Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations
Interleukin-1 receptor antagonist penetrates human brain at experimentally therapeutic concentrations
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DOI：
10.1038/sj.jcbfm.9600537
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发表时间：
2008-02-01
影响因子：
6.3
通讯作者：
Rothwell, Nancy J.
中科院分区：
文献类型：
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作者：
Clark, Simon R.;McMahon, Catherine J.;Rothwell, Nancy J.
促炎细胞因子白细胞介素（IL）-1介导几种形式的实验诱导的急性脑损伤，并已牵连在慢性神经退行性疾病。IL-1受体拮抗剂IL-1 RA可保护啮齿类动物免受缺血性脑损伤，但其分子量（17 kDa）可能限制外周给药IL-1 RA的脑渗透。因此，我们试图确定是否在大鼠中的IL-1 RA的治疗有效浓度也达到了蛛网膜下腔出血（SAH）患者的大脑中，使用外周给药方案，已被证明是安全的，并减少中风后患者的外周炎症。诱导局灶性脑缺血后，对大鼠静脉推注IL-1 RA，然后输注。测定IL-1 RA对脑缺血的作用和在脑脊液（CSF）中达到的浓度。对SAH患者同样给予白细胞介素-1受体拮抗剂，并通过脑室外引流采集CSF。在大鼠中，IL-1 RA显著减少局灶性脑缺血引起的脑损伤。30分钟时，血浆IL-1 RA浓度达到12 +/- 2 μ g/mL，在输注1至24小时之间，CSF浓度维持在91至232 ng/mL之间。在SAH患者中，IL-1 RA在15分钟内达到22 +/- 4 μ g/mL的稳态血浆浓度，CSF浓度在1至24小时之间维持在78至558 ng/mL。IL-1 RA的静脉内递送导致患者的CSF浓度与大鼠中具有神经保护作用的CSF浓度相当，因此可能具有治疗益处。
The proinflammatory cytokine interleukin (IL)-1 mediates several forms of experimentally induced acute brain injury and has been implicated in chronic neurodegenerative disorders. The IL-1 receptor antagonist, IL-1RA, protects rodents against ischaemic brain injury, but its molecular mass (17 kDa) potentially limits the brain penetration of peripherally administered IL-1RA. We therefore sought to identify whether therapeutically effective concentrations of IL-1RA in the rat were also achieved in brain of patients with subarachnoid haemorrhage (SAH), using a peripheral administration regime that had proved to be safe and reduce peripheral inflammation in patients after stroke. An intravenous bolus of IL-1RA, followed by infusion, was administered to rats after induction of focal cerebral ischaemia. The effects of IL-1RA on brain ischaemia and the concentrations achieved in cerebrospinal fluid (CSF), were determined. Interleukin-1 receptor antagonist was similarly administered to patients with SAH, and CSF was sampled via external ventricular drains. In rats, IL-1RA significantly reduced brain injury induced by focal cerebral ischaemia. The plasma IL-1RA concentrations reached 12 +/- 2 mu g/mL by 30 mins, and CSF concentrations were maintained between 91 and 232 ng/mL between 1 and 24 h of infusion. In patients with SAH, IL-1RA reached a steady-state plasma concentration of 22 +/- 4 mu g/mL by 15 mins, and CSF concentrations were maintained at 78 to 558 ng/mL between 1 and 24 h. Intravenous delivery of IL-1RA leads to CSF concentrations in patients comparable to those that are neuroprotective in rats, and might therefore be of therapeutic benefit.