3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury

International Journal of Molecular Sciences

Dong Seok Kim¹  Barry J. Hoffer²  Yung-Hsiao Chiang³  Nigel H. Greig⁴  Weiming Luo⁴  Daniela Lecca⁴  Pen-Sen Huang⁵  Jia-Yi Wang⁵  Ling-Yu Yang⁵  Ping-Yen Tsai⁵ 

[1] Aevis Bio, Inc., Daejeon 34141, Korea;Department of Neurological Surgery, Case Western Reserve University, Cleveland, OH 44106, USA;Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan;Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA;Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan;

关键词: 3,6′-dithiopomalidomide;    pomalidomide;    traumatic brain injury;    neurodegeneration;    cognitive deficits;    neuroinflammation;   

DOI  :  10.3390/ijms22158276

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown