Multifaceted Mechanisms of WY-14643 to Stabilize the Blood-Brain Barrier in a Model of Traumatic Brain Injury

Abstract

The blood-brain barrier (BBB) is damaged during ischemic insults such as traumatic brain injury or stroke. This contributes to vasogenic edema formation and deteriorate disease outcomes. Enormous efforts are pursued to understand underlying mechanisms of ischemic insults and develop novel therapeutic strategies. In the present study the effects of PPARα agonist WY-14643 were investigated to prevent BBB breakdown and reduce edema formation. WY-14643 inhibited barrier damage in a mouse BBB in vitro model of traumatic brain injury based on oxygen/glucose deprivation in a concentration dependent manner. This was linked to changes of the localization of tight junction proteins. Furthermore, WY-14643 altered phosphorylation of kinases ERK1/2, p38, and SAPK/JNK and was able to inhibit proteosomal activity. Moreover, addition of WY-14643 upregulated PAI-1 leading to decreased t-PA activity. Mouse in vivo experiments showed significantly decreased edema formation in a controlled cortical impact model of traumatic brain injury after WY-14643 application, which was not found in PAI-1 knockout mice. Generally, data suggested that WY-14643 induced cellular responses which were dependent as well as independent from PPARα mediated transcription. In conclusion, novel mechanisms of a PPARα agonist were elucidated to attenuate BBB breakdown during traumatic brain injury in vitro.

When Activator and Inhibitor of PPARα Do the Same: Consequence for Differentiation of Human Intestinal Cells

“…The observed effect of WY-14643 on villin expression in our study may also be PPARα-independent. Except involvement of the PI3K pathway, intestinal cell differentiation has also been associated with activation of p38 MAPK [ 53 , 54 ], and it has been shown that WY-14643 induces phosphorylation of this protein [ 55 , 56 , 57 ].…”

Recombinant milk fat globule-EGF factor-8 reduces apoptosis via integrin β3/FAK/PI3K/AKT signaling pathway in rats after traumatic brain injury

“…Brain water content was measured as previously studied 27 . Animals were anesthetized with sodium pentobarbital (50 mg/kg; i.p.)…”

The pivotal role of micro-environmental cells in a human blood–brain barrier in vitro model of cerebral ischemia: functional and transcriptomic analysis

“…Although a large number of research projects were carried out on novel therapies for the treatment of cerebral ischemia, clinical success to date has been marginal. Several reports showed that the stabilization of the BBB during acute insults can lead to a significant reduction in brain edema and neurological damage [19,32,43]. Nevertheless, the mechanisms during cerebral ischemia are not yet sufficiently understood.…”

“…In this context, it was shown in in vitro mouse models that co-cultivation with micro-environmental cells such as astrocytes or glioma cells significantly shortened incubation times to more in vivo relevant durations while achieving the same functional damage [29,31]. Therefore, one major objective of this study was to establish a human in vitro BBB model of cerebral ischemia that achieves a functional damage of approximately 35-60% TEER decline in less than 6 h. This TEER decline was defined in previous mouse in vitro studies as optimal for therapy testing, as too little damage makes the read-out of positive effects difficult and too much damage shows insufficient reversibility [31,32]. The other major objective was to investigate comprehensively the influences of experimental parameters on the expression of TJ proteins and ABC transporters.…”

“…As human in vitro BBB model, the most commonly used human cell line hCMEC/D3 [49] was cultivated and cocultured with rat glioma cell line C6 or primary human astrocytes/pericytes under normoxic and OGD conditions. Cell line C6 was chosen, since their usability for inducing BBB breakdown has already been proven in a mouse ischemia model [31,32].…”