Inhibition of p21-activated kinase 1 by IPA-3 attenuates secondary injury after traumatic brain injury in mice

Ji, Xiaotong; Zhang, Wei; Zhang, Lihai; Zhang, Licheng; Zhang, Shujun; Tang, Peifu

doi:10.1016/j.brainres.2014.08.026

Cited by 8 publications

(7 citation statements)

References 46 publications

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“…Although this conclusion is in contrast with several studies in other tissues of the effects of PAK2 on caspase activation [85-87], our results support the conclusion that PAK2 has a proapoptotic action in pancreatic acinar cells. This result has similarities with a study in which IPA-3 reduced caspase-3 level in brain injury [88]. PAK2 is unique among the PAK isoforms because it is also activated through proteolytic cleavage by caspases or caspase-like proteases [36,37].…”

Section: Discussion (2897/1978)supporting

confidence: 81%

“…Because an increase in apoptosis is associated with attenuation of the severity of pancreatitis, our results support the conclusion that PAK2 cleavage may play an important role in regulating the severity of this disease. This conclusion suggests that activation of PAK2 may function in a dual role (protective/non-protective) in different tissues, because with traumatic brain injury [88] inhibition of activation of PAK2 resulted in protecting the cells from secondary injury, whereas in pancreatic acinar cells its activation has a protective effect.…”

Section: Discussion (2897/1978)mentioning

confidence: 99%

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The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events

Nuche-Berenguer

Ramos-Álvarez

Jensen

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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In a recent study we explored Group-1-p21-activated kinases(GP.1-PAKs) in rat pancreatic acini. Only PAK2 was present; it was activated by gastrointestinal-hormones/neurotransmitters and growth factors in a PKC-,Src- and small-GTPases-mediated manner. PAK2 was required for enzyme-secretion and ERK/1-2-activation. In the present study we examined PAK2’s role in CCK and TPA-activation of important distal signaling cascades mediating their physiological/pathophysiological effects and analyzed its role in pathophysiological processes important in early pancreatitis. In rat pancreatic acini,PAK2-inhibition by the specific, GP.1.PAK-inhibitor, IPA-3-suppressed cholecystokinin(CCK)/TPA-stimulated activation of focal-adhesion kinases and mitogen-activated protein-kinases. PAK2-inhibition reversed the dual stimulatory/inhibitory effect of CCK/TPA on the PI3K/Akt/GSK-3β pathway. However, its inhibition did not affect PKC activation. PAK2-inhibition protected acini from CCK-induced ROS-generation; caspase/trypsin-activation, important in early pancreatitis; as well as from cell-necrosis. Furthermore, PAK2-inhibition reduced proteolytic-activation of PAK-2p34, which is involved in programmed-cell-death. To ensure that the study did not only rely in the specificity of IPA-3 as a PAK inhibitor, we used two other approaches for PAK inhibition, FRAX597 a ATP-competitive-GP.1-PAKs - inhibitor and by infection with an PAK2-dominat negative(DN)-Advirus. Those two approaches confirmed the results obtained with IPA-3. This study demonstrates that PAK2 is important in mediating CCK’s effect on the activation of signaling-pathways known to mediate its physiological/pathophysiological responses including several cellular processes linked to the onset of pancreatitis. Our results suggest that PAK2 could be a new, important therapeutic target to consider for the treatment of diseases involving deregulation of pancreatic acinar cells.

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Section: Discussion (2897/1978)supporting

confidence: 81%

Section: Discussion (2897/1978)mentioning

confidence: 99%

The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events

Nuche-Berenguer

Ramos-Álvarez

Jensen

2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…In previous studies, IPA-3 treatment ameliorated brain injury after subarachnoid hemorrhage in rats and after traumatic brain injury in mice. 20,21 They found that IPA-3 treatment significantly inhibited the phosphorylation of PAK1 and improved neurological deficits, indicating a protective role of PAK1-specific inhibition by IPA-3 in reducing brain edema and Blood Brain Barrier (BBB) disruption.…”

Section: Discussionmentioning

confidence: 97%

“…with IPA-3 (I2285, Sigma-Aldrich Co., St. Louis, MO), dissolved in 0.01 M PBS with 1% dimethyl sulfoxide, at a dose of 3.5 mg/ kg 30 minutes after surgery. 20,21 The mouse model of SCI was developed following previous studies with minor modifications. 22,23 After anesthesia with i.p.…”

Section: Experimental Sci Inductionmentioning

confidence: 99%

“…According to the kit's protocol and the previous studies, 20,22 Five-micrometerthick tissue sections containing the lesion (1 cm on each side of the lesion) were deparaffinizated, dehydrated, and washed with PBS, followed by digestion in proteinase K for 15 minutes. Sections were incubated at 378C with labeling solution containing TUNEL reaction fluid.…”

Section: Tunel Stainingmentioning

confidence: 99%

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

Zhang²,

Zhang³

et al. 2016

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Neuronal PLPP/CIN exaggerates the immune response of hippocampal microglia to LPS challenge dependent on PAK1-NF-κB-COX-2 signaling pathway

Kim,

Wang,

Lee

et al. 2025

Brain Research

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Inhibition of p21-activated kinase 1 by IPA-3 attenuates secondary injury after traumatic brain injury in mice

Cited by 8 publications

References 46 publications

The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events

The p21-activated kinase, PAK2, is important in the activation of numerous pancreatic acinar cell signaling cascades and in the onset of early pancreatitis events

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

Neuronal PLPP/CIN exaggerates the immune response of hippocampal microglia to LPS challenge dependent on PAK1-NF-κB-COX-2 signaling pathway

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