Resilience of females to acute blood–brain barrier damage and anxiety behavior following mild blast traumatic brain injury

Hubbard, William Brad; Velmurugan, G. V.; Brown, Emily P; Sullivan, Patrick G.

doi:10.1186/s40478-022-01395-8

Cited by 21 publications

(11 citation statements)

References 44 publications

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“…This study only utilized male mice in the experimental design. Given the vast importance of incorporating both sexes and examining sex as a biological variable, 29 , 30 our future steps will be to incorporate females. While this study does assay treatment in a mild model of CCI, this is still an open skull model.…”

Section: Discussionmentioning

confidence: 99%

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion

Hubbard

Vekaria

Kalimon

et al. 2023

Brain Communications

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Pioglitazone interacts through the mitochondrial protein mitoNEET to improve brain bioenergetics following traumatic brain injury. To provide broader evidence regarding the therapeutic effects of pioglitazone after traumatic brain injury, the current study is focused on immediate and delayed therapy in a model of mild brain contusion. To assess pioglitazone therapy on mitochondrial bioenergetics in cortex and hippocampus, we use a technique to isolate sub-populations of total, glia-enriched, and synaptic mitochondria. Pioglitazone treatment was initially administered at either 0.25 hr, 3 hr, 12 hr, or 24 hr following mild controlled cortical impact. At 48 hr post-injury, ipsilateral cortex and hippocampus were dissected and mitochondrial fractions were isolated. Maximal mitochondrial respiration injury-induced deficits were observed in total and synaptic fractions and 0.25 hr pioglitazone treatment following mild controlled cortical impact was able to restore respiration to sham levels. While there are no injury-induced deficits in hippocampal fractions, we do find that 3 hr pioglitazone treatment after mild controlled cortical impact can significantly increase maximal mitochondrial bioenergetics compared to vehicle-treated mild controlled cortical impact group. However, delayed pioglitazone treatment initiated at either 3 hr or 24 hr after mild brain contusion does not improve spared cortical tissue. We demonstrate that synaptic mitochondrial deficits following mild focal brain contusion can be restored with early initiation of pioglitazone treatment. Further investigation is needed to determine functional improvements with pioglitazone beyond that of overt cortical tissue sparing following mild contusion traumatic brain injury.

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Section: Discussionmentioning

confidence: 99%

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion

Hubbard

Vekaria

Kalimon

et al. 2023

Brain Communications

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“…In line with these results, models of single moderate to severe impact TBI have demonstrated disparate inflammatory outcomes in male vs. female mice acutely following injury (Bromberg et al, 2020;Doran et al, 2019;Krukowski, 2021;Krukowski et al, 2020;Späni et al, 2018;Villapol et al, 2017). Likewise, a recent study using a single mild blast exposure with body shielding reported worse acute and sub-acute neuroinflammatory and BBB outcomes in male vs. female rats (Hubbard et al, 2022).…”

Section: Discussionmentioning

confidence: 81%

“…In relation to potential sex differences in adverse behavioral outcomes following blast exposure, only three studies thus far have been reported (Hubbard et al, 2022;McNamara et al, 2022;. Hubbard et al (2022) found increased anxiety-like behavior in male but not female rats in the open field (at 2 days post) and elevated plus maze (at 14 days post) following single blast mTBI with body shielding. Conversely, McNamara et al (2022) found no injury effects in either female or male mice on the elevated plus and zero mazes when tested at 2-4 weeks post single blast exposure.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, few preclinical studies have included both male and female animals and the few that have, have exclusively focused on impact TBI, a single TBI exposure, and/or only examined acute timepoints. While a handful of reports have characterized potential sex differences following a single blast exposure (Hubbard et al, 2022;Kawa et al, 2020;McNamara et al, 2022;Russell, Richardson, et al, 2018), very little is known about the effects of repetitive blast exposure in male vs. female rodents.…”

Section: Introductionmentioning

confidence: 99%

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Timing matters: Sex differences in acute and chronic outcomes following repetitive blast mild traumatic brain injury

