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Article

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

1
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
2
School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
3
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, NIH, Baltimore, MD 21224, USA
4
Aevis Bio, Inc., Daejeon 34141, Korea
5
Aevis Bio, Inc., Gaithersburg, MD 20878, USA
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Department of Neurological Surgery, Case Western Reserve University, Cleveland, OH 44106, USA
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Department of Neurosurgery, Taipei Medical University Hospital, Taipei Medical University, Taipei 110, Taiwan
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Neuroscience Research Center, Taipei Medical University, Taipei 110, Taiwan
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Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan
*
Authors to whom correspondence should be addressed.
These authors contributed equally.
Academic Editor: Georgia Mandolesi
Int. J. Mol. Sci. 2021, 22(15), 8276; https://doi.org/10.3390/ijms22158276
Received: 15 June 2021 / Revised: 27 July 2021 / Accepted: 28 July 2021 / Published: 31 July 2021
(This article belongs to the Special Issue Molecular and Cellular Mechanisms in Inflammatory Synaptopathy)
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. View Full-Text
Keywords: 3,6′-dithiopomalidomide; pomalidomide; traumatic brain injury; neurodegeneration; cognitive deficits; neuroinflammation; microgliosis; astrogliosis; immunomodulatory imide drugs 3,6′-dithiopomalidomide; pomalidomide; traumatic brain injury; neurodegeneration; cognitive deficits; neuroinflammation; microgliosis; astrogliosis; immunomodulatory imide drugs
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MDPI and ACS Style

Huang, P.-S.; Tsai, P.-Y.; Yang, L.-Y.; Lecca, D.; Luo, W.; Kim, D.S.; Hoffer, B.J.; Chiang, Y.-H.; Greig, N.H.; Wang, J.-Y. 3,6′-Dithiopomalidomide Ameliorates Hippocampal Neurodegeneration, Microgliosis and Astrogliosis and Improves Cognitive Behaviors in Rats with a Moderate Traumatic Brain Injury. Int. J. Mol. Sci. 2021, 22, 8276. https://doi.org/10.3390/ijms22158276

AMA Style

Huang P-S, Tsai P-Y, Yang L-Y, Lecca D, Luo W, Kim DS, Hoffer BJ, Chiang Y-H, Greig NH, Wang J-Y. 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. 2021; 22(15):8276. https://doi.org/10.3390/ijms22158276

Chicago/Turabian Style

Huang, Pen-Sen, Ping-Yen Tsai, Ling-Yu Yang, Daniela Lecca, Weiming Luo, Dong Seok Kim, Barry J. Hoffer, Yung-Hsiao Chiang, Nigel H. Greig, and Jia-Yi Wang. 2021. "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 22, no. 15: 8276. https://doi.org/10.3390/ijms22158276

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