Minocycline Restores sAPPα Levels and Reduces the Late Histopathological Consequences of Traumatic Brain Injury in Mice

Abstract

Traumatic brain injury (TBI) induces both focal and diffuse lesions that are concurrently responsible for the ensuing morbidity and mortality and for which no established treatment is available. It has been recently reported that an endogenous neuroprotector, the soluble form α of the amyloid precursor protein (sAPPα), exerts neuroprotective effects following TBI. However, the emergent post-traumatic neuroinflammatory environment compromises sAPPα production and may promote neuronal degeneration and consequent brain atrophy. Hence, the aim of this study was to examine the effects of the anti-inflammatory drug minocycline on sAPPα levels, as well as on long-term histological consequences post-TBI. The weight-drop model was used to induce TBI in mice. Minocycline or its vehicle were administered three times: at 5 min (90 mg/kg, i.p.) and at 3 and 9 h (45 mg/kg, i.p.) post-TBI. The levels of sAPPα, the extent of brain atrophy, and reactive gliosis were evaluated by ELISA, cresyl violet, and immunolabeling of GFAP and CD11b, respectively. Our results revealed a post-TBI sAPPα decrease that was significantly attenuated by minocycline. Additionally, corpus callosum and striatal atrophy, ventriculomegaly, astrogliosis, and microglial activation were observed at 3 months post-TBI. All the above consequences were significantly reduced by minocycline. In conclusion, inhibition of the acute phase of post-TBI neuroinflammation was associated with the sparing of sAPPα and the protection of brain tissue in the long-term, emphasizing the potential role of minocycline as an effective treatment for TBI.

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

“…Short-term administration of minocycline (similar to the paradigm used in study 1) has been found effective in decreasing microglial activation following neonatal hypoxic ischemia (Cai et al, 2006; Cikla et al, 2016; Fan et al, 2006; Lechpammer et al, 2008), pediatric cardiac arrest (Tang et al, 2010), neonatal repetitive TBI (Hanlon et al, 2016), and adult TBI (Bye et al, 2007; Homsi et al, 2010; Siopi et al, 2011). The reduction in activated microglia was accompanied by an attenuation of neuronal damage (Cikla et al, 2016), a decrease in asphyxia-induced neurodegeneration (Tang et al, 2010), and a reduction of lesion volume following TBI (Homsi et al, 2010).…”

“…In the neonate, HI-induced microglial activation and the concomitant oligodendrocyte cell death, myelin loss and decrease in white matter volume were attenuated by minocycline (Cai et al, 2006; Fan et al, 2006; Lechpammer et al, 2008). In the adult mouse, TBI-induced loss of corpus callosum volume was attenuated by minocycline treatment (Siopi et al, 2011). In contrast, short-term administration of minocycline in the present study did not affect axonal injury or degeneration, an observation that was similar to those in a model of repetitive brain trauma in the neonate rat (Hanlon et al, 2016) and closed head injury in the adult mouse (Homsi et al, 2010).…”

“…Following TBI in the adult mouse, short-term minocycline administration led to a sustained suppression of total microglial numbers at 3 months after the injury (Homsi et al, 2010; Siopi et al, 2011). Total microglia was decreased in minocycline-treated neonatal mice up to 9 days following hypoxic-ischemia (Cikla et al, 2016).…”

“…In a model of pediatric cardiac arrest, acute treatment with minocycline reduced microglial activation along with neurodegeneration and apoptosis (Tang et al, 2010). Treatment with minocycline following TBI in the adult mouse resulted in a reduction of microglial activation and proliferation which was associated with a decrease in pro-inflammatory cytokine response, cerebral edema, lesion volume and attenuation of locomotor and spatial memory deficits (Homsi et al, 2009; Homsi et al, 2010; Siopi et al, 2011; Siopi et al, 2012). 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).…”

Repetitive Mild Traumatic Brain Injury in a Mouse Model Produces Learning and Memory Deficits Accompanied by Histological Changes

“…59,60 Moreover, in several TBI models, minocycline, which has antiinflammatory properties, has been shown to reduce histopathological consequences after mTBI in mice. 61,62 Of particular interest is a recent study by Siopi and collaborators that demonstrated that reducing neuroinflammation post-injury attenuated memory impairment in a mouse model of CHI; 63,64 however, more work is required to address the impact of microglial activation on cognitive function after TBI.…”