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.

Galantamine and Environmental Enrichment Enhance Cognitive Recovery after Experimental Traumatic Brain Injury But Do Not Confer Additional Benefits When Combined

“…The lack of additive effects with the combinational therapy in adult TBI rats is not entirely surprising as several studies from our laboratory have shown similar effects. 11,52,64,74,76 Importantly, the combination of therapies did not produce negative effects as has been seen with different treatment paradigms. 64 The findings of the current study, and those previously reported, may be due to a floor effect.…”

“…Indeed, several studies have shown negative interactions with combination therapies. 64 However, given that the decrease in behavioral outcome was only observed in gross motor function and not the more sensitive cognitive assay suggests that the effect may be due to behavioral variability vs. actual negative synergistic effects.…”

“…[58][59][60][61]63,64,67,68,70 Briefly, beam-balance consisted of placing the rat on an elevated narrow beam (1.5 cm wide) and recording the time it remained on for a maximum of 60 sec. Beam-walk consisted of recording the elapsed time to traverse the beam (2.5 cm wide x 100 cm long).…”

“…61 EE can also provide additional benefit when combined with other therapeutic strategies that on their own also confer improvement and thus this strategy is relevant to mimic clinical rehabilitation that is often paired with pharmacotherapies. [62][63][64] GAL (Sigma-Aldrich, St. Louis, MO) was prepared daily by dissolving in sterile saline, which also served as the VEH. GAL (1, 2, or 3 mg/kg) or a comparable volume of VEH (1 mL/kg) was administered intraperitoneally beginning 24 hr after cortical impact or sham injury and once daily for 3 weeks.…”

“…The route of administration is standard protocol in our laboratory. [58][59][60][61]63,64,[67][68][69] …”