The Idea that the Inhibition of Let-7i Allows for an Increase in Progesterone, Leading to a Functional Recovery in a Mouse Model of a Stroke or Ischemic Event

 

Progesterone (P4) is an observed neuroprotectant that is regulated by brain-derived neurotrophic factor (BDNF) and is overseen by cortical astrocytes that contain the progesterone receptor Pgrmc1 (Nguyen, Su & Singh 2018). Singh et al looked at the hormones effect on the brain after it experienced a stroke or a stroke-like event. Trying to decode the process of progesterone as a neurotrophin, it was suggested that microRNAs are involved in the process (Nguyen, Su & Singh 2018). The article specifically focuses on Let-7i in an “in vitro two-cell model system, which consisted of both astrocytes and neurons” (Nguyen, Su & Singh 2018).

Results showed that the microRNA Let-7i negatively impacts both the progesterone receptor and BDNF. This leads to a decrease in the release of P4 from BDNF in the glia tested (Nguyen, Su & Singh 2018). Since it was also observed that ischemic injury in the mouse model leads to an increase in Let-7i, the scientists tested combinations of variables in order to determine what grouping leads to an influx of P4. The findings show that both P4 and anti-Let7i aided in reversing the effects of the ischemic event, including halting the suppression of Pgrmc1 (Nguyen, Su & Singh 2018). When further investigated, both anti-Let-7i and P4 caused a rapid increase in motor function compared to P4 alone. After seven days, the combination treatment showed a complete recovery in motor function (Nguyen, Su & Singh 2018).

Along with a stroke, treatments for other traumatic brain injuries (TBI) are being investigated. An article, published in MedicalExpress, talks about a recently published article investigating a small-molecule drug that works to reverse the neuronal effects of a TBI. Mice were treated with an integrated stress response inhibitor (ISRIB) after they received a concussion. The study found that this drug reverses the results of the TBI on the dendritic spines (Frias, Elma S. et al 2022). With the spines being essential in neuronal communication and cognition, the experimental drug caused an increase in working memory (Frias, Elma S. et al 2022). Scientists found that by blocking the IR, this treatment was able to repair the structural damage done by the TBI and are connected to an increase in neuronal performance.

Both studies use artificial methods in an attempt to repair damages done by typically irreversible brain injuries. Using these techniques, it is proposed that eventually in humans these will aid in gaining neuronal function back as a result of the TBI or ischemic event. As was discussed, the treatment used in the event of a stroke can be applied for other injuries similar, so it is worth considering if both studies can be applied throughout the brain with an array of other injuries. As was also mentioned in the second article, one month in a mouse study represents multiple years in a human life (Frias, Elma S. et al 2022). This is a very promising idea based on these studies and others alike.

References

 

Frias, Elma S. et al, Aberrant cortical spine dynamics after concussive injury are reversed by integrated stress response inhibition, Proceedings of the National Academy of Sciences (2022). DOI: 10.1073/pnas.2209427119. doi.org/10.1073/pnas.2209427119

Nguyen T, Su C, Singh M. Let-7i inhibition enhances progesterone-induced functional recovery in a mouse model of ischemia. Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9668-E9677. doi: 10.1073/pnas.1803384115. Epub 2018 Sep 20. PMID: 30237284; PMCID: PMC6187141. Let-7i inhibition enhances progesterone-induced functional recovery in a mouse model of ischemia - PubMed (nih.gov)