Experimental Traumatology Unit, Department of Neuroscience, Karolinska Institute, 171 77 Stockholm, Sweden.
Section of Neurosurgery, Department of Neuroscience, Uppsala University, 751 85 Uppsala, Sweden.
Int J Mol Sci. 2022 Jan 10;23(2):722. doi: 10.3390/ijms23020722.
Hippocampal dysfunction contributes to multiple traumatic brain injury sequala. Female rodents' outcome is superior to male which has been ascribed the neuroprotective sex hormones 17β-estradiol and progesterone. Cytochrome P450 1B1 (CYP1B1) is an oxidative enzyme influencing the neuroinflammatory response by creating inflammatory mediators and metabolizing neuroprotective 17β-estradiol and progesterone. In this study, we aimed to describe hippocampal CYP1B1 mRNA expression, protein presence of CYP1B1 and its key redox partner Cytochrome P450 reductase (CPR) in both sexes, as well as the effect of penetrating traumatic brain injury (pTBI). A total 64 adult Sprague Dawley rats divided by sex received pTBI or sham-surgery and were assigned survival times of 1-, 3-, 5- or 7 days. CYP1B1 mRNA was quantified using in-situ hybridization and immunohistochemistry performed to verify protein colocalization. CYP1B1 mRNA expression was present in all subregions but greatest in CA2 irrespective of sex, survival time or intervention. At 3-, 5- and 7 days post-injury, expression in CA2 was reduced in male rats subjected to pTBI compared to sham-surgery. Females subjected to pTBI instead exhibited increased expression in all CA subregions 3 days post-injury, the only time point expression in CA2 was greater in females than in males. Immunohistochemical analysis confirmed neuronal CYP1B1 protein in all hippocampal subregions, while CPR was limited to CA1 and CA2. CYP1B1 mRNA is constitutively expressed in both sexes. In response to pTBI, females displayed a more urgent but brief regulatory response than males. This indicates there may be sex-dependent differences in CYP1B1 activity, possibly influencing inflammation and neuroprotection in pTBI.
海马功能障碍导致多种创伤性脑损伤后遗症。雌性啮齿动物的预后优于雄性，这归因于神经保护性激素 17β-雌二醇和孕酮。细胞色素 P450 1B1（CYP1B1）是一种氧化酶，通过产生炎症介质和代谢神经保护 17β-雌二醇和孕酮来影响神经炎症反应。在这项研究中，我们旨在描述海马 CYP1B1 mRNA 表达、CYP1B1 蛋白的存在及其关键氧化还原伴侣细胞色素 P450 还原酶（CPR）在两性中的表达，以及穿透性创伤性脑损伤（pTBI）的影响。总共 64 只成年 Sprague Dawley 大鼠按性别分为 pTBI 或假手术组，并分配 1、3、5 或 7 天的存活时间。使用原位杂交定量 CYP1B1 mRNA，并用免疫组织化学验证蛋白共定位。CYP1B1 mRNA 在所有亚区均有表达，但无论性别、存活时间或干预如何，在 CA2 中表达最高。在损伤后 3、5 和 7 天，与假手术相比，接受 pTBI 的雄性大鼠 CA2 中的表达减少。相反，接受 pTBI 的雌性大鼠在所有 CA 亚区中的表达在 3 天时增加，只有在 CA2 中，雌性的表达高于雄性。免疫组织化学分析证实了所有海马亚区的神经元 CYP1B1 蛋白，而 CPR 仅局限于 CA1 和 CA2。CYP1B1 mRNA 在两性中均持续表达。对 pTBI 的反应中，雌性表现出比雄性更紧急但短暂的调节反应。这表明 CYP1B1 活性可能存在性别依赖性差异，可能影响 pTBI 中的炎症和神经保护。
