1. Academic Validation
  2. AS1949490, an inhibitor of 5'-lipid phosphatase SHIP2, promotes protein kinase C-dependent stabilization of brain-derived neurotrophic factor mRNA in cultured cortical neurons

AS1949490, an inhibitor of 5'-lipid phosphatase SHIP2, promotes protein kinase C-dependent stabilization of brain-derived neurotrophic factor mRNA in cultured cortical neurons

  • Eur J Pharmacol. 2019 May 15;851:69-79. doi: 10.1016/j.ejphar.2019.02.003.
Hiroshi Tsuneki 1 Hitomi Yoshida 2 Kentaro Okamoto 2 Misako Yamaguchi 2 Kosuke Endo 2 Ayumi Nakano 2 Masaaki Tsuda 3 Naoki Toyooka 4 Tsutomu Wada 2 Toshiyasu Sasaoka 5
Affiliations

Affiliations

  • 1 Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: htsuneki@pha.u-toyama.ac.jp.
  • 2 Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 3 Department of Biological Chemistry, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 4 Graduate School of Science and Engineering, University of Toyama, Toyama 930-8555, Japan.
  • 5 Department of Clinical Pharmacology, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan. Electronic address: tsasaoka@pha.u-toyama.ac.jp.
Abstract

Brain-derived neurotrophic factor (BDNF), an essential factor for maintaining brain functions, has been reported to be reduced in various neurological diseases, including Alzheimer's disease and major depression. Therefore, new drugs to increase the BDNF expression need to be developed. Since phosphatidylinositol (3,4,5)-trisphosphate, a membrane signaling molecule produced by phosphoinositide 3 (PI3)-kinase in the BDNF signaling, is a candidate target of SH2 domain-containing inositol 5' Phosphatase 2 (SHIP2, a 5'-lipid Phosphatase), the present study examined the effect of a SHIP2 inhibitor AS1949490 on Bdnf expression in cultured cortical neurons. BDNF increased its own mRNA levels, and AS1949490 enhanced this positive feedback regulation. The effects of BDNF in combination with AS1949490 on the Bdnf mRNA levels were blocked by inhibitors of mitogen-activated protein kinase kinase (U0126), PI3-kinase (LY294002), Phospholipase Cγ (U73122), and protein kinase C (bisindolylmaleimide I), whereas the effect of BDNF alone was inhibited only by U0126. The mRNA stability assay using actinomycin D demonstrated that AS1949490 reduced degradation of the self-amplified Bdnf mRNA levels, and this effect was disappeared in the presence of bisindolylmaleimide I. These results suggest that BDNF promoted the Bdnf mRNA stabilization in a protein kinase C-dependent manner only in the presence of AS1949490, thereby enhancing Bdnf expression. Furthermore, behavioral analyses indicated that central administration of AS1949490 caused memory-improving and anti-depressant effects in passive avoidance test and forced swim test, respectively. Therefore, inhibition of SHIP2 appears to be valuable therapeutic strategy against neurological disorders associated with insufficient BDNF functions.

Keywords

Alzheimer's disease; Brain-derived neurotrophic factor; Lipid phosphatase; Major depression; Protein kinase C; SHIP2.

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