2. Academic Validation
  3. Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior

Phosphodiesterase 2 inhibitor Hcyb1 reverses corticosterone-induced neurotoxicity and depression-like behavior

  • Psychopharmacology (Berl). 2020 Nov;237(11):3215-3224. doi: 10.1007/s00213-019-05401-1.
Meng-Jia Zhu 1 2,  Jing Shi 3,  Yong Chen 4,  Guobing Huang 5,  Xiong-Wei Zhu 6,  Sam Zhang 2,  Xian-Feng Huang 1,  Guo-Qiang Song 1,  Han-Ting Zhang 7 8 9,  Heng-Ming Ke 10 11,  James M O'Donnell 2,  Li-Qun Wang 12,  Ying Xu 13
Affiliations

Affiliations

  • 1 School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China.
  • 2 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA.
  • 3 School of Pharmacy, Hangzhou Medical College, Hangzhou, 310053, Zhejiang Province, China.
  • 4 Department of Neurology, The People's Hospital of Yichun City, Yichun, Jiangxi Province, China.
  • 5 Department of Neurosurgery, The People's Hospital of Yichun City, Yichun, Jiangxi Province, China.
  • 6 Department of Pathology, Case Western Reserve University, Cleveland, OH, 44106, USA.
  • 7 Department of Behavioral Medicine & Psychiatry, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
  • 8 Department of Physiology & Pharmacology, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
  • 9 Department of Neuroscience, Rockefeller Neurosciences Institute, West Virginia University Health Sciences Center, Morgantown, WV, 26506, USA.
  • 10 Department of Biochemistry and Biophysics, The University of North Carolina, Chapel Hill, NC, USA.
  • 11 Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC, USA.
  • 12 School of Pharmaceutical Engineering and Life Sciences, Changzhou University, Changzhou, China. [email protected].
  • 13 Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, the State University of New York, Buffalo, NY, 14214, USA. [email protected].
PMID: 32926224 DOI: 10.1007/s00213-019-05401-1
Abstract

Rationale: Currently available PDE2 inhibitors have poor brain penetration that limits their therapeutic utility in the treatment of depression. Hcyb1 is a novel selective PDE2 Inhibitor that was introduced more lipophilic groups with polar functionality to the scaffold pyrazolopyrimidinone to improve the blood-brain barrier (BBB) penetration. Our previous study suggested that Hcyb1 increased the neuronal cell viability and exhibited antidepressant-like effects, which were parallel to the currently available PDE2 Inhibitor Bay 60-7550.

Objectives: The present study investigated whether Hcyb1 protected HT-22 cells against corticosterone-induced neurotoxicity and produced antidepressant-like effects in behavioral tests in stressed mice.

Methods: The neuroprotective effects of Hcyb1 against corticosterone-induced cell lesion were examined by cell viability (MTS) assay. The enzyme-linked immunosorbent assay (ELISA) and immunoblot analysis were used to determine the levels of cAMP or cGMP and expression of pCREB or BDNF, respectively, in the corticosterone-treated HT-22 cells. The antidepressant-like effects of Hcyb1 were determined in the tail suspension and novelty suppressed feeding tests in stressed mice.

Results: In the cell-based assay, Hcyb1 significantly increased cell viability of HT-22 cells against corticosterone-induced neurotoxicity in a time- and dose-dependent manner. Hcyb1 also rescued corticosterone-induced decreases in both cGMP and cAMP levels, pCREB/CREB and BDNF expression. These protective effects of Hcyb1 were prevented by pretreatment with either the PKA Inhibitor H89 or the PKG inhibitor KT5823. Moreover, Hcyb1 reversed acute stress-induced increases in immobility time and the latency to feed in the tail suspension and novelty suppressed feeding tests, respectively, which were prevented by pretreatment with H89 or KT5823.

Conclusion: These findings provide evidence that the neuroprotective effects of Hcyb1 are mediated by PDE2-dependent cAMP/cGMP signaling.

Keywords

BDNF; CREB; Depression; Hcyb1; PDE2 inhibitor; PKA/PKG.

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