Background and purpose Edema formation, inflammation and increased blood-brain barrier permeability contribute to poor outcomes after intracerebral hemorrhage (ICH). This study examined the therapeutic effect of Dimethyl fumarate (DMF), a fumaric acid ester that activates nuclear factor erythroid-2 related factor 2 (Nrf2) and Nrf2 heterodimerization effector musculo-aponeurotic fibrosacoma-G (MAFG) in a murine ICH model. Methods Male CD-1 mice (n=176) were subjected to intrastriatal infusion of bacterial collagenase (n=120), autologous blood (n=18) or sham surgery (n=30). After ICH, animals either received vehicle, Dimethyl fumarate (10mg or 100mg/kg) or casein kinase 2 inhibitor (E)-3-(2,3,4,5-tetrabromophenyl)acrylic acid (TBCA). Thirty-eight mice also received scrambled siRNA or MAFG siRNA 24 hours before ICH. Brain water content and neurological function were evaluated. Results Dimethyl fumarate reduced Evans blue extravasation, decreased brain water content, and improved neurological deficits at 24 and 72 hours after ICH. Casein kinase 2 inhibitor TBCA and MAFG siRNA prevented the effect of Dimethyl fumarate on brain edema and neurological function. After ICH, ICAM-1 levels increased and Casein kinase 2 levels decreased. Dimethyl fumarate reduced ICAM-1 but enhanced Casein kinase 2 levels. Again, Casein kinase 2 inhibitor TBCA and MAFG siRNA abolished the effect of Dimethyl fumarate on ICAM-1 and Casein kinase 2. Dimethyl fumarate preserved pNrf2 and MAFG expression in the nuclear lysate after ICH and the effect of Dimethyl fumarate was abolished by Casein kinase 2 inhibitor TBCA and MAFG siRNA. Dimethyl fumarate reduced microglia activation in peri-hematoma areas after ICH. The protective effect of Dimethyl fumarate on brain edema and neurological function was repeated in a blood injection mouse model. Conclusion Dimethyl fumarate ameliorated inflammation, reduced blood barrier permeability, and improved neurological outcomes by Casein kinase 2 and Nrf2 signaling pathways after experimental ICH in mice.
Intracerebral hemorrhage is the most devastating stroke subtype with high rates of mortality and morbidity. Furthermore, no clinically approved treatment exists that effectively increases survival or improves quality of life for survivors. Effective modeling is necessary to elucidate the pathophysiological mechanisms of intracerebral hemorrhage and evaluate potential therapeutic approaches. Rodent models are most utilized because of their cost-effectiveness, and because rodent brain development and structures are well documented. Herein, we describe two intracerebral hemorrhage mouse models: the autologous blood double-injection and collagenase infusion models.
Resveratrol, a caloric restriction mimetic, is a naturally occurring polyphenolic compound with antioxidant and anti-inflammatory properties. Oxidative stress has been implicated in the etiology of a number of neuropsychiatric disorders including generalized anxiety and schizophrenia. This study investigated the anxiolytic and antipsychotic potentials of resveratrol in murine models of anxiety and schizophrenia. Mice were pretreated with resveratrol (200 and 400 mg/kg) in 1% carboxymethyl cellulose for 14 days and subjected to behavioural tests on the 15th day. Anxiolytic activity of resveratrol was determined using the hole board and staircase tests while its anti-psychotic property was evaluated via apormorphine induced stereotypy and swim-induced grooming tests. Although resveratrol did not significantly reduce the mean number of head dips at doses used in the hole board test, it significantly (p < 0.01) decreased the mean episodes of rearing without significantly altering the total number of upward steps climbed in the staircase test. Resveratrol significantly (p < 0.05) reduced the mean climbing scores in the first ten minutes of the apormorphine induced stereotypic climbing and significantly decreased (p < 0.01) episodes and total duration of swim induced grooming in mice. Administration of resveratrol at doses used in this study produced anxiolysis and anti-psychotic effects in mice.
Background Hunteria umbellata (HU) (K. Schum) is used in ethnomedicine for the management of pain, diabetes mellitus and dysmenorrhoea. This study evaluated the analgesic and antioxidant activities of aqueous extract of HU stem bark and the possible mechanism(s) of action. Methods The antinociceptive effect of HU was evaluated using acetic acid mouse writhing, tail flick, hot plate and formalin-induced paw licking models. To establish the possible mechanism(s) of action of HU, separate group of animals were pretreated with naloxone (1 mg/kg, i.p.), atropine (1 mg/kg, i.p.), haloperidol (0.1 mg/kg, i.p.), ondansetron (1 mg/kg, i.p.) and phenoxybenzamine (0.1 mg/kg, i.p.), 15 min before HU. The in vivo and in vitro antioxidant potential was evaluated using established methods. Results The extract at 150 and 300 mg/kg, significantly (p<0.05) reduced the number of writhes and paw licking times and increased pain threshold in writhing assay, paw licking and hotplate tests respectively. Pretreatment of animals with ondansetron, naloxone and haloperidol, significantly (p<0.05 and p<0.01) attenuated the analgesic activity of HU. The extract demonstrated significant (p<0.05) radical scavenging activity (IC50 0.39 µg/mL), with high phenol content and reducing property. The total phenol content was 124.19 per gram of gallic acid. In vivo antioxidant assay showed significant (p<0.05) increase in catalase and superoxide levels. Conclusions Results obtained in this study suggest the involvement of serotonergic, opioidergic and dopaminergic pathways in the analgesic effect of HU stem bark, in addition to its potent antioxidant potential.
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