Profiling Neuroactive Steroid Levels After Traumatic Brain Injury in Male Mice

Abstract

The incidence of traumatic brain injuries (TBIs) in humans has rapidly increased in the last ten years. The most common causes are falls and car accidents. Approximately 80 000-90 000 persons per year will suffer some permanent disability as a result of the lesion, and one of the most common symptoms is the decline of hormone levels, also known as post-TBI hormonal deficiency syndrome. This issue has become more and more important, and many studies have focused on shedding some light on it. The hormonal decline affects not only gonadal steroid hormones but also neuroactive steroids, which play an important role in TBI recovery by neuroprotective and neurotrophic actions. The present work used an adolescent close-head murine model to analyze brain and plasma neurosteroid level changes after TBI and to establish correlations with edema and neurological impairments, 2 of the hallmarks of TBI. Our results showed changes in brain pregnenolone, testosterone, dihydrotestosterone (DHT), and 3α-diol levels whereas in plasma, the changes were present in progesterone, DHT, 3α-diol, and 3β-diol. Within them, pregnenolone, progesterone, DHT, and 3α-diol levels positively correlated with edema formation and neurological score, whereas testosterone inversely correlated with these 2 variables. These findings suggest that changes in the brain levels of some neuroactive steroids may contribute to the alterations in brain function caused by the lesion and that plasma levels of some neuroactive steroids could be good candidates of blood markers to predict TBI outcome.

Progesterone in the Brain: Hormone, Neurosteroid and Neuroprotectant

“…In mice, significant levels of progesterone, 5α-DHPROG, and 3α-5 α-THPROG were measured in brains of both young adult males and females [87][88][89][90]. In female mice, we have shown that brain levels of progesterone and 5α-DHPROG changed significantly according to estrus cycle [87].…”

Progesterone Effects in the Nervous System

“…In the case of human TBI, the beneficial effect of progesterone is controversial, although its positive effects have been demonstrated in various animal models (Cutler et al, ; Lopez‐Rodriguez et al, ; Zhang et al, ). However, only a limited number of studies emphasized the beneficial impact of progesterone treatment in humans after injury (Aminmansour et al, ; Shakeri et al, ; Brotfain et al, ; Guennoun et al, ), while others describe the failure of clinical Phase III studies (Stein, ; Ma et al, ; Wang et al, ).…”

Neurosteroid Metabolites of Gonadal Steroid Hormones in Neuroprotection: Implications for Sex Differences in Neurodegenerative Disease

“…Other studies have investigated changes in neurosteroid levels in rodent models of induced neurological deficits, as opposed to models of disease that occur spontaneously or due to genetic factors. One such study performed by Lopez-Rodriguez et al ( 2016 ) investigated the impact of right orbitofrontal and perirhinal focal lesions in male Swiss-CD1 male mice as a model of TBI on neurosteroid levels in the brain and plasma. The authors reported that progesterone levels were unaffected at time points from 24 h up to 2 weeks following TBI, while testosterone, DHT and 3α-diol exhibited more complex temporal changes.…”

“…Testosterone levels were significantly increased 2 weeks after injury compared to 24 h, but not significantly different than baseline levels. However, both DHT and 3α-diol were significantly reduced 2 weeks following injury compared to intact controls, while 3α-diol levels were positively correlated with the degree of brain edema, suggesting that a compensatory response may have occurred to increase local neuroprotective activity (Lopez-Rodriguez et al, 2016 ). Plasma levels of DHT, 3α-diol and 3β-diol were all reduced 2 weeks after TBI, though only plasma DHT and 3α-diol correlated significantly with neurological deficits (Lopez-Rodriguez et al, 2016 ).…”