Pennapa Chonpathompikunlert

Piperine, the main alkaloid of Thai black pepper, protects against neurodegeneration and cognitive impairment in animal model of cognitive deficit like condition of Alzheimer's disease

Recently, numerous medicinal plants possessing profound central nervous system effects and antioxidant activity have received much attention as food supplement to improve cognitive function against cognitive deficit condition including in Alzheimers disease condition. Based on this information, the effect of piperine, a main active alkaloid in fruit of Piper nigrum, on memory performance and neurodegeneration in animal model of Alzheimers disease have been investigated. Adult male Wistar rats (180-220 g) were orally given piperine at various doses ranging from 5, 10 and 20mg/kg BW at a period of 2 weeks before and 1 week after the intracerebroventricular administration of ethylcholine aziridinium ion (AF64A) bilaterally. The results showed that piperine at all dosage range used in this study significantly improved memory impairment and neurodegeneration in hippocampus. The possible underlying mechanisms might be partly associated with the decrease lipid peroxidation and acetylcholinesterase enzyme. Moreover, piperine also demonstrated the neurotrophic effect in hippocampus. However, further researches about the precise underlying mechanism are still required.

Piperine, the potential functional food for mood and cognitive disorders

The effect of piperine, the main alkaloid from piper nigrum, on the central nervous system is not clearly known until now. In the present study, male Wistar rats were administered piperine at various doses ranging from 5, 10 and 20mg/kg BW once daily for 4 weeks and the animals were determined the neuropharmacological activity after single, 1, 2, 3 and 4 weeks of treatment. The results showed that piperine at all dosage range used in this study possessed anti-depression like activity and cognitive enhancing effect at all treatment duration. Therefore, piperine may be served as the potential functional food to improve brain function. However, further investigations about precise underlying mechanism are still required.

Redox nanoparticle treatment protects against neurological deficit in focused ultrasound-induced intracerebral hemorrhage

BACKGROUND Intracerebral hemorrhage is reported to induce the generation of reactive oxygen species and oxidative DNA damage in the brain. AIMS We aimed to examine whether our designed redox polymer nanoparticle could reduce intracerebral hemorrhage induced by 1-MHz focused ultrasound sonication coupled with microbubble treatment. MATERIALS & METHODS Contrast-enhanced ultrasound imaging, frozen section, brain edema, neurologic deficit, the number of morphologically normal neurons, DNA oxidization and superoxide anion generation were used to investigate the neuroprotective effect of redox polymer nanoparticles. RESULTS We confirmed that the 1-MHz focused ultrasound coupled with microbubble produced intracerebral hemorrhage and showed that the redox polymer nanoparticle ameliorates intracerebral hemorrhage-induced brain edema, neurological deficit and oxidative damage. CONCLUSION These results suggest that redox polymer nanoparticle is a potential therapeutic agent for intracerebral hemorrhage induced by focused ultrasound.

Redox-active injectable gel using thermo-responsive nanoscale polyion complex flower micelle for noninvasive treatment of local inflammation

Reactive oxygen species (ROS) scavengers have not been widely used for treatment of local inflammatory reactions such as arthritis and periodontal disease because they are rapidly eliminated from the inflamed site, which results in a low therapeutic effect. Therefore, to enhance the local retention time of ROS scavengers, we developed a redox-active injectable gel (RIG) system by using poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene]-b-poly(ethylene glycol)-b-poly[4-(2,2,6,6-tetramethylpiperidine-N-oxyl)aminomethylstyrene] (PMNT-PEG-PMNT) triblock copolymer, which possesses ROS scavenging nitroxide radicals as side chains of the PMNT segment. Cationic PMNT segment in PMNT-PEG-PMNT forms polyion complexes with anionic poly(acrylic acid) (PAAc) to form a flower-like micelle (ca. 79 nm), which exhibits in situ thermo-irreversible gelation under physiological conditions. We confirmed the prolonged site-specific retention time of RIG by performing in vivo noninvasive electron spin resonance imaging and quantitative evaluation. In contrast to low-molecular-weight nitroxide radical compounds that disappeared from injection sites in less than 1h after subcutaneous injection, 40% of the RIG remained even at 3 days. We also found that RIG inhibits neutrophil infiltration and cytokine production, which leads to suppression of hyperalgesia. These findings indicate the potential of RIG as an innovative approach for treatment of local inflammation.

Suppression of NSAID-induced small intestinal inflammation by orally administered redox nanoparticles.

Patients regularly taking non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin (IND) have a risk of small intestinal injuries. In this study, we have developed an oral nanotherapeutics by using a redox nanoparticle (RNP(O)), which is prepared by self-assembly of an amphiphilic block copolymer that possesses nitroxide radicals as side chains of hydrophobic segment via ether linkage, to reduce inflammation in mice with IND-induced small intestinal injury. The localization and accumulation of RNP(O) in the small intestine were determined using fluorescent-labeled RNP(O) and electron spin resonance. After oral administration, the accumulation of RNP(O) in both the jejunum and ileum tissues was about 40 times higher than those of low-molecular-weight nitroxide radical compounds, and RNP(O) was not absorbed into the bloodstream via the mesentery, thereby avoiding the adverse effects of nitroxide radicals in the entire body. RNP(O) remarkably suppressed inflammatory mediators such as myeloperoxidase, superoxide anion, and malondialdehyde in the small intestines of IND-treated mice. Compared to low-molecular-weight nitroxide radical compounds, RNP(O) also significantly increased the survival rate of mice treated daily with IND. On the basis of these results, RNP(O) is promising as a nanotherapeutics for treatment of inflammation in the small intestine of patients receiving NSAIDs.

