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

Joanna Gdula-Argasińska,Kinga Sałat,Natalia Malikowska,Anna Lipkowska,Tadeusz Librowski,Adrian Podkowa

doi:10.1007/s00210-016-1230-x

Joanna Gdula-Argasińska, Kinga Sałat + Show 4 more

Open Access

https://doi.org/10.1007/s00210-016-1230-x

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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 abstractEffect of pregabalin on fear-motivated memory and markers of brain tissue inflammation in diabetic mice

Highlights

Diabetes mellitus is one of the most prevalent chronic diseases characterized by elevated blood glucose levels due to defects in insulin secretion or its action
Available studies indicate that diabetes mellitus is a risk factor for vascular type dementia (Zuloaga et al 2015), but in recent years, a strong link has been shown between Alzheimer’s disease (AD), the most common form of dementia, and diabetes mellitus (Gasparini et al 2002; Biessels et al 2006; Pasquier et al 2006; Baquer et al 2009; Datusalia and Sharma 2014; Solmaz et al 2015), indicating that impairments of insulin secretion or action can seriously influence the proper functioning of peripheral tissues, and brain functions, being a cause of cognitive decline in diabetic patients (Pasquier et al 2006)
As a part of our research, we evaluated the influence of STZ and pregabalin on the expression of the following proteins in the mouse brain: cyclooxygenase-2 (COX-2), cytosolic prostaglandin E2 synthase, nuclear factor-like 2 (Nrf2), nuclear factor-ĸB (NF-ĸB) p50 and p65, aryl hydrocarbon receptor (AhR), and glucose transporter type-4 (GLUT4)

Summary

Introduction

Diabetes mellitus is one of the most prevalent chronic diseases characterized by elevated blood glucose levels due to defects in insulin secretion or its action Metabolic impairments of this disorder are a substantial cause of severe biochemical, molecular, and functional complications in many organs of the body, leading to progressive damage to the whole organism (Baquer et al 2009). Much attention is paid to the approaches which aim to achieve relief of DNP (Schreiber et al 2015) This pathological condition affects more than 25 % of diabetic patients (Tesfaye et al 2013), significantly worsening their quality of life through a negative impact on sleep, mood, and everyday functionality. The use of analgesic adjuvants (e.g., anticonvulsant drugs, antidepressant drugs) is regarded as one of the therapeutic mainstreams in the pharmacotherapy of DNP (Finnerup et al 2015)

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