Department of Acute Brain and Cardiovascular Injury, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
Department of Neuroscience, Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.
J Neuroinflammation. 2024 May 28;21(1):141. doi: 10.1186/s12974-024-03133-4.
The lectin pathway (LP) of complement mediates inflammatory processes linked to tissue damage and loss of function following traumatic brain injury (TBI). LP activation triggers a cascade of proteolytic events initiated by LP specific enzymes called MASPs (for Mannan-binding lectin Associated Serine Proteases). Elevated serum and brain levels of MASP-2, the effector enzyme of the LP, were previously reported to be associated with the severity of tissue injury and poor outcomes in patients with TBI. To evaluate the therapeutic potential of LP inhibition in TBI, we first conducted a pilot study testing the effect of an inhibitory MASP-2 antibody (α-MASP-2), administered systemically at 4 and 24 h post-TBI in a mouse model of controlled cortical impact (CCI). Treatment with α-MASP-2 reduced sensorimotor and cognitive deficits for up to 5 weeks post-TBI. As previous studies by others postulated a critical role of MASP-1 in LP activation, we conducted an additional study that also assessed treatment with an inhibitory MASP-1 antibody (α-MASP-1). A total of 78 mice were treated intraperitoneally with either α-MASP-2, or α-MASP-1, or an isotype control antibody 4 h and 24 h after TBI or sham injury. An amelioration of the cognitive deficits assessed by Barnes Maze, prespecified as the primary study endpoint, was exclusively observed in the α-MASP-2-treated group. The behavioral data were paralleled by a reduction of the lesion size when evaluated histologically and by reduced systemic LP activity. Our data suggest that inhibition of the LP effector enzyme MASP-2 is a promising treatment strategy to limit neurological deficits and tissue loss following TBI. Our work has translational value because a MASP-2 antibody has already completed multiple late-stage clinical trials in other indications and we used a clinically relevant treatment protocol testing the therapeutic mechanism of MASP-2 inhibition in TBI.
补体凝集素途径（LP）介导炎症过程，与创伤性脑损伤（TBI）后组织损伤和功能丧失有关。LP 激活触发 LP 特异性酶（称为 MASPs（甘露聚糖结合凝集素相关丝氨酸蛋白酶））引发的一系列蛋白水解事件。以前有报道称，LP 的效应酶 MASP-2 的血清和脑组织水平升高与 TBI 患者的组织损伤严重程度和预后不良有关。为了评估 LP 抑制在 TBI 中的治疗潜力，我们首先进行了一项初步研究，测试了在皮质撞击伤模型中，在 TBI 后 4 小时和 24 小时系统给予抑制性 MASP-2 抗体（α-MASP-2）的效果。MASP-2 治疗可减少 TBI 后长达 5 周的感觉运动和认知缺陷。由于其他先前的研究提出 MASP-1 在 LP 激活中起关键作用，我们进行了另一项研究，也评估了抑制性 MASP-1 抗体（α-MASP-1）的治疗效果。共有 78 只小鼠在 TBI 或假损伤后 4 小时和 24 小时分别接受α-MASP-2、α-MASP-1 或同种型对照抗体腹膜内治疗。通过巴恩斯迷宫评估的认知缺陷的改善，预先指定为主要研究终点，仅在α-MASP-2 治疗组中观察到。行为数据与组织学评估的病变大小减少和系统 LP 活性降低相平行。我们的数据表明，抑制 LP 效应酶 MASP-2 是一种有前途的治疗策略，可以限制 TBI 后的神经功能缺损和组织损失。我们的工作具有转化价值，因为一种 MASP-2 抗体已经在其他适应症中完成了多项后期临床试验，并且我们使用了一种临床相关的治疗方案来测试 MASP-2 抑制在 TBI 中的治疗机制。
