Behavioral and biochemical investigations to explore pharmacological potential of PPAR-gamma agonists in vascular dementia of diabetic rats

Abstract

Vascular dementia (VaD) is the second most common dementing illness. We have recently reported that diabetes induces VaD in rats. The present study has been designed to investigate the potential of peroxisome-proliferator-activated receptors-gamma (PPAR-γ) agonists in diabetes induced VaD of Wistar Albino rats. The rats were administered, single dose of streptozotocin (STZ) for the induction of diabetes. Morris water-maze (MWM) test was employed for testing learning and memory. Serum glucose, bodyweight, vascular endothelial function, serum nitrite/nitrate levels, aortic and brain oxidative stress levels (viz. aortic superoxide anion levels, brain thiobarbituric acid reactive species and brain glutathione levels) and brain acetylcholinesterase activity were also tested. STZ treated animals performed poorly on MWM hence reflecting impairment of learning and memory behavior with a significant reduction in body weight, impairment of vascular endothelial function, and decrease in serum nitrite/nitrate levels, increase in serum glucose, aortic and brain oxidative stress levels and brain acetylcholinesterase activity. Treatment of PPAR-γ agonists, pioglitazone as well as rosiglitazone significantly reversed, diabetes induced impairment of learning and memory behavior, endothelial function, and changes in various biochemical parameters. It is concluded that PPAR-γ modulators pioglitazone and rosiglitazone may be considered as potential pharmacological agents for the management of diabetes induced VaD.

Introduction

Diabetes and dementia have become a major public health concern worldwide due to being common diseases in the elderly population. Vascular dementia (VaD) a dementia of vascular origin is considered to be the second most common cause of dementia after Alzheimer's disease (AD) (Liu et al., 2010). Diabetes has been found to be consistently associated with the risk of VaD and there is the significant association between glucose intolerance and the risks of both VaD and AD (Sekita and Kiyohara, 2010). Diabetic people had a 1.5 to 4 fold risk for AD as well as VaD. High glucose concentration, a major pathological characteristic of diabetes, may have toxic effects on neurons in the brain through osmotic insults and oxidative stress. The insulin resistance (i.e., hyperinsulinemia) in people with impaired glucose tolerance has been one of risk factors for cognitive decline (Araki, 2010). Furthermore, diabetes is associated with an increased release of inflammatory cytokines, and the excess inflammation may be neurotoxic (Umegaki, 2010). Oxidative stress and vascular endothelial are recognized as important contributing factors in the pathogenesis of AD and dementia of vascular origin (de la Torre, 2008, Viswanathan et al., 2009). Only limited therapeutic interventions are available to reduce the incidence of VaD.

Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated transcription factors belonging to the nuclear receptors super family which are present in three isoforms as α, β/δ and γ (Arck et al., 2010). PPAR-γ is present on vascular cells, exert protective role in the vascular endothelial dysfunction (Beyer et al., 2008). Disruption or down regulation of these receptors have been reported to result in vascular endothelial dysfunction (Kleinhenz et al., 2009). PPAR-γ receptors are distributed broadly in central nervous system (Sarruf et al., 2009), and activation of these receptors prevents neuronal death by reduction of oxidative stress (Zhao et al., 2009) and inflammatory mechanisms (Glatz et al., 2010). PPAR-γ agonists in addition to their anti-diabetic activity have been shown to provide beneficial effect in various CNS disorders (Chaturvedi et al., 2009, Jain et al., 2009, Kiaei, 2008, Kumari et al., 2010, Schintu et al., 2009, Zhang et al., 2010a, Zhang et al., 2010b). Furthermore, PPAR-γ agonists have the potential to modulate various signaling molecules/pathways, including mitogen-activated protein kinases, signal transducer and activator of transcription, amyloid precursor protein degradation, beta-site amyloid precursor protein cleaving enzyme 1 and Wnt signaling (Kaundal and Sharma, 2010). Moreover, it has been recently reported that, PPAR-γ is involved in improvement of memory and cognitive function in AD (Hanyu and Sato, 2010). Also, cell culture studies suggest that, PPAR-γ agonists exert neuroprotective effects on cultured microglia and astrocytes by virtue of their inhibitory effect on amyloid beta elaborated pro-inflammatory cytokines (Jing and Ting, 1998, Ricote et al., 1999). However, the potential of PPAR-γ agonist in vascular dementia is still unexplored. Therefore, the present study has been undertaken to investigate the beneficial effect of PPAR-γ agonists, pioglitazone and rosiglitazone in diabetes induced vascular dementia in rats. Donepezil a well known acetylcholinesterase inhibitor served as a positive control in this investigation.