Exogenous progesterone is neuroprotective following injury to the male zebra finch brain

Abstract

The use of progesterone following brain injury has a controversial history. On one hand, some lab-based models have showed progesterone as being neuroprotective, but on the other, clinical trials have showed quite the opposite. One of many complaints that arose from this discrepancy was the lack of a diverse pool of animal models and paradigms employed during the preclinical phase. However, over the past decade, the zebra finch has emerged as an optimal organism for the study of steroid-mediated neuroprotection. Following an injury, steroid hormones and receptors are upregulated, serving to decrease neuroinflammation and overall damage to the brain. As compared to other vertebrate models, zebra finches can upregulate expression of both estrogens and androgens at a faster and more robust response, suggesting that vertebrates differ in their neuroprotective mechanisms and timing following injury. Therefore, to expand the types organisms studied in pre-clinical trials, we chose to use zebra finches. While the majority of work in the zebra finch brain has focused on estrogens and androgens, we sought to clarify the role of progesterone following injury. Adult male zebra finches were given daily injections of progesterone following a penetrating injury and then were assessed for the size of injury and expression of various genes associated with neuroinflammation and cell survival. Treatment with progesterone decreased the injury size in zebra finches over controls and increased expression of various genes associated with cell survival and neuroinflammation. These data suggest that progesterone does mediate neuroprotection, most likely through the alteration of neuroinflammatory and cell survival pathways.

Estrogen Formation and Inactivation Following TBI: What we Know and Where we Could go

“…Females may be using progesterone in combination with estradiol as neuroprotective steroids following injury. These results are compelling as we have previously found a role for progesterone in cell survival following TBI in the brain (105) and this supports a large body of research examining progesterone treatment following TBI (136,137). Interestingly, like with estradiol despite positive pre-clinical studies, larger clinical, and human trials of progesterone use following TBI have been unsuccessful (138).…”

“…Importantly, DHEA-S prevents against rodent hippocampal neuronal cell loss and damage observed following ischemia and stroke (102). Additionally, the progesterone precursor pregnenolone and pregnenolone-sulfate also exhibit neuroprotective benefits (103)(104)(105). More work is necessary to discern estrogen mediated STS effects vs. DHEA mediated ones following TBI.…”

Progestogen-induced alterations and their ecological relevance in different embryonic and adult behaviours of an invertebrate model species, the great pond snail (Lymnaea stagnalis)

“…p38alpha and JNK1 are considered as stress-activated protein kinases that participate in the cellular response to metabolic and other (environmental) stress conditions such as hormones (Bengal et al 2020 ). Furthermore, p38 expression was previously shown to increase in the vertebrate CNS after progestogen treatment (Blackshear et al 2017 ). We have found that these molecules show significant quantitative changes during the progestogen exposure (Supplementary Fig.…”

Steroid profiling in brain and plasma of adult zebra finches following traumatic brain injury

“…Finally, P4 was non‐detectable in zebra finch entopallium. This was unexpected as treatment of P4 following injury decreases injury size in zebra finches over controls and increases expression of various genes associated with cell survival and neuroinflammation 56 . Furthermore, P4 in mice was upregulated 72 h following injury, but declined at 2 weeks 68 .…”