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Updated: Jun 22, 2026
Rat Model of Closed-Head Mild Traumatic Injury and its Validation
Published on: September 22, 2023
Sex differences in XIAP cleavage after traumatic brain injury in the rat
Helen M Bramlett1, Ofelia Furones-Alonso, George Lotocki
1Department of Neurological Surgery, Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL 33101, USA. hbramlett@miami.edu
Abstract:
Sex influences histological and behavioral outcomes following traumatic brain injury (TBI), but the underlying sex-dependent pathomechanisms regulating outcome measures remain poorly defined. Here, we investigated the TBI-induced regulation of the X-linked inhibitor of apoptosis protein (XIAP) that, in addition to suppressing cell death by inhibition of caspases, is involved in signaling cascades, including immune regulation and cell migration. Since estrogen has been shown to have anti-apoptotic properties, we specifically examined sex differences and the influence of estrogen on XIAP processing after TBI. Sprague-Dawley male (TBI-M), female (TBI-F), ovariectomized female (TBI-OVX) and ovariectomized females supplemented with estrogen (TBI-OVX+EST) were subjected to moderate (1.7-2.2atm) fluid percussion (FP) injury. Animals were sacrificed 24h after FP injury; cortical tissue (ipsilateral and contralateral) was dissected and analyzed for XIAP processing by immunoblot analysis (n=6-7/group) or confocal microscopy (n=2-3/group). Significant differences in XIAP cleavage products in the ipsilateral cortex were found between groups (p<0.03). Post hoc analysis showed an increase in XIAP processing in both TBI-F and TBI-OVX+EST compared to TBI-M and TBI-OVX (p<0.05), indicating that more XIAP is cleaved following injury in intact females and TBI-OVX+EST than in TBI-M and TBI-OVX groups. Co-localization of XIAP within neurons also demonstrated sex-dependent changes. Based on these data, it appears that the processing of XIAP after injury is different between males and females and may be influenced by exogenous estrogen treatment.
Insights
Sex influences traumatic brain injury (TBI) outcomes. This study found that X-linked inhibitor of apoptosis protein (XIAP) processing differs between sexes after TBI, potentially influenced by estrogen.
Area of Science:
- Neuroscience
- Immunology
- Endocrinology
Background:
- Sex significantly impacts histological and behavioral outcomes after traumatic brain injury (TBI).
- The sex-dependent molecular mechanisms underlying TBI outcomes are not well understood.
- X-linked inhibitor of apoptosis protein (XIAP) plays roles in cell death inhibition, immune regulation, and cell migration.
Purpose of the Study:
- To investigate sex differences in the regulation of X-linked inhibitor of apoptosis protein (XIAP) processing following TBI.
- To determine the influence of estrogen on XIAP processing after TBI.
- To explore the role of XIAP in sex-dependent TBI pathomechanisms.
Main Methods:
- Adult male and female Sprague-Dawley rats underwent moderate fluid percussion (FP) TBI.
- Experimental groups included male TBI, female TBI, ovariectomized female TBI, and ovariectomized female TBI with estrogen supplementation.
- XIAP processing in cortical tissue was analyzed 24 hours post-injury using immunoblot analysis and confocal microscopy.
Main Results:
- Significant differences in XIAP cleavage products were observed in the ipsilateral cortex between experimental groups.
- XIAP processing was significantly increased in intact females (TBI-F) and estrogen-supplemented ovariectomized females (TBI-OVX+EST) compared to males (TBI-M) and non-supplemented ovariectomized females (TBI-OVX).
- Sex-dependent changes in XIAP co-localization within neurons were also detected.
Conclusions:
- XIAP processing after TBI exhibits sex-dependent regulation.
- Estrogen appears to influence XIAP processing following TBI, with higher processing observed in the presence of estrogen.
- These findings suggest that XIAP pathway modulation by sex hormones may contribute to sex differences in TBI outcomes.
