1-(2-4-dichlorobenzyl)indazole-3-carbohydrazide and Brain-Edema

Adjudin, a small molecular compound that is used as a male contraceptive, has been reported to play a neuroprotective role in an ischemic stroke injury model. However, its effect on traumatic brain injury (TBI) has not been assessed. Hence, we investigated the effects of adjudin on cerebral edema using a mouse model of TBI and explored the underlying mechanisms. Adult male C57BL/6 mice received controlled cortical impact (CCI) injury, then an injection of adjudin (50 mg/kg). The mice were euthanized 3 days post-CCI injury, and samples were collected for further analysis. Cultured primary mouse astrocytes were used for in vitro experiments. Adjudin treatment significantly attenuated cerebral edema on Day 3 and improved neurobehavioral outcomes on Days 3, 7, and 14 after CCI injury, compared with the vehicle group. Additionally, the evaluation of Evans blue extravasation and expression of tight junction proteins demonstrated remarkable effects of adjudin on blood-brain barrier protection. Further, adjudin treatment significantly decreased the gene and protein expression of aquaporin 4 in post-injury mice and inhibited progression of neuroinflammation in both mice and cultured astrocytes. The Western blot results of the peritraumatic protein samples demonstrated that adjudin significantly blocked the phosphorylation of IKKα, IκBα/β, and NF-κB p65, which resulted in a reduction of NF-κB p65 nuclear translocation. In conclusion, adjudin attenuated the development of TBI-induced cerebral edema at least partly via anti-inflammatory effects and inhibition of the NF-κB pathway. These findings suggest that adjudin is a potential therapeutic intervention preventing the development of cerebral edema after TBI.

Topics: Animals; Blood-Brain Barrier; Brain Edema; Brain Injuries, Traumatic; Disease Models, Animal; Hydrazines; Indazoles; Male; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Recovery of Function

Neuroinflammation caused by microglial activation plays a key role in ischemia, neurodegeneration and many other CNS diseases. In this study, we found that Adjudin, a potential non-hormonal male contraceptive, exhibits additional function to reduce the production of proinflammatory mediators. Adjudin significantly inhibited LPS-induced IL-6 release and IL-6, IL-1β, TNF-α expression in BV2 microglial cells. Furthermore, Adjudin exhibited anti-inflammatory properties by suppression of NF-κB p65 nuclear translocation and DNA binding activity as well as ERK MAPK phosphorylation. To determine the in vivo effect of Adjudin, we used a permanent middle cerebral artery occlusion (pMCAO) mouse model and found that Adjudin could reduce ischemia-induced CD11b expression, a marker of microglial activation. Furthermore, Adjudin treatment attenuated brain edema and neurological deficits after ischemia but did not reduce infarct volume. Thus, our data suggest that Adjudin may be useful for mitigating neuroinflammation.

Topics: Analysis of Variance; Animals; Anti-Inflammatory Agents; Brain Edema; Brain Infarction; CD11b Antigen; Cell Line, Transformed; Cell Survival; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Interactions; Hydrazines; Indazoles; Infarction, Middle Cerebral Artery; Lipopolysaccharides; Male; Mice; Mice, Inbred ICR; Microglia; Nervous System Diseases; NF-kappa B; Psychomotor Performance; Signal Transduction; Time Factors