The role of HCN channels on the effects of T-type calcium channels and GABAA receptors in the absence epilepsy model of WAG/Rij rats.

In this study we used ivabradine (IVA), a hyperpolarization-activated cyclic nucleotide-gated (HCN) channel blocker, to identify its effect on spike-wave discharges (SWDs); and aimed to determine the role of IVA on the effects of T-type calcium channel blocker NNC 55-0396, GABAA receptor agonist muscimol and antagonist bicuculline in male WAG/Rij rats. After tripolar electrodes for electrocorticogram (ECoG) recordings were placed on the WAG/Rij rats' skulls, 5, 10, and 20 mg/kg IVA were intraperitoneally administered for 7 consecutive days and ECoG recordings were obtained on days 0th, 3rd, 6th, and 7th for three hours before and after injections. While acute injection of 5, 10, and 20 mg/kg IVA did not affect the total number and the mean duration of SWDs, subacute administration (7 days) of IVA decreased the SWDs parameters 24 hours after the 7th injection. Interestingly, when IVA was administered again 24 hours after the 6th IVA injection, it increased the SWDs parameters. Western-blot analyses showed that HCN1 and HCN2 expressions decreased and HCN4 increased in the 5-month-old WAG/Rij rats compared to the 1-month-old WAG/Rij and 5-month-old native Wistar rats, while subacute IVA administration increased the levels of HCN1 and HCN2 channels, except HCN4. Subacute administration of IVA reduced the antiepileptic activity of NNC, while the proepileptic activity of muscimol and the antiepileptic activity of bicuculline were abolished. It might be suggested that subacute IVA administration reduces absence seizures by changing the HCN channel expressions in WAG/Rij rats, and this affects the T-type calcium channels and GABAA receptors.

Asiatic acid exerts an anti-psoriatic effect in the imiquimod-induced psoriasis model in mice.

Background: Psoriasis is a common skin disorder related to inflammation and immune response. However, many treatment modalities are present in the clinics, and drug conformity halts chronic treatment. Therefore, novel treatment options are still needed. In this study, the possible protective effect of asiatic acid is one of the active compounds present in Centella Asiatica, was investigated in the imiquimod-induced psoriasis murine model.Methods:Imiquimod (62.5 mg) was administered dorsal skin of the mice for 6 days. Animals were co-treated with low-dose (25 mg/kg, p.o.) and high-dose (100 mg/kg, p.o.) asiatic acid. The dorsal skin of the animals was daily scored for erythema, thickness, and scaling. At the end of the treatments, serum levels of IL-17A and IL-23 were determined by ELISA. Additionally, the dorsal skins of animals were histopathologically evaluated.Results: Asiatic acid (high-dose) prevented imiquimod-induced skin lesions and protected dermal integrity in addition decreasing mast cell infiltration due to the imiquimod. Furthermore, asiatic acid (high-dose) suppressed the imiquimod-induced increase in serum levels of IL-17A and IL-23.Conclusion: These results indicate that asiatic acid showed an anti-psoriatic effect in the imiquimod-induced psoriasis model via mediating IL-17A and IL-23 pathways. Because wound healing properties of asiatic acid are described, further investigations should be carried out to understand deeper mechanisms and possible use in dermatological pathologies such as psoriasis.

GLP-1 agonist liraglutide improves ouabain-induced mania and depressive state via GSK-3ß pathway.

Bipolar disorder (BD) is a severe mental illness characterized by aberrant mood changes between hypomania and mania or mixed states and depression. Metabolic changes also accompany disease progression and cause significant morbidity. Symptomatic treatment options are available, but asymptomatic patients and poor drug responders are significant problems. Based on the most common pharmacological agent that is used in the treatment, lithium and its main mechanisms of action, oxidative stress, and glycogen synthase kinase-3ß (GSK-3ß) signaling are extensively investigated. However, knowledge about the effects of compounds that positively affect oxidative stress and GSK-3ß signaling, such as glucagon-like peptide-1 (GLP-1) mimetics, liraglutide, is still missing. Therefore, in this study, we aimed to investigate the effects of liraglutide on the ouabain-induced bipolar disease model in rats. After intracerebroventricular single dose ouabain administration, animals were treated with 100, 200, and 400 µg/kg liraglutide (s.c.) and valproic acid (200 mg/kg, i.p.) for 10 d. The locomotion and depressive states of animals were assessed by an open field, forced swimming test, and sucrose preference tests. Serum total antioxidant (TAS) and oxidant states (TOS) and glutathione, malonyl dialdehyde (MDA) levels in the brain tissue were determined. GSK-3ß phosphorylation was evaluated by western blotting. Our results demonstrated that liraglutide attenuated ouabain-induced hyperlocomotion and depressive state. Additionally, liraglutide prevented oxidative stress after ouabain administration. Decreased GSK-3ß phosphorylation due to the ouabain insult was alleviated by liraglutide treatment. These findings indicate that the manic and depressive-like behaviors are ameliorated by liraglutide, which exerted antioxidant action, possibly improving GSK-3ß phosphorylation.