Functional Assessment of Long-Term Deficits in Rodent models of Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) ranks as the leading cause of mortality and disability in the young population worldwide. The annual US incidence of TBI in the general population is estimated at 1.7 million per year, with an estimated financial burden in excess of US$75 billion a year in the USA alone. Despite the prevalence and cost of TBI to individuals and society, no treatments have passed clinical trial to clinical implementation. The rapid expansion of stem cell research and technology offers an alternative to traditional pharmacological approaches targeting acute neuroprotection. However, preclinical testing of these approaches depends on the selection and characterization of appropriate animal models. In this article we consider the underlying pathophysiology for the focal and diffuse TBI subtypes, discuss the existing preclinical TBI models and functional outcome tasks used for assessment of injury and recovery, identify criteria particular to preclinical animal models of TBI in which stem cell therapies can be tested for safety and efficacy, and review these criteria in the context of the existing TBI literature. We suggest that 2 months post-TBI is the minimum period needed to evaluate human cell transplant efficacy and safety. Comprehensive review of the published TBI literature revealed that only 32% of rodent TBI papers evaluated functional outcome ≥1 month post-TBI, and only 10% evaluated functional outcomes ≥2 months post-TBI. Not all published papers that evaluated functional deficits at a minimum of 2 months post-TBI reported deficits; hence, only 8.6% of overall TBI papers captured in this review demonstrated functional deficits at 2 months or more postinjury. A 2-month survival and assessment period would allow sufficient time for differentiation and integration of human neural stem cells with the host. Critically, while trophic effects might be observed at earlier time points, it will also be important to demonstrate the sustainability of such an effect, supporting the importance of an extended period of in vivo observation. Furthermore, regulatory bodies will likely require at least 6 months survival post-transplantation for assessment of toxicology/safety, particularly in the context of assessing cell abnormalities.

Repeated mild traumatic brain injury: potential mechanisms of damage

“…239 Tests assessing psychological sequelae have also been employed to detect anxiety-and depressivelike behavior. Behavioral impairments have been consistently revealed in closed-head animal models of repeated mTBI, incorporating various degrees of head movement and inter-injury intervals.…”

One Step at a Time, Stem Cell Therapy for Traumatic Brain Injury Needs Two More Breakthroughs

“…1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action.…”

“…1,[23][24][25] Several preclinical studies have evaluated the efficacy of rodent neural precursor cells in TBI rodent models. 22,[26][27][28][29][30] The culturing NSCs in vitro started as an attempt to grow multipotent embryonic cortical tissue (the word neural stem cells was not yet coined) and successfully accomplished in 1989 at the University of Miami.…”

“…53,54 A review of literature shows human cell therapy in rat TBI that measure cognitive benefit have not addressed donor cell fate past one-month posttransplantation. 1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26 The successful preclinical ALS, SCI and stroke studies.…”

“…1,55 Further the experts in the field recommended that 8-week survival period prior to assessments would allow sufficient time for differentiation and integration of human neural stem cells with the host and possibly validate the presumed mechanism of action. 1,26 The successful preclinical ALS, SCI and stroke studies. 40,41,44,56 have employed a different immunosuppression technique that was pioneered by Hefferan et al 40 This technique relies on three agents namely: mycophenylate mofetil, tacrolimus and methyl prednisolone.…”