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J Neuroinflammation. 2016 Jun 28;13(1):168. doi: 10.1186/s12974-016-0631-6.

Pomalidomide mitigates neuronal loss, neuroinflammation, and behavioral impairments induced by traumatic brain injury in rat.

Author information

1
Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan.
2
Department of Nursing, Hsin Sheng Junior College of Medical Care and Management, Taoyuan, Taiwan.
3
Department of General Surgery, Chi Mei Medical Center, Tainan and Liouying, Taiwan.
4
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA.
5
Department of Anatomy and Anthropology, Sackler School of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, Israel.
6
Graduate Program on Neuroregeneration, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
7
Department of Neurosurgery, Case Western Reserve University School of Medicine, Cleveland, OH, USA.
8
Drug Design & Development Section, Translational Gerontology Branch, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, USA. greign@mail.NIH.gov.
9
Graduate Institute of Medical Science, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan. jywang2010@tmu.edu.tw.
10
Department of Physiology, College of Medicine, Taipei Medical University, 250 Wu-Hsing St., Taipei, 110, Taiwan. jywang2010@tmu.edu.tw.

Abstract

BACKGROUND:

Traumatic brain injury (TBI) is a global health concern that typically causes emotional disturbances and cognitive dysfunction. Secondary pathologies following TBI may be associated with chronic neurodegenerative disorders and an enhanced likelihood of developing dementia-like disease in later life. There are currently no approved drugs for mitigating the acute or chronic effects of TBI.

METHODS:

The effects of the drug pomalidomide (Pom), an FDA-approved immunomodulatory agent, were evaluated in a rat model of moderate to severe TBI induced by controlled cortical impact. Post-TBI intravenous administration of Pom (0.5 mg/kg at 5 or 7 h and 0.1 mg/kg at 5 h) was evaluated on functional and histological measures that included motor function, fine more coordination, somatosensory function, lesion volume, cortical neurodegeneration, neuronal apoptosis, and the induction of pro-inflammatory cytokines (TNF-α, IL-1β, IL-6).

RESULTS:

Pom 0.5 mg/kg administration at 5 h, but not at 7 h post-TBI, significantly mitigated the TBI-induced injury volume and functional impairments, neurodegeneration, neuronal apoptosis, and cytokine mRNA and protein induction. To evaluate underlying mechanisms, the actions of Pom on neuronal survival, microglial activation, and the induction of TNF-α were assessed in mixed cortical cultures following a glutamate challenge. Pom dose-dependently ameliorated glutamate-mediated cytotoxic effects on cell viability and reduced microglial cell activation, significantly attenuating the induction of TNF-α.

CONCLUSIONS:

Post-injury treatment with a single Pom dose within 5 h significantly reduced functional impairments in a well-characterized animal model of TBI. Pom decreased the injury lesion volume, augmented neuronal survival, and provided anti-inflammatory properties. These findings strongly support the further evaluation and optimization of Pom for potential use in clinical TBI.

KEYWORDS:

Controlled cortical impact; Glutamate excitotoxicity; Interleukin-1β; Interleukin-6; Neuroinflammation; Neuronal apoptosis; Pomalidomide; Thalidomide; Traumatic brain injury; Tumor necrosis factor-α

PMID:
27353053
PMCID:
PMC4924242
DOI:
10.1186/s12974-016-0631-6
[Indexed for MEDLINE]
Free PMC Article

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