title: Effect of pregabalin on contextual memory deficits and inflammatory state-related protein expression in streptozotocin-induced diabetic mice.
abstract: 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. Graphical abstract Effect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice.
authors.affiliation: Faculty of Pharmacy, Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Krakow, Poland. salat.kinga@gmail.com.
authors.forename: Kinga
authors.initials: K
authors.lastname: Sałat
authors.affiliation: Faculty of Pharmacy, Department of Radioligands, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Krakow, Poland.
authors.forename: Joanna
authors.initials: J
authors.lastname: Gdula-Argasińska
authors.affiliation: Faculty of Pharmacy, Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Krakow, Poland.
authors.forename: Natalia
authors.initials: N
authors.lastname: Malikowska
authors.affiliation: Faculty of Pharmacy, Department of Pharmacodynamics, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Krakow, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Podkowa
authors.affiliation: Faculty of Pharmacy, Department of Radioligands, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Krakow, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Lipkowska
authors.affiliation: Faculty of Pharmacy, Department of Radioligands, Jagiellonian University Medical College, 9 Medyczna St, 30-688, Krakow, Poland.
authors.forename: Tadeusz
authors.initials: T
authors.lastname: Librowski
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology* / Q000633:toxicity; D000975:Antioxidants / Q000494:pharmacology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D015415:Biomarkers / Q000097:blood; D001786:Blood Glucose / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D005106:Exploratory Behavior / Q000187:drug effects; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D018836:Inflammation Mediators / Q000378:metabolism*; D008297:Male; D008568:Memory / Q000187:drug effects*; D008569:Memory Disorders / Q000139:chemically induced / Q000517:prevention & control* / Q000523:psychology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D000069583:Pregabalin / Q000494:pharmacology* / Q000633:toxicity; D013311:Streptozocin; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D000975:Antioxidants; D015415:Biomarkers; D001786:Blood Glucose; D018836:Inflammation Mediators; D000069583:Pregabalin; D013311:Streptozocin
keywords: Contextual memory; Diabetic neuropathic pain; Inflammatory state-related proteins; Passive avoidance task; Pregabalin; Streptozotocin