Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice

Diabetes mellitus is a metabolic disease characterized by hyperglycemia due to defects in insulin secretion or its action. Complications from long-term diabetes consist of numerous biochemical, molecular, and functional tissue alterations, including inflammation, oxidative stress, and neuropathic pain. There is also a link between diabetes mellitus and vascular dementia or Alzheimer’s disease. Hence, it is important to treat diabetic complications using drugs which do not aggravate symptoms induced by the disease itself. Pregabalin is widely used for the treatment of diabetic neuropathic pain, but little is known about its impact on cognition or inflammation-related proteins in diabetic patients. Thus, this study aimed to evaluate the effect of intraperitoneal (ip) pregabalin on contextual memory and the expression of inflammatory state-related proteins in the brains of diabetic, streptozotocin (STZ)-treated mice. STZ (200 mg/kg, ip) was used to induce diabetes mellitus. To assess the impact of pregabalin (10 mg/kg) on contextual memory, a passive avoidance task was applied. Locomotor and exploratory activities in pregabalin-treated diabetic mice were assessed by using activity cages. Using Western blot analysis, the expression of cyclooxygenase-2 (COX-2), cytosolic prostaglandin E synthase (cPGES), nuclear factor (erythroid-derived 2)-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), as well as glucose transporter type-4 (GLUT4) was assessed in mouse brains after pregabalin treatment. Pregabalin did not aggravate STZ-induced learning deficits in vivo or influence animals’ locomotor activity. We observed significantly lower expression of COX-2, cPGES, and NF-κB p50 subunit, and higher expression of AhR and Nrf2 in the brains of pregabalin-treated mice in comparison to STZ-treated controls, which suggested immunomodulatory and anti-inflammatory effects of pregabalin. Antioxidant properties of pregabalin in the brains of diabetic animals were also demonstrated. Pregabalin does not potentiate STZ-induced cognitive decline, and it has antioxidant, immunomodulatory, and anti-inflammatory properties in mice. These results confirm the validity of its use in diabetic patients. [Figure: see text

Spatial learning and long-term memory impairments in RasGrf1 KO, Pttg1 KO, and double KO mice

Background: RasGrf1 is a guanine-nucleotide releasing factor that enhances Ras activity. Human PTTG1 is an oncoprotein found in pituitary tumors and later identified as securin, a protein isolated from yeast with a reported role in chromosome separation. It has been suggested that RasGrf1 is an important upstream component of signal transduction pathways regulating Pttg1 expression and controlling beta cell development and their physiological response. At memory formation level, there are contradictory data regarding the role of RasGrf1, while Pttg1 has not been previously studied. Both proteins are expressed in the mammalian hippocampus, which is one of the key brain areas for spatial learning and memory. Objective: The aim of this work was to study a potential link between RasGrf1 and Pttg1 in memory formation. Method: Spatial learning and memory test in the Pttg1 KO, RasGrf1 KO, and Pttg1-RasGrf1 double KO and their correspondent WT mice using a Barnes maze. Results: In comparison with the WT control mice, Pttg1 KO mice learned how to solve the task in a less efficient way, suggesting problems in memory consolidation. RasGrf1 KO mice performance was similar to controls, and they learned to use the best searching strategy. Double KO mice reached a better spatial learning level than WT. Conclusion: A role for Pttg1 in memory consolidation/formation is suggested, while our RasGrf1 KO mice do not show hippocampus associated memory defects

Pharmacological activity of the compound HBK-10 after chronic administration.

Około 5% ludzi żyjących na świecie cierpi na depresję. Niestety dzisiejsza farmakoterapia tego schorzenia często jest nieskuteczna, a nawet jeśli przynosi ulgę pacjentom to najczęściej wiąże się z szeregiem uciążliwych działań niepożądanych. Celem badania było określenie potencjalnej aktywności przeciwdepresyjnej oraz zbadanie prawdopodobnego mechanizmu działania związku HBK-10. Potencjalną aktywność przeciwdepresyjną związku HBK-10 zbadano w teście wymuszonego pływania (FST) u myszy. Przeanalizowano działanie dwóch dawek związku, zarówno po podaniu jednorazowym jak i 21-dniowym podaniu przewlekłym. W podobny sposób oceniono aktywność HBK-10 w mysim modelu depresji indukowanej kortykosteronem. Kolejno zbadano wpływ HBK-10 na aktywność w FST trzech leków przeciwdepresyjnych, wykazujących odmienne mechanizmy działania (fluoksetyny, reboksetyny i bupropionu). W tym samym teście oceniono działanie HBK-10 po zablokowaniu biosyntezy serotoniny u myszy. W celu wykluczenia uzyskania fałszywie pozytywnych wyników przeprowadzono także test spontanicznej aktywności lokomotorycznej u myszy.Uzyskane wyniki wskazują na zależną od dawki potencjalną aktywność przeciwdepresyjną HBK-10 w FST u myszy zarówno po podaniu jednorazowym jak i przewlekłym. Badana pochodna okazała się skuteczna także w modelu depresji indukowanym kortykosteronem. HBK-10 nasilał działanie subaktywnych dawek fluoksetyny i reboksetyny, ale nie bupropionu, w FST u myszy. Zablokowanie biosyntezy serotoniny znosiło „przeciwdepresyjną” aktywność HBK-10 w FST. Związek ten nie wpływał na spontaniczną ruchliwość myszy. W mechanizm działania HBK-10 najprawdopodobniej zaangażowane są dwa systemy – serotoninergiczny oraz noradrenergiczny, z czego ten pierwszy wydaje się być dominującą komponentą. Uzyskane wyniki są solidną podstawą do podjęcia dalszych badań określających bezpieczeństwo oraz dokładny profil działania HBK-10.Nowadays about 5% of world population suffer from depression. Unfortunately, an increase in resistance to therapy is observed and even if treatment is effective, it is associated with number of adverse effect. The aim of this study was to evaluate antidepressant-like activity and to determine possible mechanism of action of HBK-10.To assess antidepressant-like activity of HBK-10 the forced swim test (FST) in mice was performed. The activity of compound administered at two doses, both after acute and chronic (21 days) treatment, was analyzed. Similarly, antidepressant-like activity of HBK-10 in mouse model of depression induced by corticosterone was evaluated. Next, the influence of HBK-10 on the activity in FST in mice of subactive doses of three antidepressants with different mechanisms of action (fluoxetine, reboxetine, bupropion) was determined. Moreover, the activity of tested compound in FST after inhibition of serotonin biosynthesis was evaluated. In order to exclude false positive results, the spontaneous locomotor activity test in mice was performed. Obtained results indicate dose-dependent antidepressant-like activity of HBK-10, both after acute and chronic treatment, in FST in mice. Furthermore HBK-10 was effective in mouse model of depression. Tested compound potentiated the activity of fluoxetine and reboxetine, but not bupropion, in FST in mice. The inhibition of serotonin biosynthesis antagonized antidepressant-like activity of HBK-10 in FST in mice. HBK-10 probably acts through two systems: serotonergic and noradrenergic, and the first seems to play dominant role. The results of this preliminary study fully justify taking further experiments for HBK-10 to determine its action profile and safety

Sex-dependent response to treatment in mSPS-subjected mice

Sex-dependent response to treatment in mSPS-subjected mice: raw data pending publication at doi: 10.3389/fphar.2021.69159