Traumatic brain injury (TBI) is caused by mechanical force to the head, most often in traffic accidents, sports or falls. Annually over 50 million people worldwide suffer TBI and for over 40% it causes chronic disabilities. TBI initiates complex secondary damage, including e.g. inflammation, neurodegeneration, and oxidative stress. Despite hundreds of pre-clinical and clinical studies, there is no pharmacotherapy that could prevent disabilities post-TBI.
In his doctoral thesis, Anssi Lipponen, MSc, aimed to characterise chronic transcriptomic profiles after fluid percussion injury (FPI) induced TBI in three brain areas and investigate whether DNA methylation or transcription factors regulate transcriptomics. Moreover, the aim was to identify novel pharmacotherapy candidates by using a systems biology approach and to set up a stepwise validation pipeline.
Transcriptomics analysis found upregulation of immunity and inflammatory as well as downregulation of ion-channel and mitochondrial genes in the cortex and thalamus three months post-TBI. DNA methylation was not found as a main regulator of chronic transcriptomics. However, transcription factors Cebpd, Pax6, Spi1, and Tp73 were upregulated chronically post-TBI and are potential regulators of transcriptomics.
A systems biology approach utilizing transcriptomics and identified transcription factors indicated antidepressants, neuroleptics and anti-cancer drugs used in clinics as candidates to enhance recovery after TBI. Desmethylclomipramine, the main metabolite of clomipramine antidepressant indicated a wide therapeutic time window, anti-inflammatory and neuroprotective effects, and favourable target engagement and pharmacokinetics. In an in vivo trial, clomipramine did not affect motoric functions or spatial memory after rat FPI. Rather, treatment impaired the somatomotoric recovery, and caused weight loss. Further analyses indicated that the treatment prolonged upregulation of plasma cytokine levels which might be caused by adverse effects, emphasizing the need of in vivo validation of in silico findings.
To summarize, the pipeline described in the thesis provides a rational stepwise procedure for evaluating the effects of systems-biology–discovered compounds to be repurposed for TBI and to accelerate discovery of drugs for TBI.
The doctoral dissertation of Anssi Lipponen, Master of Science, entitled A systems biology approach for identification and stepwise validation of pharmacotherapy candidates for traumatic brain injury, will be examined at the Faculty of Health Sciences on 21 February 2020. The Opponent in the public examination will be Professor Niklas Marklund of Lund University, and the Custos will be Professor Asla Pitkänen of the University of Eastern Finland.
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