Nano-hesperetin ameliorates 6-hydroxydopamine-induced behavioral deficits and oxidative damage by up-regulating gene expression of antioxidant enzymes.

Objective: Hesperetin (Hst) has shown several pharmacological effects. The efficacy of Hst is highly restricted in vivo due mainly to poor bioavailability. This investigation was intended to compare the influence of Hst and nano-Hst treatment on 6-hydroxydopamine (6-OHDA)-induced behavioral deficits and oxidative stress in rats. Materials and Methods: Forty-two Wistar male rats were equally assigned to 6 groups: control, 6-OHDA, Hst5, Hst10, nano-Hst5, and nano-Hst10. Treatment with Hst and nano-Hst was initiated 1 day after the intrastriatal injection of 6-OHDA and continued for 28 days. Behavioral deficits were evaluated using apomorphine-induced rotation test (AIRT), narrow beam test (NBT) and novel object recognition test (NORT), and the hippocampus and striatum were used to evaluate oxidative stress-related parameters. Results: The rats injected only with 6-OHDA showed learning and memory deficits but Hst and nano-Hst treatments improved it (p<0.001). Compared to the control group, a marked promotion in Malondialdehyde (MDA) levels along with a marked reduction in activities and gene expression of antioxidant enzymes and reduced glutathione (GSH) levels in the hippocampus and striatum were observed in the 6-OHDA group (p<0.01). However, administration of Hst and nano-Hst remarkably diminished MDA levels (p<0.01), and significantly increased the activities (p<0.01) and gene expression of antioxidant enzymes (p<0.05) and GSH levels (p<0.01) compared to the 6-OHDA group. In most parameters, nano-Hst has shown better therapeutic effects than Hst. Conclusion: Our findings reveal that Hst can be considered as a potential candidate for the treatment of neurodegenerative diseases and that nano-Hst may have better bioavailability.

Anti-apoptotic effect of silymarin-loaded chitosan nanoparticles on hippocampal caspase-3 and Bcl-2 expression following cerebral ischemia/reperfusion injury.

BACKGROUND: Cerebral ischemia/reperfusion (I/R) causes memory and learning impairments and apoptosis in the hippocampus. The aim of present study aimed to investigate the anti-apoptotic effects of silymarin-loaded chitosan nanoparticles (SM-CS-NPs) on the expression of Bcl-2 and Caspase-3 genes in hippocampal neurons after I/R injury. MATERIAL AND METHODS: SM and SM-CS-NPs were orally administered (15 mg/kg) for 14 days, and then cerebral I/R injury was induced by the bilateral common carotid artery occlusion (BCCAO). One day after I/R induction, memory and learning impairments and various biochemical estimations were assessed. RESULTS: Our results indicated that SM-CS-NPs improved I/R-induced memory and learning impairments and oxidative damage in the hippocampal region. The qRT-PCR analysis indicated that SM-CS-NPs pretreatment inhibited I/R-induced neuronal apoptosis by increasing the expression of Bcl-2 and decreasing the expression of Caspase-3 in the hippocampus. CONCLUSION: These findings suggest that SM-CS-NPs exert neuroprotective effects, and the neuroprotection is likely to be associated with the regulation of Bcl-2 and Caspase-3, leading to inhibition of apoptotic cell death in hippocampal neurons.

Evaluation of hesperetin-loaded on multiple wall carbon nanotubes on cerebral ischemia/reperfusion injury in rats.

The present study aimed to develop novel hesperetin-loaded on multiple wall carbon nanotubes (Hst-MWCNTs) to resolve the restricted bioavailability of hesperetin (Hst) and to enhance its preventive effect on cerebral ischemia-reperfusion (I/R). The physicochemical characteristics of Hst-MWCNTs were evaluated by Fourier-transform infrared spectra (FT-IR) and field emission scanning electron microscopy (FE-SEM). Forty male Wistar rats were randomly divided into five groups (control, I/R, MWCNTs, Hst, and Hst-MWCNTs). Hst, MWCNTs and Hst-MWCNTs (15 mg/kg orally) were pretreated for 14 days, and then I/R was induced by bilateral common carotid artery occlusion (BCCAO). Learning and memory deficits were evaluated using the novel object recognition test (NORT). The percentage of infarct size, catalase (CAT), superoxide dismutase (SOD), glutathione reductase (GRx), glutathione peroxidase (GPx) activities, malondialdehyde (MDA), and glutathione (GSH) levels was evaluated. Caspase-3 and Bcl-2 expressions were detected by qRT-PCR and Western blot analysis. Compared to the I/R group, Hst-MWCNTs considerably reduced learning and memory deficits, infarct size, and MDA levels. CAT, SOD, GRx, GPx activities and GSH levels were significantly increased in the Hst-MWCNTs group than in the I/R group. Additionally, Hst-MWCNTs significantly reduced the Caspase-3 expression but increased the Bcl-2 expression. All these results indicated that MWCNTs could be used as a promising novel carrier to enhance the oral bioavailability of Hst and to treat cerebral I/R injury.

Preventive effect of silymarin-loaded chitosan nanoparticles against global cerebral ischemia/reperfusion injury in rats.

Chitosan-based polymeric nanocarrier has been utilized as a novel drug delivery device in recent years due to its prominent role in the treatment of central nervous system disorders. The aim of this study was to investigate the anti-oxidative and anti-inflammatory effects of silymarin-loaded chitosan nanoparticles (SM-CS-NPs) on rat model of global cerebral ischemia/reperfusion (I/R). All rats were randomly distributed into four groups: Control, I/R, SM and SM-CS-NPs. Oral administration of SM and SM-CS-NPs was started 14 days prior to bilateral common carotid artery occlusion (BCCAO). Depressive-like behaviors, infarct volume, some oxidative stress markers and inflammatory factors were assessed after induction of I/R. SM-CS-NPs pretreatment significantly ameliorated depressive-like behaviors and infarct volume after I/R. SM-CS-NPs also significantly decreased the levels of malondialdehyde (MDA), and expression of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), and significantly increased the activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GRx), and glutathione (GSH) levels in I/R brain. The current study demonstrated that SM-CS-NPs pretreatment effectively prevents oxidative and inflammatory damage in the brain caused by I/R, and it can be considered as a useful pretreatment to attenuate the negative effects of I/R.