Inhibition of Heat Shock Protein 90 Attenuates the Damage of Blood-Brain Barrier Integrity in Traumatic Brain Injury Mouse Model

Abstract

Heat shock protein 90 (HSP90) is widely found in brain tissue. HSP90 inhibition has been proven to have neuroprotective effects on ischemic strokes. In order to study the role of HSP90 in traumatic brain injury (TBI), we carried out the present study. A novel inhibitor of the HSP90 protein, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DA), has been investigated for its function on the blood-brain barrier (BBB) damage after traumatic brain injury (TBI) in mouse models. These C57BL/6 mice were used as a TBI model and received 17-DA (0.1 mg/kg/d, intraperitoneally) until the experiment ended. To find out whether 17-DA may protect against TBI in vitro, bEnd.3 cells belonging to mouse brain microvascular endothelium were used. The HSP90 protein expressions were raised after TBI at the pericontusional area, especially at 3 d. Our study suggested that 17-DA-treated mice improved the recovery ability of neurological deficits and decreased brain edema, Evans blue extravasation, and the loss of tight junction proteins (TJPs) post-TBI. 17-DA significantly promoted cell proliferation and alleviated apoptosis by inhibiting the generation of intracellular reactive oxygen species (ROS) to downregulate cleaved caspase-3, matrix metallopeptidase- (MMP-) 2, MMP-9, and P-P65 in bEnd.3 cells after the injury. As a result, we assumed that the HSP90 protein was activated post-TBI, and inhibition of HSP90 protein reduced the disruption of BBB and improved the neurobehavioral scores in a mouse model of TBI through the action of 17-DA, which inhibited ROS generation and regulated MMP-2, MMP-9, NF-κB, and caspase-associated pathways. Thus, blocking HSP90 protein may be a potential therapeutic strategy for TBI.

Angelica acutiloba Kitagawa flower induces A549 cell pyroptosis via the NF-κB/NLRP3 pathway for anti-lung cancer effects

“…We also found that KAE and PLA caused oxidative stress in A549 cells, leading to the generation of ROS and activation of NF-κB [ 43 ], a transcription factor involved in a variety of important processes, including inflammation, immunity, and tumour development. NF-κB is an important regulator of the production of inflammatory factors and, upon activation, enters the nucleus to regulate transcription and translation, including the increased content of NLRP3 proteins [ 44 ].…”

The Effect of Sericin on Heat Shock Proteins 60 and 90, and TLR2 and TLR4 Induced by Chronic Heat Stress in Male Mice

“…Therefore, blocking the HSP90 protein may be a potential therapeutic strategy for TBI. 35 HSP60 functions as an immunomodulatory molecule and a mitochondrial chaperone, thus it can activate the antigen-presenting cells of the immune system, including an auto-immunogen, at the site of inflammation. 36,37 Additionally, it becomes upregulated in reaction to mitochondrial impairment and is believed to be an indicator of mitochondrial stress.…”

Regulation of Epithelial and Endothelial Barriers by Molecular Chaperones

“…For example, 17-AAG treatment attenuated endotoxin-induced vascular leakage in rat retinas [ 70 ]. Another Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), blocked the disruption of the blood–brain barrier in a rat model of intracerebral hemorrhage [ 71 ], mouse models of cerebral ischemic stroke [ 72 ], and traumatic brain injury [ 73 ]. In these animal models, the attenuation of vascular permeability caused by Hsp90 inhibition was accompanied by the restored expression of key TJ proteins, such as occludin, ZO-1, and claudin-5 [ 70 , 71 , 72 , 73 ].…”

“…Similar to the described in vitro studies, in vivo protection of the vascular barriers is not a specific effect of Hsp90 inhibitors. Rather, it is a part of their general anti-inflammatory and tissue-protective activities that result in suppressed NF-kB signaling, decreased cytokine production, and upregulation of AKT activity [ 70 , 71 , 72 , 73 ].…”

“…Another Hsp90 inhibitor, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), blocked the disruption of the blood-brain barrier in a rat model of intracerebral hemorrhage [71], mouse models of cerebral ischemic stroke [72], and traumatic brain injury [73]. In these animal models, the attenuation of vascular permeability caused by Hsp90 inhibition was accompanied by the restored expression of key TJ proteins, such as occludin, ZO-1, and claudin-5 [70][71][72][73]. Similar to the described in vitro studies, in vivo protection of the vascular barriers is not a specific effect of Hsp90 inhibitors.…”