Minocycline Transiently Reduces Microglia/Macrophage Activation but Exacerbates Cognitive Deficits Following Repetitive Traumatic Brain Injury in the Neonatal Rat

Abstract

Elevated microglial/macrophage-associated biomarkers in the cerebrospinal fluid of infant victims of abusive head trauma (AHT) suggest that these cells play a role in the pathophysiology of the injury. In a model of AHT in 11-day-old rats, 3 impacts (24 hours apart) resulted in spatial learning and memory deficits and increased brain microglial/macrophage reactivity, traumatic axonal injury, neuronal degeneration, and cortical and white-matter atrophy. The antibiotic minocycline has been effective in decreasing injury-induced microglial/macrophage activation while simultaneously attenuating cellular and functional deficits in models of neonatal hypoxic ischemia, but the potential for this compound to rescue deficits after impact-based trauma to the immature brain remains unexplored. Acute minocycline administration in this model of AHT decreased microglial/macrophage reactivity in the corpus callosum of brain-injured animals at 3 days postinjury, but this effect was lost by 7 days postinjury. Additionally, minocycline treatment had no effect on traumatic axonal injury, neurodegeneration, tissue atrophy, or spatial learning deficits. Interestingly, minocycline-treated animals demonstrated exacerbated injury-induced spatial memory deficits. These results contrast with previous findings in other models of brain injury and suggest that minocycline is ineffective in reducing microglial/macrophage activation and ameliorating injury-induced deficits following repetitive neonatal traumatic brain injury.

Differential effects of minocycline on microglial activation and neurodegeneration following closed head injury in the neonate rat

“…Minocycline or vehicle was injected every 12 hours for 3 days for a total of 6 injections (45 mg/Kg/injection or 0.2 mL/Kg/injection). This dose and dosing paradigm was successful in reducing acute microglial activation in neonate repetitive TBI (Hanlon et al, 2016) and other models of neonate HI (Buller et al, 2009). Details of animal numbers as a function of outcome measure and time point are presented in Table 2.…”

“…Similarly, minocycline administration following moderate-severe contusive trauma to the adult rat brain reduced microglial activation and improved behavioral function (Abdel Baki et al, 2010; Lam et al, 2013). In contrast, minocycline did not attenuate cell death, axonal injury or tissue loss despite reducing active microglia following either diffuse brain trauma in the adult mouse (Bye et al, 2007) or repetitive brain trauma in the neonate rat (Hanlon et al, 2016). Depleting the brain of its resident microglia exacerbates cell death following neonatal stroke (Faustino et al, 2011) but appears to not affect the extent of white matter injury following TBI (Bennett and Brody, 2014).…”

White matter damage after traumatic brain injury: A role for damage associated molecular patterns

“…Similarly, inhibition of CX3CR1, a receptor involved in microglial chemotaxis, decreased microglial activation, reduced IL-1β production, attenuated white matter injury, and improved neurocognitive function in a pre-clinical model of vascular cognitive impairment [196]. While the aforementioned findings suggest a detrimental role for microglia after TBI, minocycline failed to attenuate traumatic axonal injury, tissue atrophy, neurodegeneration, or spatial learning deficits in a pediatric head trauma model [197]. Thus, additional experimentation is required to ascertain whether the effects of microglial activation are model dependent, time dependent, and/or age specific after TBI.…”

Pre-clinical models in pediatric traumatic brain injury—challenges and lessons learned

“…There were a few early reports on the use of PND 6–8 rats exposed to shaking plus hypoxemia to model AHT [28–30]. More recently several reports in PND 11 rats have used single or multiple closed head impacts also to model AHT in infants [15, 31–33]. A timeline of model development and utilization in pediatric TBI is provided in Figure 1.…”

“…The most common tool used to assess cognitive outcome in TBI models is the Morris water maze (MWM). Regarding model development and therapy testing, it is important to note that developing rats do not reach adult levels of proficiency in the MWM until PND 21–23 [31]. The MWM has thus, with this caveat, been successfully used to assess behavioral outcomes in developmental TBI model for over 15 years including CCI, fluid percussion (FPI), and impact acceleration diffuse brain injury [9,14,16].…”