MicroRNA profiling identifies a novel compound with antidepressant properties

Abstract

Patients with traumatic brain injury (TBI) are frequently diagnosed with depression. Together, these two leading causes of death and disability significantly contribute to the global burden of healthcare costs. However, there are no drug treatments for TBI and antidepressants are considered off-label for depression in patients with TBI. In molecular profiling studies of rat hippocampus after experimental TBI, we found that TBI altered the expression of a subset of small, non-coding, microRNAs (miRNAs). One known neuroprotective compound (17β-estradiol, E2), and two experimental neuroprotective compounds (JM6 and PMI-006), reversed the effects of TBI on miRNAs. Subsequent in silico analyses revealed that the injury-altered miRNAs were predicted to regulate genes involved in depression. Thus, we hypothesized that drug-induced miRNA profiles can be used to identify compounds with antidepressant properties. To confirm this hypothesis, we examined miRNA expression in hippocampi of injured rats treated with one of three known antidepressants (imipramine, fluoxetine and sertraline). Bioinformatic analyses revealed that TBI, potentially via its effects on multiple regulatory miRNAs, dysregulated transcriptional networks involved in neuroplasticity, neurogenesis, and circadian rhythms- networks known to adversely affect mood, cognition and memory. As did E2, JM6, and PMI-006, all three antidepressants reversed the effects of TBI on multiple injury-altered miRNAs. Furthermore, JM6 reduced TBI-induced inflammation in the hippocampus and depression-like behavior in the forced swim test; these are both properties of classic antidepressant drugs. Our results support the hypothesis that miRNA expression signatures can identify neuroprotective and antidepressant properties of novel compounds and that there is substantial overlap between neuroprotection and antidepressant properties.

Downregulation of microRNA-9-5p promotes synaptic remodeling in the chronic phase after traumatic brain injury

“…In recent years, many researchers have reported that non-coding RNAs play an important role in maintaining stable and normal NVU function. MicroRNAs (miRNAs) are short (19)(20)(21)(22)(23)(24)(25)(26)(27)(28) nucleotides) endogenous non-coding RNAs that regulate protein synthesis at the post-transcriptional level 16 . Previous studies have verified that the levels of various miRNAs are significantly changed in brain tissues after TBI, which can restore the normal function of the NVU by inhibiting the apoptosis of neurons and reducing the destruction of the BBB.…”

Comprehensive RNA Expression Analysis Revealed Biological Functions of Key Gene Sets and Identified Disease-Associated Cell Types Involved in Rat Traumatic Brain Injury

“…Additionally, the single-nuclei sequencing dataset GSE137869 [ 10 ] was retrieved for cell marker identification. Among the datasets, GSE2871 [ 11 ] was used for WGCNA; GSE2392 [ 12 ], GSE2871 [ 11 ], and GSE45997 [ 13 ] were used in the GSEA analysis; GSE1911 [ 14 ], GSE2392 [ 12 ], GSE24047 [ 15 , 16 ], GSE31357 [ 17 ], GSE59645 [ 18 ], GSE64978 [ 19 ], GSE67836 [ 20 ], GSE68207 [ 19 ], GSE80174 [ 21 ], GSE86579 [ 22 ], GSE111452 [ 23 ], and GSE115614 [ 18 ] were analyzed for validation. Among the samples in the above datasets, only samples from wild-type rats with no additional treatment or disease other than TBI were included.…”

Mechanistic insights gained from cell and molecular analysis of the neuroprotective potential of bioactive natural compounds in an immortalized hippocampal cell line

“…Fresh frozen sections were post-fixed for 20 min in 4°C paraformaldehyde, incubated overnight with 1 o antibody (mouse anti-CD11b; 1:2000), the following morning incubated with a 2 o antibody (Alexa 594 goat anti-mouse; 1:400) at ambient temperature, and then mounted with nuclear stain DAPI for imaging. Detailed procedure available in Sell et al, [ 8 ].…”

“…Like many thousands of researchers who are engaged in elucidating the underlying mechanisms of and finding therapeutic treatments for traumatic brain injury (TBI) [ 1 – 3 ], we have extensively used animal models of TBI to study the underlying molecular mechanisms [ 4 , 5 ] and importantly, to test several experimental compounds for potentially neuroprotective effects [ 6 – 8 ]. However, the lesson we have learned from two decades of extensive in vivo studies is that evaluating novel compounds for neuroprotective effects in animal models of TBI is a protracted, labor-intensive and costly endeavor with no guarantee of success.…”