3,6′-dithiopomalidomide ameliorates hippocampal neurodegeneration, microgliosis and astrogliosis and improves cognitive behaviors in rats with a moderate traumatic brain injury

Pen Sen Huang, Ping Yen Tsai, Ling Yu Yang, Daniela Lecca, Weiming Luo, Dong Seok Kim, Barry J. Hoffer, Yung Hsiao Chiang, Nigel H. Greig, Jia Yi Wang

Research output: Contribution to journalArticlepeer-review

Abstract

Traumatic brain injury (TBI) is a leading cause of disability and mortality worldwide. It can instigate immediate cell death, followed by a time-dependent secondary injury that results from disproportionate microglial and astrocyte activation, excessive inflammation and oxidative stress in brain tissue, culminating in both short-and long-term cognitive dysfunction and behavioral deficits. Within the brain, the hippocampus is particularly vulnerable to a TBI. We studied a new pomalidomide (Pom) analog, namely, 3,6′-dithioPom (DP), and Pom as immunomodulatory imide drugs (IMiD) for mitigating TBI-induced hippocampal neurodegeneration, microgliosis, astrogliosis and behavioral impairments in a controlled cortical impact (CCI) model of TBI in rats. Both agents were administered as a single intravenous dose (0.5 mg/kg) at 5 h post injury so that the efficacies could be compared. Pom and DP significantly reduced the contusion volume evaluated at 24 h and 7 days post injury. Both agents ameliorated short-term memory deficits and anxiety behavior at 7 days after a TBI. The number of degenerating neurons in the CA1 and dentate gyrus (DG) regions of the hippocampus after a TBI was reduced by Pom and DP. DP, but not Pom, significantly attenuated the TBI-induced microgliosis and DP was more efficacious than Pom at attenuating the TBI-induced astrogliosis in CA1 and DG at 7D after a TBI. In summary, a single intravenous injection of Pom or DP, given 5 h post TBI, significantly reduced hippocampal neurodegeneration and prevented cognitive deficits with a concomitant attenuation of the neuroinflammation in the hippocampus.

Original languageEnglish
Article number8276
JournalInternational journal of molecular sciences
Volume22
Issue number15
DOIs
Publication statusPublished - Aug 1 2021

Keywords

  • 3,6′-dithiopomalidomide
  • Astrogliosis
  • Cognitive deficits
  • Immunomodulatory imide drugs
  • Microgliosis
  • Neurodegeneration
  • Neuroinflammation
  • Pomalidomide
  • Traumatic brain injury

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

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