Doxycycline improves traumatic brain injury outcomes in a murine survival model

Abstract

BACKGROUND Traumatic brain injury (TBI) has significant morbidity and cost implications. Primary treatment modalities aim to decrease intracranial pressure; however, therapies targeting the underlying pathophysiology of a TBI are limited. The TBI-induced microvascular leak and secondary injury are largely due to proteolysis of the blood-brain barrier (BBB) by matrix metalloproteinase-9. We previously observed doxycycline's inhibitory affinity on matrix metalloproteinase-9 resulting in preserved BBB integrity in nonsurvival murine studies. This study sought to determine the effect of doxycycline on functional motor and behavioral outcomes in the setting of a TBI murine survival model. METHODS C57BL/6J mice were assigned to a sham, TBI, or TBI with doxycycline arm. A moderate TBI was induced utilizing a controlled cortical impactor. The TBI with doxycycline cohort received a dose of doxycycline (20 mg/kg) 2 hours after injury and every 12 hours until postoperative day (POD) 6. All mice underwent preoperative testing for weight, modified neurological severity score, wire grip, and ataxia analysis (DigiGait). Postoperative testing was performed on POD 1, POD 3, and POD 6 for the same measures. SAS 9.4 was used for comparative analysis. RESULTS Fifteen sham mice, 15 TBI mice, and 10 TBI with doxycycline mice were studied. Mice treated with doxycycline had significantly improved modified neurological severity score and wire grip scores at POD 1 (all p < 0.05). Mice treated with doxycycline had significantly improved ataxia scores by POD 3 and POD 6 (all p < 0.05). There was no significant difference in rate of weight change between the three groups. CONCLUSION Mice treated with doxycycline following TBI demonstrated improved behavioral and motor function suggesting doxycycline's role in preserving murine BBB integrity. Examining the role of doxycycline in human TBIs is warranted given the relative universal accessibility, affordability, and safety profile of doxycycline.

Three-dimensional-printed collagen/chitosan/secretome derived from HUCMSCs scaffolds for efficient neural network reconstruction in canines with traumatic brain injury

“…Comprehensive reporting of neurological scores in TBI literature has been described, as there are many outcome measures that can be assessed by subjective priority, leading to evitable bias [ 57 , 58 ]. MEP revealed that 3D-CC-ST treatment could obviously address the questions of neurological dysfunction.…”

The effect of doxycycline on neuron-specific enolase in patients with traumatic brain injury: a randomized controlled trial

“…Currently, available therapeutic options provide only symptomatic relief and unable to halt the progression of secondary injury that occur following TBI. 2 Recent preclinical studies 10 , 16 , 27 showed doxycycline as a promising choice that ameliorates the secondary brain injury. Hence, this study was designed to clinically investigate the benefit of adjunctive doxycycline use in acute TBI.…”

“…Limited data are available regarding doxycycline use in TBI. One study showed improved neurological functions in mice treated with doxycycline following TBI; doxycycline preserved the BBB integrity by inhibiting the activity of the matrix metalloproteinase-9, 16 one of the main proteolytic enzymes implicated in BBB disruption. Recently, a randomized controlled trial assessed the effects of minocycline, a tetracycline derivative, on neurological outcomes in patients with brain trauma.…”