3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

Chih Tung Lin, Daniela Lecca, Ling Yu Yang, Weiming Luo, Michael T. Scerba, David Tweedie, Pen Sen Huang, Yoo Jin Jung, Dong Seok Kim, Chih Hao Yang, Barry J. Hoffer, Jia Yi Wang, Nigel H. Greig

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Traumatic brain injury (TBI) causes mortality and disability worldwide. It can initiate acute cell death followed by secondary injury induced by microglial activation, oxidative stress, inflammation and autophagy in brain tissue, resulting in cognitive and behavioral deficits. We evaluated a new pomalidomide (Pom) analog, 3,6’-dithioPom (DP), and Pom as immunomodulatory agents to mitigate TBI-induced cell death, neuroinflammation, astrogliosis and behavioral impairments in rats challenged with controlled cortical impact TBI. Both agents significantly reduced the injury contusion volume and degenerating neuron number evaluated histochemically and by MRI at 24 hr and 7 days, with a therapeutic window of 5 hr post-injury. TBI-induced upregulated markers of microglial activation, astrogliosis and the expression of proinflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater potency. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.

Original languageEnglish
Article numbere54726
Pages (from-to)1-78
Number of pages78
JournaleLife
Volume9
DOIs
Publication statusPublished - Jun 2020

Keywords

  • 3,6’-Dithiopomalidomide
  • Autophagy
  • COX2
  • INOS
  • LPS
  • Neuroinflammation
  • Pomalidomide
  • Traumatic brain injury
  • α-synuclein

ASJC Scopus subject areas

  • Neuroscience(all)
  • Immunology and Microbiology(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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