Abstract
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.
Highlights
Traumatic brain injury (TBI), one of the leading causes of disability, morbidity, and mortality worldwide, currently has no effective treatment
Our results show that 3,6 -DT improves somatosensory and neurological functions, but not contralateral swing or beam walking
Since injury-induced inflammatory responses that contribute to the histological and behavioral pathophysiology of TBI were predominantly affected, our findings suggest that 3,6 -DT has neuroprotective properties, and that functional improvement is perhaps provided, in large part, through the modulation of inflammation
Summary
Traumatic brain injury (TBI), one of the leading causes of disability, morbidity, and mortality worldwide, currently has no effective treatment. The primary brain injury occurs at the time of initial impact and produces a series of direct insults such as acute cell death due to mechanical disruption. Secondary injury arises from subsequent physiological processes such as excitotoxicity that triggers a number of events including peri-lesion depolarization and the more delayed mechanisms of inflammation and apoptosis. The inflammatory response from activated microglia, recruited neutrophils and macrophages, and oxidative stress, contribute to secondary brain damage and, subsequently, lead to a progressive pathology [1,2,3,4] producing additional injury to neural tissues [5]. Therapeutic options to treat primary injury are limited since these processes are usually complete by the time of clinical presentation, but modulation of secondary injury pathways in the early-injury period has considerable clinical potential to improve outcomes after TBI
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