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Combination Therapy Proves Effective in Brain Injury Treatment

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Review of “Propranolol and Mesenchymal Stromal Cells Combine to Treat Traumatic Brain Injury” from Stem Cells Translational Medicine by Stuart P. Atkinson

While the initial consequences of a traumatic brain injury (TBI) are devastating enough, survivors face varying physical, cognitive, and psychosocial deficits caused by secondary tissue injuries. Analysis of various treatment regimens has suggested that propranolol, a β-adrenergic receptor blocker, can reduce mortality after TBI while mesenchymal stem cell (MSC) treatment can influence long-term behavior via a reduction of the inflammatory environment surrounding the injury site [1]. But can these two modalities combine to give an additive effect [2, 3]?

This is the question that researchers from the laboratory of Scott D. Olson (University of Texas Health Science Center at Houston, USA) aimed to answer using controlled cortical impact injury (CCI) in rats to model TBI and secondary effects [4]. They hope their results will culminate in a safe and effective treatment modality for this all too common injury and its consequences.

Kota et al. first found that propranolol treatment itself was sufficient to reduce fluid accumulation on the brain (cerebral edema) and reduce inflammation in the brain, as measured by the reduced accumulation of activated microglia/macrophages. However, propranolol treatment in combination with MSC infusion mediated an additional decrease in serum levels of epinephrine (high epinephrine is linked to poor prognosis [5]) and an increase in BBB integrity. Excitingly, these improvements also correlated to an increase in short-term levels of neurogenesis.

All good so far for this new combination! But do these outcomes lead to functional changes? At 120 days, spatial learning and memory assessments made using the Morris water maze demonstrated significant improvements in the propranolol and MSC-treated rats as compared to propranolol-only or MSC-only treatment. The improvements in memory shown in the adjoined figure, where the red paths show the trails taken to find a hidden platform, indicate that propranolol and MSC can additively improve outcome following TBI. Lastly, the authors deemed the treatment safe, as they found no adverse effects within the time course of the study.

Safe and effective – what more do you want! This study, the first of its kind, will hopefully spur further research into the specific mechanisms in play, and also towards trials in human patients. When different forces combine, great things can be achieved!

References

  1. Wang Y, Chen X, Cao W, et al. Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat Immunol 2014;15:1009-1016.
  2. Margulies S, Hicks R, and Combination Therapies for Traumatic Brain Injury Workshop L Combination therapies for traumatic brain injury: prospective considerations. J Neurotrauma 2009;26:925-939.
  3. Stoica B, Byrnes K, and Faden AI Multifunctional drug treatment in neurotrauma. Neurotherapeutics 2009;6:14-27.
  4. Kota DJ, Prabhakara KS, van Brummen AJ, et al. Propranolol and Mesenchymal Stromal Cells Combine to Treat Traumatic Brain Injury. Stem Cells Transl Med 2016;5:33-44.
  5. Patel MB, McKenna JW, Alvarez JM, et al. Decreasing adrenergic or sympathetic hyperactivity after severe traumatic brain injury using propranolol and clonidine (DASH After TBI Study): study protocol for a randomized controlled trial. Trials 2012;13:177.