MicroRNA profiling identifies a novel compound with antidepressant properties

Autor: Ian J. Bolding, Deborah R. Boone, Michael T. Falduto, Maria-Adelaide Micci, Douglas S. DeWitt, Cesar Cardenas, Karen E. O. Torres, Harris A. Weisz, Hannah E. Willey, Donald S. Prough, Helen L. Hellmich, Stacy L. Sell
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
Imipramine
Critical Care and Emergency Medicine
Traumatic Brain Injury
Bioinformatics
Hippocampus
Biochemistry
0302 clinical medicine
Animal Cells
Sertraline
Brain Injuries
Traumatic
Medicine and Health Sciences
Trauma Medicine
Neurons
Sulfonamides
Multidisciplinary
Estradiol
Depression
Pharmaceutics
Drugs
Brain
Antidepressants
Antidepressive Agents
3. Good health
Nucleic acids
Antidepressant
Medicine
Anatomy
Cellular Types
Traumatic Injury
medicine.drug
Research Article
Traumatic brain injury
Science
Neuroprotection
03 medical and health sciences
Drug Therapy
Fluoxetine
Neuroplasticity
Mental Health and Psychiatry
medicine
Genetics
Animals
Humans
Non-coding RNA
Pharmacology
Natural antisense transcripts
Biology and life sciences
business.industry
Mood Disorders
Computational Biology
Cell Biology
medicine.disease
Rats
Gene regulation
Disease Models
Animal
MicroRNAs
Thiazoles
030104 developmental biology
Gene Expression Regulation
Cellular Neuroscience
RNA
Gene expression
business
Neurotrauma
030217 neurology & neurosurgery
Behavioural despair test
Neuroscience
Zdroj: PLoS ONE, Vol 14, Iss 8, p e0221163 (2019)
PLoS ONE
ISSN: 1932-6203
Popis: 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.
Databáze: OpenAIRE
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