Small-molecule-induced Rho-inhibition: NSAIDs after spinal cord injury

被引:61
作者
Kopp, M. A.
Liebscher, T. [2 ]
Niedeggen, A. [2 ]
Laufer, S. [3 ]
Brommer, B.
Jungehulsing, G. J. [1 ]
Strittmatter, S. M. [1 ,4 ,5 ]
Dirnagl, U.
Schwab, J. M. [1 ]
机构
[1] Charite Univ Med Berlin, Dept Neurol & Expt Neurol, Ctr Stroke Res Berlin, D-10117 Berlin, Germany
[2] Trauma Hosp Berlin, Treatment Ctr Spinal Cord Injuries, Berlin, Germany
[3] Univ Tubingen, Inst Pharm, Dept Pharmaceut & Med Chem, Tubingen, Germany
[4] Yale Univ, Sch Med, Program Cellular Neurosci Neurodegenerat & Repair, New Haven, CT USA
[5] Yale Univ, Sch Med, Dept Neurol, New Haven, CT 06510 USA
关键词
Plasticity; Axonal damage; Spinal cord; Clinical trial; Ibuprofen; NONSTEROIDAL ANTIINFLAMMATORY DRUGS; CHONDROITIN SULFATE PROTEOGLYCANS; MYELIN-ASSOCIATED GLYCOPROTEIN; CENTRAL-NERVOUS-SYSTEM; CNS AXON REGENERATION; NOGO-66; RECEPTOR; FUNCTIONAL RECOVERY; NEUROPATHIC PAIN; NEURONAL DAMAGE; BLOOD-FLOW;
D O I
10.1007/s00441-012-1334-7
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Limited axonal plasticity within the central nervous system (CNS) is a major restriction for functional recovery after CNS injury. The small GTPase RhoA is a key molecule of the converging downstream cascade that leads to the inhibition of axonal re-growth. The Rho-pathway integrates growth inhibitory signals derived from extracellular cues, such as chondroitin sulfate proteoglycans, Nogo-A, myelin-associated glycoprotein, oligodendrocyte-myelin glycoprotein, Ephrins and repulsive guidance molecule-A, into the damaged axon. Consequently, the activation of RhoA results in growth cone collapse and finally outgrowth failure. In turn, the inhibition of RhoA-activation blinds the injured axon to its growth inhibitory environment resulting in enhanced axonal sprouting and plasticity. This has been demonstrated in various CNS-injury models for direct RhoA-inhibition and for downstream/upstream blockade of the RhoA-associated pathway. In addition, RhoA-inhibition reduces apoptotic cell death and secondary damage and improves locomotor recovery in clinically relevant models after experimental spinal cord injury (SCI). Unexpectedly, a subset of "small molecules" from the group of non-steroid anti-inflammatory drugs, particularly the FDA-approved ibuprofen, has recently been identified as (1) inhibiting RhoA-activation, (2) enhancing axonal sprouting/regeneration, (3) protecting "tissue at risk" (neuroprotection) and (4) improving motor recovery confined to realistic therapeutical time-frames in clinically relevant SCI models. Here, we survey the effect of small-molecule-induced RhoA-inhibition on axonal plasticity and neurofunctional outcome in CNS injury paradigms. Furthermore, we discuss the body of preclinical evidence for a possible clinical translation with a focus on ibuprofen and illustrate putative risks and benefits for the treatment of acute SCI.
引用
收藏
页码:119 / 132
页数:14
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