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
Affiliations
Chih-Tung Lin
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
Daniela Lecca
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States
Ling-Yu Yang
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
Weiming Luo
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States
Michael T Scerba
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States
Pen-Sen Huang
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan
Yoo-Jin Jung
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States
Dong Seok Kim
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States; AevisBio Inc, Gaithersburg, United States; AevisBio Inc, Daejeon, Republic of Korea
Chih-Hao Yang
Department of Pharmacology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
Barry J Hoffer
Department of Neurological Surgery, Case Western Reserve University, Cleveland, United States
Jia-Yi Wang
Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei, Taiwan; Neuroscience Research Center, Taipei Medical University, Taipei, Taiwan
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program National Institute on Aging, NIH, Baltimore, United States
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 pro-inflammatory cytokines, iNOS, COX-2, and autophagy-associated proteins were suppressed, leading to an amelioration of behavioral deficits with DP providing greater efficacy. Complementary animal and cellular studies demonstrated DP and Pom mediated reductions in markers of neuroinflammation and α-synuclein-induced toxicity.
