Cyclosorus terminans extract and pioglitazone equally alleviate metabolic disturbance and brain pathology in prediabetic rats

Abstract

Background Long‐term high‐fat diet consumption causes prediabetic conditions with brain pathology, as indicated by peripheral and brain insulin resistance, neuroinflammation, neuronal necroptosis, microglial and astrocyte hyperactivation and increased Alzheimer’s disease‐related proteins including amyloid precursor protein (APP). Although pioglitazone, a peroxisome proliferator‐activated receptor (PPAR)‐γ agonist clinically used to treat type 2 diabetes mellitus, has been shown to improve the metabolic and brain functions in prediabetic condition, this drug can lead to several adverse effects. Recently, an in vitro study showed that Cyclosorus terminans extract, which acts as a natural PPAR‐γ agonist, possessed anti‐diabetic and anti‐obesity properties in adipose‐derived stem cells. However, the comparative efficacy of Cyclosorus terminans extract and pioglitazone on metabolic and brain functions in the prediabetic model has not been elucidated. Method Thirty male rats were fed with either a normal diet (ND) or a high‐fat diet (HFD) for 14 weeks. At week 13, ND‐fed rats received vehicle (NDV; n = 6) for additional 2 weeks. HFD‐fed rats were divided into four subgroups to receive either vehicle (HFV; n = 6), 100 mg/kg/day of Cyclosorus terminans extract (I‐100; n = 6), 200 mg/kg/day of Cyclosorus terminans extract (I‐200; n = 6); or 20 mg/kg/day of pioglitazone (Pio; n = 6) for additional 2 weeks. At the end of experimental period, blood and brains were collected to determine metabolic and brain functions. Result HFD‐fed rats exhibited a prediabetic condition as characterized by obesity with peripheral insulin resistance. In addition, neuroinflammation, neuronal necroptosis, microglial and astrocyte hyperactivation, and APP expression significantly increased in HFD‐induced prediabetic rats. Cyclosorus terminans extract (100 mg/kg/day) did not attenuate the metabolic disturbance and brain pathologies in HFD‐induced prediabetic rats. Interestingly, 200 mg/kg/day of Cyclosorus terminans extract and pioglitazone equally attenuated peripheral insulin resistance, neuroinflammation, neuronal necroptosis, microglial and astrocyte hyperactivation, and APP expression in HFD‐induced prediabetic rats (P < 0.05, Figure 1). Conclusion These findings suggest that Cyclosorus terminans extract may be another therapeutic approach for improving metabolic and brain functions in prediabetic patients who have contraindications to pioglitazone therapy.