The use of nitroxide radical-containing nanoparticles coupled with piperine to protect neuroblastoma SH-SY5Y cells from Aβ-induced oxidative stress.

The antioxidant effect and potential mechanism of nitroxide radical-containing nanoparticles (RNPs) coupled with piperine (PI) were investigated in human neuroblastoma SH-SY5Y cells. The effects of RNP/PI on SH-SY5Y cell lines was determined by WST assay for cell viability, nitroblue tetrazolium and deoxyribose assay for reactive oxygen species generation, ELISA assay for reactive oxygen species products and apoptotic cell death, and biochemical techniques for catalase and glutathione peroxidase activity. The RNP/PI significantly reduced the reactive oxygen species level and reactive oxygen species products compared with those of cells treated with RNPs alone. The RNP/PI treatment enhanced catalase and glutathione peroxidase activity. The combination of RNP/PI has been found to have an augmented antioxidant effect on an Alzheimers model in vitro. The mechanism of the protective effect of this combination therapy was correlated in this study with its ability to reduce the generation of reactive oxygen species and prevent apoptosis via scavenging enzyme action pathways.

Recovery of Cognitive Dysfunction via Orally Administered Redox-Polymer Nanotherapeutics in SAMP8 Mice

Excessively generated reactive oxygen species are associated with age-related neurodegenerative diseases. We investigated whether scavenging of reactive oxygen species in the brain by orally administered redox nanoparticles, prepared by self-assembly of redox polymers possessing antioxidant nitroxide radicals, facilitates the recovery of cognition in 17-week-old senescence-accelerated prone (SAMP8) mice. The redox polymer was delivered to the brain after oral administration of redox nanoparticles via a disintegration of the nanoparticles in the stomach and absorption of the redox polymer at small intestine to the blood. After treatment for one month, levels of oxidative stress in the brain of SAMP8 mice were remarkably reduced by treatment with redox nanoparticles, compared to that observed with low-molecular-weight nitroxide radicals, resulting in the amelioration of cognitive impairment with increased numbers of surviving neurons. Additionally, treatment by redox nanoparticles did not show any detectable toxicity. These findings indicate the potential of redox polymer nanotherapeutics for treatment of the neurodegenerative diseases.

TEMPOL protects human neuroblastoma SH-SY5Y cells against ß-amyloid-induced cell toxicity

Amyloid-β peptide (Aβ) has been implicated in the pathogenesis of Alzheimers disease (AD). It can cause cell death in Alzheimers disease by evoking a cascade of oxidative damage to neurons. Antioxidant compounds may help to elucidate and develop a treatment for Alzheimers disease. In the present study, we investigated the protective effect of TEMPOL (4-hydroxy-2,2,6,6-tetramethyl-1-piperidinyloxy), a cyclic nitroxide which is particularly effective at reducing oxidative injury, on Aβ(1-42)-induced SH-SY5Y cell toxicity. Exposure of cells to 20 μM Aβ(1-42) for 48 h caused viability loss and apoptotic increase, and pre-treatment with TEMPOL for 24 h significantly reduced the viability loss and apoptotic rate. In addition, TEMPOL inhibited Aβ(1-42)-induced superoxide anion generation and hydroxyl radical generation to a striking degree. Based on these results, it is concluded that TEMPOL effectively protects SH-SY5Y cells against β-amyloid-induced damage by suppressing the generation of reactive oxygen species especially, superoxide anion.

Indomethacin-loaded redox nanoparticles improve oral bioavailability of indomethacin and suppress its small intestinal inflammation

BACKGROUND Continuous administration of low-dose nonsteroidal anti-inflammatory drugs such as indomethacin (IND) is associated with an increased risk of gastrointestinal damage. In this study, the authors developed IND-loaded redox nanoparticles (IND@RNP(O)) with core-shell-type polymeric micelles possessing nitroxide radicals as reactive oxygen species scavengers. RESULTS Orally administered IND@RNP(O) significantly accumulated in the intestinal mucosa and improved blood uptake of IND. Because of the reactive oxygen species-scavenging effect, IND@RNP(O) did not cause severe inflammation in the small intestine; this effect sharply contrasted with those of orally administered free-IND and IND-loaded polymeric micelles that do not possess reactive oxygen species scavengers. CONCLUSION Oral IND@RNP(O) administration is a useful approach for improving the oral bioavailability of IND and suppressing its adverse effects.

Chronic treatment with a smart antioxidative nanoparticle for inhibition of amyloid plaque propagation in Tg2576 mouse model of Alzheimer’s disease

The present study aimed to assess whether our newly developed redox nanoparticle (RNPN) that has antioxidant potential decreases Aβ levels or prevents Aβ aggregation associated with oxidative stress. The transgenic Tg2576 Alzheimer’s disease (AD) mice were used to investigate the effect of chronic ad libitum drinking of RNPN solution for 6 months, including memory and learning functions, antioxidant activity, and amyloid plaque aggregation. The results showed that RNPN-treated mice had significantly attenuated cognitive deficits of both spatial and non-spatial memories, reduced oxidative stress of lipid peroxide, and DNA oxidation. RNPN treatment increased the percent inhibition of superoxide anion and glutathione peroxidase activity, neuronal densities in the cortex and hippocampus, decreased Aβ(1-40), Aβ(1-42) and gamma (γ)-secretase levels, and reduced Aβ plaque observed using immunohistochemistry analysis and thioflavin S staining. Our results suggest that RNPN may be a promising candidate for AD therapy because of its antioxidant properties and reduction in Aβ aggregation, thereby suppressing its adverse side effect.