Resumo

Traumatic brain injury (TBI) is the leading cause of death among individuals younger than 44 years old. Extradural haemorraghe is a common finding in those traumatized patients. Because of its acute evolution and high mortality rate (when not surgically treated), such lesion is considered the main neurosurgical emergency. On the other hand, Alzheimer´s disease (AD) affects mainly older individuals, being the most important chronic neurodegenerative disease, leading to death about a decade after the initial symptoms. Several studies have proposed a possible link between previous TBI and higher risk of AD development later. The aim of this study is to further investigate this pathophysiological relationship as well as the possible participation of amyloid-beta oligomers (ADDLS) on the secondary traumatic brain lesion. Wistar male adult rats were submitted to experimental extra-axial (extradural) brain compression (simulating an extradural haematoma) and followed postoperatively. One group of animals were submitted to long term memory analysis on the first week after surgery and sacrificed at the end of the second week. Their brains were removed and tissue was stained with Fluorojade C to detect neurodegeneration. Additionally, Western-blot analysis for serine racemase (SR), the enzyme responsible for conversion of L-serine to D-serine, was carried out. Cerebrospinal fluid (CSF) was investigated by Dot-blot for ADDLS. Another group was sacrificed on the immediate postoperative time and the brain tissue was analyzed by electron microscopy to detect primary brain lesions. Data we obtained indicated that traumatized rats had significant deficit in long term memory in comparison with controls (sham-traumatized rats) (p<0, 0001). Macroscopically, cerebral cortex ipsilateral to the lesion displayed the most extensive neuronal death as indicated by the cavitation just under the point of brain compression. In line with memory tests, traumatized animals displayed evidence of neurodegeneration in both hippocampi two weeks after brain trauma. In order to clarify the chronology of neuronal death we carried out electron microscopy analysis of brain tissue immediately after extradural compression. Images obtained revealed signs of neuronal death only ipsilaterally to the traumatized region, thus indicating that contralateral neurodegeneration is a secondary phenomenon (nonexistent at the moment of trauma). Western-blot analysis suggested reduction in SR level in traumatized tissue in comparison with the non-traumatized controls. This reduction is most intense ipsilateraly to the lesion. No reduction of enzyme level was observed in dorsal-contralateral region. Decrease in SR levels could be linked to cellular mechanism of self-protection against excitotoxicity, once D-serine is a NMDA receptor co-agonist, overactivated in several types of brain injuries. Dot-blot analysis pointed to the presence of ADDLS in CSF of TBI animals. ADDLS were not detected in CSF of sham-traumatized rats, suggesting that brain compression induced production of ADDLS. The possible connection between ADDLS production in traumatized rats and the widespread secondary injury observed is under investigation. Thus, the production of ADDLS can be an important factor to trigger the late neurodegenerative process observed in extradural brain trauma. Therefore, therapeutical strategies aiming the blockade of neuronal death in AD models may be also useful in TBI neuroprotection.