Artikel
Minocycline application after traumatic brain injury in rats leads to a decrease in neuronal death and improvement of functional outcome
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Veröffentlicht: | 13. Mai 2014 |
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Objective: After traumatic brain injury (tbi) apoptotic cell death occurs in addition to necrosis. Delayed neuronal death may be triggered by the invasion of microglia after ischemia as well as tbi and may lead to greater traumatic lesions and worse outcome. The application of minocycline, a tetracycline derivative, reduces microglial invasion, leading to smaller lesion volumes and better outcome after ischemia. Our own data could affirm a decrease in microglial and apoptotic neurons adjacent to the tbi lesion. This study was designed to investigate whether minocycline is able to reduce necrotic and apoptotic neuronal death in the hippocampus and if it has influence on functional outcome after tbi in rats.
Method: Tbi was inflicted on male Wistar rats using the controlled cortical impact model (Dixon 1991). The treatment group received minocycline i.p. starting 1 h after tbi (90 mg/kgbw). In the subsequent 96 h animals 45 mg/kgbw of minocycline were administered twice daily. Control animals received saline instead. 12 h after the last injection, one group of was sacrificed and brains were removed and processed either for TUNEL or microglia staining. Another group was tested for functional outcome using beam balance and beam walking tests for 10 days. The Morris water maze was used to test learning and memory function. Animals were then sacrificed and brains were removed and processed for TUNEL and standard histological staining.
Results: Staining for ED-1 showed a significant reduction in microglial invasion and TUNEL staining demonstrated a lower number of apoptotic neurons in the minocycline group after tbi compared to controls. The minocycline treated animals showed better results at beam balance and beam walking tests during the first days but no significant difference was found between the groups after 10 days. All minocycline treated animals showed significantly better results in the Morris water maze at all times. Histological staining revealed a reduced number of apoptotic and necrotic neurons in the ipsilateral hippocampus.
Conclusions: Our results demonstrate that minocycline is able to reduce neuronal cell death after tbi around the lesion site but also in the ipsilateral hippocampus and lead to a better functional outcome, especially in respect to memory and learning. This might be due to the fact that minocycline reduces microglia invasion and glutamate overexpression. Since minocycline can be administered as late as 1 h after tbi, it may be a useful tool in the treatment of tbi patients.