TY - JOUR
T1 - Carbamoylated erythropoietin produces antidepressant-like effects in male and female mice
AU - Sampath, Dayalan
AU - McWhirt, Joshua
AU - Sathyanesan, Monica
AU - Newton, Samuel S.
N1 - Funding Information:
This work was supported by US Public Health Service grants MH106640 (SSN), the University of South Dakota and the use of facilities at the Sioux Falls VA Healthcare system. We thank Nicholas Pekas for assistance with data analysis.
Publisher Copyright:
© 2019 The Authors
PY - 2020/1/10
Y1 - 2020/1/10
N2 - Major depressive disorder and related illnesses are globally prevalent, with a significant risk for suicidality if untreated. Antidepressant drugs that are currently prescribed do not benefit 30% of treated individuals. Furthermore, there is a delay of 3 or more weeks before a reduction in symptoms. Results from preclinical studies have indicated an important role for trophic factors in regulating behavior. Erythropoietin (Epo), which is widely prescribed for anemia, has been shown to produce robust neurotrophic actions in the CNS. Although Epo's antidepressant activity has been successfully demonstrated in multiple clinical trials, the inherent ability to elevate RBC counts and other hematological parameters preclude its development as a mainstream CNS drug. A chemically engineered derivative, carbamoylated Epo (Cepo) has no hematological activity, but retains the neurotrophic actions of Epo. Cepo is therefore an attractive candidate to be tested as an antidepressant. Objective: To evaluate the antidepressant properties of Cepo in established antidepressant-responsive rodent behavioral assays. Methods: Adult male and female BALB/c mice were used for this study. Cepo (30 μgrams/ kg BWT) or vehicle (PBS) was administered intraperitoneally for 4 days before the test of novelty induced hypophagia and subsequently at five hours before testing in forced swim test (FST), tail suspension test (TST) and open field test (OFT). To obtain mechanistic insight we examined the phosphorylation of the transcription factor cAMP response element binding protein (CREB). Results: Administration of Cepo at 30 μgrams/ kg BWT, for 4 days produced significant reduction in latency to consume a palatable drink in a novel environment in male and female mice. Male BALB/c mice had a significant reduction in immobility in both tail suspension and forced swim tests, and female mice exhibited lower immobility in the forced swim test.
AB - Major depressive disorder and related illnesses are globally prevalent, with a significant risk for suicidality if untreated. Antidepressant drugs that are currently prescribed do not benefit 30% of treated individuals. Furthermore, there is a delay of 3 or more weeks before a reduction in symptoms. Results from preclinical studies have indicated an important role for trophic factors in regulating behavior. Erythropoietin (Epo), which is widely prescribed for anemia, has been shown to produce robust neurotrophic actions in the CNS. Although Epo's antidepressant activity has been successfully demonstrated in multiple clinical trials, the inherent ability to elevate RBC counts and other hematological parameters preclude its development as a mainstream CNS drug. A chemically engineered derivative, carbamoylated Epo (Cepo) has no hematological activity, but retains the neurotrophic actions of Epo. Cepo is therefore an attractive candidate to be tested as an antidepressant. Objective: To evaluate the antidepressant properties of Cepo in established antidepressant-responsive rodent behavioral assays. Methods: Adult male and female BALB/c mice were used for this study. Cepo (30 μgrams/ kg BWT) or vehicle (PBS) was administered intraperitoneally for 4 days before the test of novelty induced hypophagia and subsequently at five hours before testing in forced swim test (FST), tail suspension test (TST) and open field test (OFT). To obtain mechanistic insight we examined the phosphorylation of the transcription factor cAMP response element binding protein (CREB). Results: Administration of Cepo at 30 μgrams/ kg BWT, for 4 days produced significant reduction in latency to consume a palatable drink in a novel environment in male and female mice. Male BALB/c mice had a significant reduction in immobility in both tail suspension and forced swim tests, and female mice exhibited lower immobility in the forced swim test.
KW - Antidepressant mechanism of action
KW - Behavioral despair
KW - Carbamoylated erythropoietin
KW - Phosphorylated CREB
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U2 - 10.1016/j.pnpbp.2019.109754
DO - 10.1016/j.pnpbp.2019.109754
M3 - Article
C2 - 31454554
AN - SCOPUS:85071425393
SN - 0278-5846
VL - 96
JO - Progress in Neuro-Psychopharmacology and Biological Psychiatry
JF - Progress in Neuro-Psychopharmacology and Biological Psychiatry
M1 - 109754
ER -