lesion area and pNF-H after TBI in rats. In addition, FBA reduced the cumulative seizure duration and had a promising effect in alleviating status epilepticus.
Overall, this thesis indicates that FBA has a promising effect in promoting recovery after TBI suggesting that CADD is a promising approach to identify novel treatments for TBI.
How can the results of your doctoral research be utilised in practice?
This study demonstrates the importance of performing multiple drug discovery approaches when searching for a drug that has a beneficial disease modifying effect on TBI outcome. As FBA emerged as a promising drug, more studies need to be done to fully understand its mechanism of action (MOA), pharmacokinetics and toxicity profile. In addition future studies are needed to determine whether this promising effect of FBA could impend epileptogenesis and prevent PTE. After thorough investigation and successful validation FBA could then proceed to clinical trials.
What are the key research methods and materials used in your doctoral research?
In this thesis investigational drugs identified to be repurposed to promote recovery from TBI were first tested in vitro in neuronal-BV2 microglial co-cultures. The effect of the drugs to promote neuronal survival was assessed using a MAP-2 immunoassay. In addition, the effect of the drugs to reduce nitrite levels (oxidative stress) and TNFα (neuroinflammation) was assessed using Griess reagent nitrite assay and ELISA TNFα respectively. The most promising drugs were tested in vivo to assess their effects in promoting recovery from TBI in rats. After LFPI-TBI treatments were initiated in the immediate phase (1 h or 2 h) after injury. To assess the effects of the drugs in vivo behavioral tests (neuroscore, beam walking test), immunohistochemistry, ELISA was used. The effect of the drugs on cortical lesion area was determined by preparing cortical unfolded maps. Seizure occurrence and epileptiform activity were monitored using video electroencephalography.
The doctoral dissertation of Natallie Kajevu, MSc, entitled Identification of treatments for repurposing to enhance recovery outcome after traumatic brain injury will be examined at the Faculty of Health Sciences. The Opponent in the public examination will be Associate Professor Hana Kubová of The Czech Academy of Sciences, and the Custos will be Professor Asla Pitkänen of the University of Eastern Finland. The public examination will be held in English.
For further information, please contact:
Natallie Kajevu, MSc, natallie.kajevu@uef.fi
