Alzheimer's disease (AD) is a neurodegenerative disorder imposing great threat to an individual's cognitive capability. Mounting evidence suggests that type 2 diabetes mellitus (T2DM) and AD is closely associated with impaired insulin signalling and glucose metabolism in the brain. Member of the peroxisome proliferator-activated receptor (PPAR) family, especially PPARγ agonists, has been well known for their insulin-sensitizing actions, but due to low water solubility, poor penetration into the brain and associated toxicity limit their use clinically. Therefore, this study has been undertaken to investigate the neuroprotective potential of rosiglitazone embedded nanocarrier system on streptozotocin (STZ) induced mice model of AD. In vitro neuroprotective efficacy of rosiglitazone was determined on SH-SY5Y cells by assessing the messenger ribonulceic acid (mRNA) expression level of genes implicated for cognitive function. AD in mice was developed by intracerebroventricular (ICV) administration of STZ (3 mg/kg) directly into the lateral ventricles of the mice brain. The cognitive parameters and mRNA expression levels were evaluated after treatment with the free form of rosiglitazone as well as its nano-formulated form. It was observed that rosiglitazone elicits neuroprotection on SH-SY5Y cells as evidenced from the upregulation of genes such as cyclic-AMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), glial cell derived neurotrophic factor (GDNF), and nerve growth factor (NGF), which are involved in cognitive functions. Further, the nano-formulated rosiglitazone induced better neuroprotective efficacy than its free drug treatment on animal model of AD as evidenced by attenuating the behavioural and cognitive abnormalities, oxido-nitrosative stress and pro-inflammatory cytokines, i.e. tumour necrosis factor-α (TNF-α) and interleukin-6 (IL-6a) along with improved antioxidant enzymes (superoxide dismutase (SOD), reduced glutathione (GSH), acetylcholine, neuronal density and expression of CREB, BDNF, GDNF and NGF in the hippocampal region. Based on the results, it can be concluded that rosiglitazone nanoformulation exerts strong neuroprotection via increasing the mRNA expression of growth factors and inhibition of oxidative stress, and neuroinflammation eventually prevents neuronal injury in AD.
Keywords: Alzheimer’s disease; Insulin resistance; Nanoformulation; Peroxisome proliferator activated receptor-gamma; Rosiglitazone; Streptozotocin.