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Inhibition of p21-Activated Kinase 1 by IPA-3 Promotes Locomotor Recovery After Spinal Cord Injury in Mice

Inhibition of p21-Activated Kinase 1 by IPA-3 Promotes Locomotor Recovery After Spinal Cord Injury in Mice

Xinran Ji, Yiling Zhang, Lihai Zhang, Hua Chen, Ye Peng, Peifu Tang

Spine (Phila Pa 1976). 2016 Jun;41(11):919-25.

PMID: 26863260

Abstract:

Study design:
Ninety-six male adult CD-1 mice were randomly divided into sham, spinal cord injury (SCI) + vehicle, and SCI + IPA-3 groups. Expression of matrix metalloproteinase (MMP)-2 and MMP-9, production of tumor necrosis factors (TNF)-α and interleukin (IL)-1β, tissue edema, blood-spinal cord barrier penetrability, neural cell apoptosis, and neurological function recovery were measured.
Objective:
The aim of the study was to evaluate the effect of specific inhibition of p21-activated kinase 1 (PAK1) by IPA-3 on SCI and the underlying mechanisms thereof.
Summary of background data:
SCI is a devastating clinical condition that may result in long-lasting and deteriorating functional deficits. The major goal of SCI treatment is to limit the development of secondary injury. IPA-3, a PAK1 inhibitor, exhibited neuroprotection against secondary damage after traumatic brain injury and subarachnoid hemorrhage (SAH).
Methods:
MMP-2, MMP-9, and cleaved caspase-3 expression were assessed by Western blot. Inflammatory cytokines TNF-α and IL-1β were detected by enzyme-linked immunosorbent assay (ELISA). The blood-spinal cord barrier disruption was measured by water content and Evans blue extravasation of the spinal cord. Neuronal apoptosis was evaluated by Nissl staining and Terminal-deoxynucleoitidyl Transferase Mediated Nick End Labeling (TUNEL) assay. The locomotor behavior of hind limb was evaluated by Basso Mouse Scale (BMS) at 1, 3, 7, 14, and 28 days post-injury.
Results:
Compared with SCI + vehicle mice, IPA-3 treatment showed decreased p-PAK1, MMP-2, MMP-9, cleaved caspase-3, TNF-α, and IL-1β expression. Moreover, inhibition of PAK1 by IPA-3 reduced spinal cord water content and Evans blue extravasation, increased neuronal survival, and reduced TUNEL-positive cells at 24 hours after SCI. Furthermore, IPA-3 improved spinal cord functional recovery 7 days after SCI.
Conclusion:
Inhibition of PAK1 by IPA-3 promoted recovery of neurological function, possibly by downregulating the expression of MMP-2, MMP-9, TNF-α, and IL-1β. Our data suggest that PAK1 may be a potential therapeutic target in patients with SCI.
Level of evidence:
1.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP42521824	IPA-3		42521-82-4	Price

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