Sexually Dimorphic Behavioral and Genetic Outcomes Associated With Administration of TA65 (A Telomerase Activator) Following Repetitive Traumatic Brain Injury: A Pilot Study

Eric Eyolfson,Haris Malik,Richelle Mychasiuk

doi:10.3389/fneur.2020.00098

Abstract

Children and adolescents have the highest rates of traumatic brain injury (TBI), with mild TBI (mTBI) accounting for most of these injuries. This demographic also often suffers from post-injury symptomologies that may persist for months. Telomere length (TL) has previously been used as a marker for outcomes following repetitive mild TBI (RmTBI) and it may be possible that telomere elongation can reduce post-traumatic behavioral impairments. Telomerase activator-65 (TA-65) is a telomerase small-molecule activator purified from the root of Chinese herbs that has been anecdotally reported to have anti-aging and life-extending potential. We hypothesized that RmTBI would shorten TL but administration of TA-65 would reverse RmTBI-induced telomere shortening and behavioral deficits. Male and female Sprague-Dawley rats were orally administered TA-65 or a placebo substance for 30 consecutive days [postnatal day (P) 25–55]. Following the injury protocol (mTBIs on P33, 36, and 40), rats went through a behavioral test battery designed to examine symptomologies commonly associated with mTBI (balance and motor coordination, exploratory behavior, short-term working memory, and anxiety- and depressive-like behaviors). TL in ear and brain tissue (prefrontal cortex and hippocampus) and relative expression of TERT and Tep1 via qPCR were assessed 15 days following the last injury. We observed a heterogenous response between males and females, with TA65 administration resulting in increased mRNA expression of TERT and Tep1 in female rats that experienced RmTBI, which was accompanied by some functional recovery on motor behavior and footslips in the beam walk task and depressive-like behavior in the forced swim task.

Highlights

Traumatic brain injury (TBI) is a major public health issue and is one of the most common causes of death and disability in childhood and adolescence [1]
We found that TA65 treatment exacerbated some behavioral symptomologies in male rodents, while offering a small benefit to females with repetitive mTBI (RmTBI)
With respect to Telomere length (TL), we found that TA65 treatment increased ear notch TL in females, and prefrontal cortex (PFC) TL in males, while attenuating normal reductions in telomere length over time

Summary

Introduction

Traumatic brain injury (TBI) is a major public health issue and is one of the most common causes of death and disability in childhood and adolescence [1]. Mild TBI (mTBI), or concussion, has been recently spotlighted within the media and accounts for 80% of all TBI’s [2]. The adolescent age group is at particularity high risk for mTBI, with male adolescents experiencing. Of all adolescent mTBIs, sport accounts for >60% of reported injuries [4]. Adolescents are at high risk for chronic post-injury deficits [5] and the long-term consequences of repetitive mTBI (RmTBI) during this critical period of brain development are largely unknown. Recent adult literature has linked RmTBI to prolonged neurocognitive and behavioral changes, worse prognoses and long-term neurological sequelae, and poorer executive function, depression scores, and cognitive changes that have been related to the number of injuries received [6, 7]

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