Szczygielski Jacek, Hubertus Vanessa, Kruchten Eduard, Müller Andreas, Albrecht Lisa Franziska, Mautes Angelika E, Schwerdtfeger Karsten, Oertel Joachim
Department of Neurosurgery, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany.
Institute of Neuropathology, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Germany.
Front Neurol. 2019 Mar 26;10:273. doi: 10.3389/fneur.2019.00273. eCollection 2019.
Acetazolamide (ACZ), carbonic anhydrase inhibitor, has been successfully applied in several neurosurgical conditions for diagnostic or therapeutic purposes. Furthermore, neuroprotective and anti-edematous properties of ACZ have been postulated. However, its use in traumatic brain injury (TBI) is limited, since ACZ-caused vasodilatation according to the Monro-Kellie doctrine may lead to increased intracranial blood volume / raise of intracranial pressure. We hypothesized that these negative effects of ACZ will be reduced or prevented, if the drug is administered after already performed decompression. To test this hypothesis, we used a mouse model of closed head injury (CHI) and decompressive craniectomy (DC). Mice were assigned into following experimental groups: sham, DC, CHI, CHI+ACZ, CHI+DC, and CHI+DC+ACZ ( = 8 each group). 1d and 3d post injury, the neurological function was assessed according to Neurological Severity Score (NSS) and Beam Balance Score (BBS). At the same time points, brain edema was quantified by MRI investigations. Functional impairment and edema volume were compared between groups and over time. Among the animals without skull decompression, the group additionally treated with acetazolamide demonstrated the most severe functional impairment. This pattern was reversed among the mice with decompressive craniectomy: CHI+DC treated but not CHI+DC+ACZ treated animals showed a significant neurological deficit. Accordingly, radiological assessment revealed most severe edema formation in the CHI+DC group while in CHI+DC+ACZ animals, volume of brain edema did not differ from DC-only animals. In our CHI model, the response to acetazolamide treatment varies between animals with decompressive craniectomy and those without surgical treatment. Opening the cranial vault potentially creates an opportunity for acetazolamide to exert its beneficial effects while vasodilatation-related risks are attenuated. Therefore, we recommend further exploration of this potentially beneficial drug in translational research projects.
乙酰唑胺（ACZ），一种碳酸酐酶抑制剂，已成功应用于多种神经外科疾病的诊断或治疗。此外，ACZ还具有神经保护和抗水肿特性。然而，其在创伤性脑损伤（TBI）中的应用受到限制，因为根据Monro-Kellie学说，ACZ引起的血管扩张可能导致颅内血容量增加/颅内压升高。我们假设，如果在已经进行减压后给药，ACZ的这些负面影响将减少或避免。为了验证这一假设，我们使用了闭合性颅脑损伤（CHI）和减压颅骨切除术（DC）的小鼠模型。将小鼠分为以下实验组：假手术组、DC组、CHI组、CHI+ACZ组、CHI+DC组和CHI+DC+ACZ组（每组n = 8）。在损伤后1天和3天，根据神经严重程度评分（NSS）和光束平衡评分（BBS）评估神经功能。在同一时间点，通过MRI检查对脑水肿进行定量分析。比较各组之间以及不同时间的功能损害和水肿体积。在没有颅骨减压的动物中，额外接受乙酰唑胺治疗的组表现出最严重的功能损害。在进行了减压颅骨切除术的小鼠中，这种模式发生了逆转：接受CHI+DC治疗但未接受CHI+DC+ACZ治疗的动物出现了明显的神经功能缺损。相应地，影像学评估显示CHI+DC组脑水肿形成最严重，而在CHI+DC+ACZ组动物中，脑水肿体积与仅接受DC治疗的动物没有差异。在我们的CHI模型中，减压颅骨切除术的动物和未接受手术治疗的动物对乙酰唑胺治疗的反应有所不同。打开颅腔可能为乙酰唑胺发挥其有益作用创造机会，同时与血管扩张相关的风险也会降低。因此，我们建议在转化研究项目中进一步探索这种可能有益的药物。
