1. Targeting Oxidative Stress with Antioxidant Duotherapy after Experimental Traumatic Brain Injury.
- Author
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Kyyriäinen J, Kajevu N, Bañuelos I, Lara L, Lipponen A, Balosso S, Hämäläinen E, Das Gupta S, Puhakka N, Natunen T, Ravizza T, Vezzani A, Hiltunen M, and Pitkänen A
- Subjects
- Animals, Antioxidants pharmacology, Brain drug effects, Brain metabolism, Brain pathology, Brain Injuries, Traumatic genetics, Brain Injuries, Traumatic metabolism, Cell Line, Cell Survival drug effects, Cells, Cultured, Disease Models, Animal, Gene Expression drug effects, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Male, Mice, Inbred C57BL, Microglia cytology, Microglia metabolism, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism, Neurons cytology, Neurons metabolism, Rats, Sprague-Dawley, Mice, Rats, Acetylcysteine pharmacology, Brain Injuries, Traumatic drug therapy, Isothiocyanates pharmacology, Microglia drug effects, Neurons drug effects, Oxidative Stress drug effects, Sulfoxides pharmacology
- Abstract
We assessed the effect of antioxidant therapy using the Food and Drug Administration-approved respiratory drug N -acetylcysteine (NAC) or sulforaphane (SFN) as monotherapies or duotherapy in vitro in neuron-BV2 microglial co-cultures and validated the results in a lateral fluid-percussion model of TBI in rats. As in vitro measures, we assessed neuronal viability by microtubule-associated-protein 2 immunostaining, neuroinflammation by monitoring tumor necrosis factor (TNF) levels, and neurotoxicity by measuring nitrite levels. In vitro, duotherapy with NAC and SFN reduced nitrite levels to 40% ( p < 0.001) and neuroinflammation to -29% ( p < 0.001) compared with untreated culture. The treatment also improved neuronal viability up to 72% of that in a positive control ( p < 0.001). The effect of NAC was negligible, however, compared with SFN. In vivo, antioxidant duotherapy slightly improved performance in the beam walking test. Interestingly, duotherapy treatment decreased the plasma interleukin-6 and TNF levels in sham-operated controls ( p < 0.05). After TBI, no treatment effect on HMGB1 or plasma cytokine levels was detected. Also, no treatment effects on the composite neuroscore or cortical lesion area were detected. The robust favorable effect of duotherapy on neuroprotection, neuroinflammation, and oxidative stress in neuron-BV2 microglial co-cultures translated to modest favorable in vivo effects in a severe TBI model.
- Published
- 2021
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