Baskin

Logsdon

Lee

et al. 2022

Preprint

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Background: Repetitive blast-related mild traumatic brain injury (mTBI) caused by exposure to high explosives is increasingly common among warfighters as well as civilians. While women have been serving in military positions with increased risk of blast exposure since 2016, there are few published reports examining sex as a biological variable in models of blast mTBI, greatly limiting diagnosis and treatment capabilities. As such, here we examined acute and chronic outcomes of repetitive blast trauma in female and male mice in relation to potential behavioral, inflammatory, microbiome, and vascular dysfunction. Methods: In this study we utilized a well-established blast overpressure model to induce repetitive (3x) blast-mTBI in both female and male mice. Acutely following repetitive exposure, we measured serum and brain cytokine levels, blood-brain barrier (BBB) disruption, fecal microbial abundance, and locomotion and anxiety-like behavior in the open field assay. Chronically, in female and male mice we assessed behavioral correlates of mTBI and PTSD-related symptoms commonly reported by Veterans with a history of blast-mTBI using the elevated zero maze, acoustic startle, and conditioned odorant aversion paradigms. Results: Repetitive blast exposure resulted in similar and disparate patterns of acute serum and brain cytokine as well as gut microbiome changes in female and male mice. Acute BBB disruption following repetitive blast exposure was apparent in both sexes. While female and male blast mice both exhibited acute locomotor and anxiety-like deficits in the open field assay, only male mice exhibited chronic adverse behavioral outcomes. Discussion: Representing a novel survey of potential sex differences following repetitive blast trauma, our results demonstrate unique similar and divergent patterns of blast-induced dysfunction in female vs. male mice and highlight novel targets for future diagnosis and therapeutic development.

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“… 69 Sex differences in response to blast exposure have been little studied, although two recent reports have suggested that blast responses in female rats may differ. 70 , 71 With the increasing number of female veterans, these studies assume a high importance.…”

Section: Discussionmentioning

confidence: 99%

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury

Garcia

Perez

Gasperi

et al. 2023

Neurotrauma Reports

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Many military veterans who experienced blast-related traumatic brain injuries (TBIs) in the conflicts in Iraq and Afghanistan suffer from chronic cognitive and mental health problems, including post-traumatic stress disorder (PTSD). Male rats subjected to repetitive low-level blast exposure develop chronic cognitive and PTSD-related traits that develop in a delayed manner. Ketamine has received attention as a treatment for refractory depression and PTSD. (2R,6R)-hydroxynorketamine [(2R,6R)-HNK] is a ketamine metabolite that exerts rapid antidepressant actions. (2R,6R)-HNK has become of clinical interest because of its favorable side-effect profile, low abuse potential, and oral route of administration. We treated three cohorts of blast-exposed rats with (2R,6R)-HNK, beginning 7–11 months after blast exposure, a time when the behavioral phenotype is established. Each cohort consisted of groups ( n = 10–13/group) as follows: 1) Sham-exposed treated with saline, 2) blast-exposed treated with saline, and 3) blast-exposed treated with a single dose of 20 mg/kg of (2R,6R)-HNK. (2R,6R)-HNK rescued blast-induced deficits in novel object recognition (NOR) and anxiety-related features in the elevated zero maze (EZM) in all three cohorts. Exaggerated acoustic startle was reversed in cohort 1, but not in cohort 3. (2R,6R)-HNK effects were still present in the EZM 12 days after administration in cohort 1 and 27 days after administration in NOR testing of cohorts 2 and 3. (2R,6R)-HNK may be beneficial for the neurobehavioral syndromes that follow blast exposure in military veterans. Additional studies will be needed to determine whether higher doses or more extended treatment regimens may be more effective.

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Resilience of females to acute blood–brain barrier damage and anxiety behavior following mild blast traumatic brain injury

Cited by 21 publications

References 44 publications

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion

Pioglitazone restores mitochondrial function but does not spare cortical tissue following mild brain contusion

Timing matters: Sex differences in acute and chronic outcomes following repetitive blast mild traumatic brain injury

(2R,6R)-Hydroxynorketamine Treatment of Rats Exposed to Repetitive Low-Level Blast Injury

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