Acute Minocycline Treatment Mitigates the Symptoms of Mild Blast-Induced Traumatic Brain Injury

Abstract

Mild traumatic brain injury (mTBI) represents a significant challenge for the civilian and military health care systems due to its high prevalence and overall complexity. Our earlier works showed evidence of neuroinflammation, a late onset of neurobehavioral changes, and lasting memory impairment in a rat model of mild blast-induced TBI (mbTBI). The aim of our present study was to determine whether acute treatment with the non-steroidal anti-inflammatory drug minocycline (Minocin®) can mitigate the neurobehavioral abnormalities associated with mbTBI, Furthermore, we aimed to assess the effects of the treatment on select inflammatory, vascular, neuronal, and glial markers in sera and in brain regions associated with anxiety and memory (amygdala, prefrontal cortex, ventral, and dorsal hippocampus) following the termination (51 days post-injury) of the experiment. Four hours after a single exposure to mild blast overpressure or sham conditions, we treated animals with a daily dose of minocycline (50 mg/kg) or physiological saline (vehicle) for four consecutive days. At 8 and 45 days post-injury, we tested animals for locomotion, anxiety, and spatial memory. Injured animals exhibited significantly impaired memory and increased anxiety especially at the later testing time point. Conversely, injured and minocycline treated rats’ performance was practically identical to control (sham) animals in the open field, elevated plus maze, and Barnes maze. Protein analyses of sera and brain regions showed significantly elevated levels of all of the measured biomarkers (except VEGF) in injured and untreated rats. Importantly, minocycline treatment normalized serum and tissue levels of the majority of the selected inflammatory, vascular, neuronal, and glial markers. In summary, acute minocycline treatment appears to prevent the development of neurobehavioral abnormalities likely through mitigating the molecular pathologies of the injury in an experimental model of mbTBI.

Reversal of Established Traumatic Brain Injury-Induced, Anxiety-Like Behavior in Rats after Delayed, Post-Injury Neuroimmune Suppression

“…To our knowledge, this is the first study to examine delayed immunosuppression at long-term injury time points, because other immunosuppressive treatments targeting anxiety-like behaviors have been administered before or within hours of injury. 34,37,38,[66][67][68][69] These results indicate that the persistence of post-traumatic anxiety may reflect chronic neuroinflammatory neuropathy, a possibility supported by the observation of activated microglia and astrocytes, key cells mediating inflammatory processes, many years after injury in long-term survivors of TBI. [9][10][11][12] Chronic post-traumatic neuroinflammation suggests the presence of a self-perpetuating positive feedback loop, possibly involving reactivation and further promotion of inflammatory mediators after injury in an inflammation-damage-inflammation cycle.…”

Targeting Microglia to Prevent Post-Traumatic Epilepsy

“…To our knowledge, this is the first study to examine delayed immunosuppression at long-term injury time points, because other immunosuppressive treatments targeting anxiety-like behaviors have been administered before or within hours of injury. 34,37,38,[66][67][68][69] These results indicate that the persistence of post-traumatic anxiety may reflect chronic neuroinflammatory neuropathy, a possibility supported by the observation of activated microglia and astrocytes, key cells mediating inflammatory processes, many years after injury in long-term survivors of TBI. [9][10][11][12] Chronic post-traumatic neuroinflammation suggests the presence of a self-perpetuating positive feedback loop, possibly involving reactivation and further promotion of inflammatory mediators after injury in an inflammation-damage-inflammation …”

“…However, there have been recent seminal reports by Vink and colleagues (63-65) of post-traumatic anxiety-like behavior in rats using an impact-acceleration model of diffuse TBI and noting significant decreases in open field exploration due to freezing (a natural defensive fear response of rats). Several other groups have since reported similar post-traumatic anxiety in rodents using a variety of TBI methods, postinjury measurement time-points, and behavioral measures (66)(67)(68)(69)(70). Freezing behavior was not measured directly in these studies, although freezing was consistently reported to cause decreased exploratory behavior in the open field test (63)(64)(65), suggesting a dominant fear response that is associated with pathological anxiety.…”

“…and durable for >24 hr. (64,65,(68)(69)(70). Interestingly it has recently been shown that MN166 administration can increase the anti-inflammatory cytokine IL-10 expression close to 40 fold in vivo (71).…”

Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke

“…In a study examining the use of minocycline in a blast injury model of TBI in rats, researchers noted a decrease in post-TBI anxiety via the elevated plus maze at 46 days post-injury accompanied by decreased corticosterone levels and improvements in spatial memory via Barnes maze testing post-injury as late as 47 days post-TBI [237]. Minocycline administration also decreased inlammatory and neuron and glial injury-associated markers c-reactive protein, monocyte-chemotactic protein-1, neuron-speciic enolase, S100 β, tau, and neuroilament H in this study [237].…”