Post-Injury Neuroprotective Effects of the Thalidomide Analog 3,6'-Dithiothalidomide on Traumatic Brain Injury

• Published in: International journal of molecular sciences Vol. 20; no. 3; p. 502
• Main Authors: Batsaikhan, Buyandelger, Wang, Jing-Ya, Scerba, Michael T, Tweedie, David, Greig, Nigel H, Miller, Jonathan P, Hoffer, Barry J, Lin, Chih-Tung, Wang, Jia-Yi
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 24.01.2019; MDPI
• Subjects: 3,6′-dithiothalidomide; Adhesives; Animal models; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Apoptosis; Blood-brain barrier; Brain Injuries, Traumatic - drug therapy; Cell culture; Cell Line; Contusions; Culture media; Evaluation; Immunoglobulins; Inflammation; Investigations; Lipopolysaccharides; Male; Mice; Motor ability; neurodegeneration; neuroinflammation; neurological deficits; Neurons - drug effects; Neurons - metabolism; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nitric oxide; Nitric-oxide synthase; Oxidative stress; Rats; Rats, Sprague-Dawley; Thalidomide; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; Thalidomide - therapeutic use; Toxicity; Trauma; Traumatic brain injury; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; Tumor necrosis factor-α; neurodegeneration; traumatic brain injury; neurological deficits; neuroinflammation; oxidative stress; 3,6′-dithiothalidomide
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms20030502

Traumatic brain injury (TBI) is a major cause of mortality and disability worldwide. Long-term deficits after TBI arise not only from the direct effects of the injury but also from ongoing processes such as neuronal excitotoxicity, inflammation, oxidative stress and apoptosis. Tumor necrosis factor-α (TNF-α) is known to contribute to these processes. We have previously shown that 3,6'-dithiothalidomide (3,6'-DT), a thalidomide analog that is more potent than thalidomide with similar brain penetration, selectively inhibits the synthesis of TNF-α in cultured cells and reverses behavioral impairments induced by mild TBI in mice. In the present study, we further explored the therapeutic potential of 3,6'-DT in an animal model of moderate TBI using Sprague-Dawley rats subjected to controlled cortical impact. A single dose of 3,6'-DT (28 mg/kg, i.p.) at 5 h after TBI significantly reduced contusion volume, neuronal degeneration, neuronal apoptosis and neurological deficits at 24 h post-injury. Expression of pro-inflammatory cytokines in the contusion regions were also suppressed at the transcription and translation level by 3,6'-DT. Notably, neuronal oxidative stress was also suppressed by 3,6'-DT. We conclude that 3,6'-DT may represent a potential therapy to ameliorate TBI-induced functional deficits.