Sex-related responses after traumatic brain injury: Considerations for preclinical modeling.

Traumatic brain injury (TBI) has historically been viewed as a primarily male problem, since men are more likely to experience a TBI because of more frequent participation in activities that increase risk of head injuries. This male bias is also reflected in preclinical research where mostly male animals have been used in basic and translational science. However, with an aging population in which TBI incidence is increasingly sex-independent due to falls, and increasing female participation in high-risk activities, the attention to potential sex differences in TBI responses and outcomes will become more important. These considerations are especially relevant in designing preclinical animal models of TBI that are more predictive of human responses and outcomes. This review characterizes sex differences following TBI with a special emphasis on the contribution of the female sex hormones, progesterone and estrogen, to these differences. This information is potentially important in developing and customizing TBI treatments.

Retention of normal glia function by an isoform-selective protein kinase inhibitor drug candidate that modulates cytokine production and cognitive outcomes.

BACKGROUND: Brain p38α mitogen-activated protein kinase (MAPK), a potential therapeutic target for cognitive dysfunction based on the neuroinflammation-synaptic dysfunction cycle of pathophysiology progression, offers an innovative pharmacological strategy via inhibiting the same activated target in both glia and neurons, thereby enhancing the possibility for efficacy. The highly selective, brain-penetrant p38αMAPK inhibitor MW150 attenuates cognitive dysfunction in two distinct Alzheimer's disease (AD)-relevant models and avoids the problems encountered with previous mixed-kinase inhibitor drug candidates. Therefore, it is essential that the glial effects of this CNS-active kinase inhibitor be addressed in order to anticipate future use in clinical investigations. METHODS: We explored the effects of MW150 on glial biology in the AD-relevant APP/PS1 knock-in (KI) mouse model where we previously showed efficacy in suppression of hippocampal-dependent associative and spatial memory deficits. MW150 (2.5 mg/kg/day) was administered daily to 11-12-month-old KI mice for 14 days, and levels of proinflammatory cytokines IL-1ß, TNFα, and IL-6 measured in homogenates of mouse cortex using ELISA. Glial markers IBA1, CD45, CD68, and GFAP were assessed by immunohistochemistry. Microglia and amyloid plaques were quantified by immunofluorescence staining followed by confocal imaging. Levels of soluble and insoluble of Aß40 and Aß42 were measured by ELISA. The studies of in vivo pharmacodynamic effects on markers of neuroinflammation were complemented by mechanistic studies in the murine microglia BV2 cell line, using live cell imaging techniques to monitor proliferation, migration, and phagocytosis activities. RESULTS: Intervention with MW150 in KI mice during the established therapeutic time window attenuated the increased levels of IL-1ß and TNFα but not IL-6. MW150 treatment also increased the IBA1+ microglia within a 15 µm radius of the amyloid plaques, without significantly affecting overall microglia or plaque volume. Levels of IBA1, CD45, CD68, GFAP, and Aß40 and Aß42 were not affected by MW150 treatment. MW150 did not significantly alter microglial migration, proliferation, or phagocytosis in BV2 cells. CONCLUSIONS: Our results demonstrate that MW150 at an efficacious dose can selectively modulate neuroinflammatory responses associated with pathology progression without pan-suppression of normal physiological functions of microglia.

Quality of life after traumatic brain injury: a cross-sectional analysis uncovers age- and sex-related differences over the adult life span.

Traumatic brain injury (TBI) is the leading cause of disability in the working population and becomes increasingly prevalent in the elderly. Thus, TBI is a major global health burden. However, age- and sex-related long-term outcome regarding patient's health-related quality of life (HRQoL) is yet not clarified. In this cross-sectional study, we present age- and sex-related demographics and HRQoL up to 10 years after TBI using the Quality of Life after Brain Injury (QOLIBRI) instrument. The QOLIBRI total score ranges from zero to 100 indicating good (≥ 60), moderate (40-59) or unfavorable (< 40) HRQoL. Two-thirds of the entire chronic TBI cohort (102 males; 33 females) aged 18-85 years reported good HRQoL up to 10 years after TBI. TBI etiology differed between sexes with females suffering more often from traffic- than fall-related TBI (p = 0.01) with increasing prevalence during aging (p = < 0.001). HRQoL (good/moderate/unfavorable) differed between sexes (p < 0.0001) with 17% more females reporting moderate outcome (p = 0.01). Specifically, older females (54-76-years at TBI) were affected, while males constantly reported good HRQoL (p = 0.017). Cognition (p = 0.014), self-perception (p = 0.009), and emotions (p = 0.016) rather than physical problems (p = 0.1) constrained older females' HRQoL after TBI. Experiencing TBI during aging does not influence HRQoL outcome in males but females suggesting that female brains cope less well with a traumatic injury during aging. Therefore, older females need long-term follow-ups after TBI to detect neuropsychiatric sequels that restrict their quality of life. Further investigations are necessary to uncover the mechanisms of this so far unknown phenomenon.