Pre-Clinical Testing of Therapies for Traumatic Brain Injury

Abstract

Despite the large number of promising neuroprotective agents identified in experimental traumatic brain injury (TBI) studies, none has yet shown meaningful improvements in long-term outcome in clinical trials. To develop recommendations and guidelines for pre-clinical testing of pharmacological or biological therapies for TBI, the Moody Project for Translational Traumatic Brain Injury Research hosted a symposium attended by investigators with extensive experience in pre-clinical TBI testing. The symposium participants discussed issues related to pre-clinical TBI testing including experimental models, therapy and outcome selection, study design, data analysis, and dissemination. Consensus recommendations included the creation of a manual of standard operating procedures with sufficiently detailed descriptions of modeling and outcome measurement procedures to permit replication. The importance of the selection of clinically relevant outcome variables, especially related to behavior testing, was noted. Considering the heterogeneous nature of human TBI, evidence of therapeutic efficacy in multiple, diverse (e.g., diffuse vs. focused) rodent models and a species with a gyrencephalic brain prior to clinical testing was encouraged. Basing drug doses, times, and routes of administration on pharmacokinetic and pharmacodynamic data in the test species was recommended. Symposium participants agreed that the publication of negative results would reduce costly and unnecessary duplication of unsuccessful experiments. Although some of the recommendations are more relevant to multi-center, multi-investigator collaborations, most are applicable to pre-clinical therapy testing in general. The goal of these consensus guidelines is to increase the likelihood that therapies that improve outcomes in pre-clinical studies will also improve outcomes in TBI patients.

Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish

“…Traumatic Brain Injury (TBI) affects 1.7 million people in the U.S. annually and is one of the leading causes of death and disability worldwide (Dixon 2017;Maas et al 2017). Despite its prevalence, treatments have not yet been developed that effectively reduce consequences of TBI, which can include cognitive impairment, emotional lability, post-traumatic epilepsy, and death (Zaloshnja et al 2008;Bazarian et al 2009;Diamond et al 2015;Tortella 2016;Juengst et al 2017;DeWitt et al 2018;Ng and Lee 2019). Neurologic damage following TBI results from both primary and secondary injuries.…”

Sex as a Biological Variable in Preclinical Modeling of Blast-Related Traumatic Brain Injury

“…Related to the need for proper design of shock studies, there has been a recent convergence of views regarding a critical aspect of blast research progress with the paramount need for standardization of results reporting for blast studies (23,206,208,210,216,(223)(224)(225)(226)(227). Clear description of static, dynamic, stagnation, and reflected pressure and how these properties are measured and interpreted are critical.…”

Teriflunomide Modulates Vascular Permeability and Microglial Activation after Experimental Traumatic Brain Injury

“…54 Several studies have been done to test novel outcome measures to assess clinical neuroinflammation. [55][56][57] A number of promising studies are utilizing radiolabeled positron emission tomography (PET) ligands to evaluate activated microglia in situ in patients. 58 In our study, daily teriflunomide administration prevented BBB breakdown 4 days post-injury at the lowest dose of 1 mg/kg.…”