Cathepsin B (CatB), a lysosomal cysteine protease, is important to brain function and may have dual utility as a peripheral biomarker of moderate-severe traumatic brain injury (TBI). The present study determined levels of pro- and mature (mat) CatB protein as well as cysteine protease activity within the frontal cortex (FC; proximal injury site), hippocampus (HC; distal injury site), and cerebral spinal fluid (CSF) collected 1–7 days after craniotomy and penetrating ballistic-like brain injury (PBBI) in rats. Values were compared with naïve controls. Further, the utility of CatB protein as a translational biomarker was determined in CSF derived from patients with severe TBI. Craniotomy increased matCatB levels in the FC and HC, and led to elevation of HC activity at day 7. PBBI caused an even greater elevation in matCatB within the FC and HC within 3–7 days. After PBBI, cysteine protease activity peaked at 3 days in the FC and was elevated at 1 day and 7 days, but not 3 days, in the HC. In rat CSF, proCatB, matCatB, and cysteine protease activity peaked at 3 days after craniotomy and PBBI. Addition of CA-074, a CatB-specific inhibitor, confirmed that protease activity was due to active matCatB in rat brain tissues and CSF at all time-points. In patients, CatB protein was detectable from 6 h through 10 days after TBI. Notably, CatB levels were significantly higher in CSF collected within 3 days after TBI compared with non-TBI controls. Collectively, this work indicates that CatB and its cysteine protease activity may serve as collective molecular signatures of TBI progression that differentially vary within both proximal and distal brain regions. CatB and its protease activity may have utility as a surrogate, translational biomarker of acute-subacute TBI.

中文翻译：

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穿透性创伤性脑损伤触发组织蛋白酶 B 蛋白水平的失调，与脑和脑脊髓液中的半胱氨酸蛋白酶活性无关。

组织蛋白酶 B (CatB) 是一种溶酶体半胱氨酸蛋白酶，对脑功能很重要，可能作为中重度创伤性脑损伤 (TBI) 的外周生物标志物具有双重用途。本研究确定了收集的额叶皮层（FC；近端损伤部位）、海马（HC；远端损伤部位）和脑脊髓液 (CSF) 内的前和成熟 (mat) CatB 蛋白以及半胱氨酸蛋白酶活性的水平大鼠开颅和穿透性弹道样脑损伤 (PBBI) 后 1-7 天。将值与初始对照进行比较。此外，在源自严重 TBI 患者的 CSF 中确定了 CatB 蛋白作为翻译生物标志物的效用。开颅术增加了 FC 和 HC 中的 matCatB 水平，并导致第 7 天的 HC 活性升高。PBBI 在 3-7 天内导致 FC 和 HC 内 matCatB 的升高甚至更大。PBBI 后，半胱氨酸蛋白酶活性在 FC 中的第 3 天达到峰值，并在 HC 中的第 1 天和第 7 天升高，但不是第 3 天。在大鼠 CSF 中，proCatB、matCatB 和半胱氨酸蛋白酶活性在开颅手术和 PBBI 后 3 天达到峰值。添加 CA-074，一种 CatB 特异性抑制剂，证实蛋白酶活性是由于大鼠脑组织和 CSF 中所有时间点的活性 matCatB。在患者中，TBI 后 6 小时至 10 天可检测到 CatB 蛋白。值得注意的是，与非 TBI 对照相比，TBI 后 3 天内收集的 CSF 中的 CatB 水平显着更高。总的来说，这项工作表明，CatB 及其半胱氨酸蛋白酶活性可以作为 TBI 进展的集体分子特征，这些特征在近端和远端大脑区域内不同。CatB 及其蛋白酶活性可用作急性-亚急性 TBI 的替代翻译生物标志物。