Combination therapies for neurobehavioral and cognitive recovery after experimental traumatic brain injury: Is more better?

Abstract

Traumatic brain injury (TBI) is a significant health care crisis that affects two million individuals in the United Sates alone and over ten million worldwide each year. While numerous monotherapies have been evaluated and shown to be beneficial at the bench, similar results have not translated to the clinic. One reason for the lack of successful translation may be due to the fact that TBI is a heterogeneous disease that affects multiple mechanisms, thus requiring a therapeutic approach that can act on complementary, rather than single, targets. Hence, the use of combination therapies (i.e., polytherapy) has emerged as a viable approach. Stringent criteria, such as verification of each individual treatment plus the combination, a focus on behavioral outcome, and post-injury vs. pre-injury treatments, were employed to determine which studies were appropriate for review. The selection process resulted in 37 papers that fit the specifications. The review, which is the first to comprehensively assess the effects of combination therapies on behavioral outcomes after TBI, encompasses five broad categories (inflammation, oxidative stress, neurotransmitter dysregulation, neurotrophins, and stem cells, with and without rehabilitative therapies). Overall, the findings suggest that combination therapies can be more beneficial than monotherapies as indicated by 46% of the studies exhibiting an additive or synergistic positive effect versus on 19% reporting a negative interaction. These encouraging findings serve as an impetus for continued combination studies after TBI and ultimately for the development of successful clinically relevant therapies.

Keywords: Cognition; Combination therapies; Controlled cortical impact; Environmental enrichment; Fluid percussion; Neurobehavioral; Stem cells; Traumatic brain injury.

Fig. 1

Cartoon illustrating the progression and consequences of TBI. As noted, TBI consists of a primary impact, which leads to immediate cell death at the site of injury with subsequent progression into a secondary phase of TBI pathology. The second phase initiates a plethora of pathophysiological cascades that leads to further damage as well as neurobehavioral and cognitive dysfunction. For clarity, only a few of the TBI-induced responses are portrayed.

Fig. 2

Bar graphs showing the total number of papers that reported positive, neutral, or negative outcomes with the combinational therapy approach after TBI. As illustrated, 17 papers reported positive outcomes, 13 were neutral, and only 7 were negative. The figure further illustrates how inflammation, oxidative stress, neurotransmitters, neurotrophic, and stem cell therapies fit into each outcome.