Antioxidant and neuroprotective effects of synthesized sintenin derivatives

Three series of sintenin derivatives (compounds 1–14) were designed and prepared and their antioxidative and neuroprotective effects were evaluated. The in vitro models of scavenging 1,1-diphenyl-2-picrylhydrazyl (DPPH) radicals, chelating ferrous ions, inhibiting the rat brain homogenates lipid peroxidation, and protecting neurons damaged by hydrogen peroxide were employed for bioassays. It was found that sintenin derivatives 4 and 13 showed remarkable antioxidative and neuroprotective activities.     

Neuroprotective effects of (E)-3,4-diacetoxystyryl sulfone and sulfoxide derivatives in vitro models of Parkinson's disease

(E)-3,4-dihydroxystyryl aralkyl sulfones and sulfoxides have been reported as novel multifunctional neuroprotective agents in previous studies, which as phenolic compounds display antioxidative and antineuroinflammatory properties. To further enhance the neuroprotective effects and study structure-activity relationship of the derivatives, we synthesized their acetylated derivatives, (E)-3,4-diacetoxystyryl sulfones and sulfoxides, and examined their neuroprotective effects in vitro models of Parkinson’s disease. The results indicate that (E)-3,4-diacetoxystyryl sulfones and sulfoxides can significantly inhibit kinds of neuron cell injury induced by toxicities, including 6-OHDA, NO, and H₂O₂. More important, they show higher antineuroinflammatory properties and similar antioxidative properties to corresponding un-acetylated compounds. Thus, we suggest that (E)-3,4-diacetoxystyryl sulfones and sulfoxides may have potential for the treatment of neurodegenerative disorders, especially Parkinson’s disease.     

Protective role of hispolon and its derivatives against apoptosis in cortical neurons induced by electromagnetic radiation from 4G mobile phone

Electromagnetic radiation (EMR) from wireless devices, particularly mobile phones, is a potentially growing public health concern. In this study, the neuronal effects of EMR on primary cortical neurons (PCNs) from neonatal rat cerebral cortex and the protective role of hispolon (HIS) and its derivatives were investigated as a measure of cranial exposure during mobile phone use. PCNs were isolated and cultured from day-old neonatal rats, then exposed for 2 h to EMR emitted by a mobile phone operating at a frequency of 2100 MHz with 1.6 W/Kg specific absorption rate (SAR) in call-answered mode treated with HIS and its derivatives. The induction of apoptosis through modulation of pro and anti-apoptotic genes via mitochondrial pathway and the protection by the test compounds was assessed. Pyrazole derivatives decreased apoptosis by modulating the levels of pro and anti-apoptotic genes by reducing the levels of reactive oxygen species (ROS) via mitochondrial damage, which was observed in the EMR exposed PCNs. The pyrazole compounds were found to have antioxidative and anti-apoptotic properties. Thus, the neuroprotective mechanisms of the pyrazole derivatives can be investigated further, which may make them appropriate as lead compounds in developing neuroprotective formulations.     

Inhibition of β-amyloid–induced neurotoxicity by planar analogues of procyanidin B3

Reactive oxygen species (ROS) are known to be produced during the amyloid beta (Aβ) aggregation process. Both ROS production and Aβ fibril formation can result in nerve cell injury. Proanthocyanidins are oligomers of catechin that can act as inhibitors of Aβ aggregation. Procyanidin B3 (Cat-Cat), the dimer of (+)-catechin, can easily cross the blood-brain barrier. Previously, we synthesized two derivatives of Cat-Cat, namely Cat-PCat and PCat-PCat, in which the geometry of one or both catechin molecules in Cat-Cat was constrained to be planar. The antioxidative activities of Cat-PCat and PCat-PCat were found to be stronger than that of Cat-Cat, with PCat-PC at exhibiting the most potent activity. These compounds are predicted to protect against Aβ-induced neurotoxicity via inhibition of Aβ aggregation as well as by antioxidative effects toward Aβ-induced intracellular ROS generation. PCat-PCat exhibited the most potent neuroprotective effects against Aβ-induced cytotoxicity, which resulted from inhibition of β-sheet structure formation during the Aβ aggregation process. PCat-PCat may be a promising lead compound for the treatment of Alzheimer’s disease.     

Potent antioxidative activity of cacalol, a sesquiterpene contained in Cacalia delphiniifolia Sleb et Zucc

The potent antioxidative sesquiterpene, cacalol, was isolated from Cacalia delphiniifolia Sleb et Zucc, and identified by an analysis of the MS and NMR spectral data. Cacalol showed potent antioxidative activity in a rat brain homogenate model (IC(50) of 40 nM). Cacalol also proved to be a potent neuroprotective substance which could protect neuronal hybridoma N18-RE-105 cells from L-glutamate toxicity.     

Development of new indole-derived neuroprotective agents

There is a great deal of interest in neurotrophin therapy to prevent neuronal degeneration. The present study aimed at synthesizing new functionalized indole derivatives with structures justifying neuroprotective activity using L-tryptophan (TRP) as starting material. The potential neuroprotective effect of these newly synthesized agents against acrylamide (ACR) induced neurotoxicity was investigated in adult female rats. The novel indole derivatives, indolylmethyl pyridine derivatives 9a,b, pyrimidinylindolyl propanone derivatives 12a-c, pyrazolylindolyl propanone derivatives 14a,b, and indolyl tetrazolopropanoic acid derivative 17 were synthesized and their chemical structures were confirmed by studying their analytical and spectral data. The administration of ACR [ip, 50mgkg(-1) body weight (b. wt.)] alone resulted in significant increase in brain malondialdehyde level (MDA) and lactate dehydrogenase (LDH) activity whereas it caused significant decrease in brain monoamines levels and antioxidant enzymes activity. Treatment with the indole derivatives 9b, 12c, 14a, and 17 (ip, 50mgkg(-1) b. wt.) prior to ACR produced neuroprotective activity with various intensities depending on the structure of each compound. Compound 17 in which the tetrazole ring was attached to the TRP moiety ranked as the strongest neuroprotective agent. All the tested compounds have been shown to possess antioxidant properties offering promising efficacy against oxidative stress induced by ACR administration.     

Brassinosteroids and analogs as neuroprotectors: synthesis and structure-activity relationships

We have demonstrated previously that the brassinosteroid (BR) 24-epibrassinolide exerts neuroprotective effects deriving from its antioxidative properties. In this study, we synthesized 2 natural BRs and 5 synthetic analogs and analyzed their neuroprotective actions in neuronal PC12 cells, against 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin known to induce oxidative stress and degenerescence of dopaminergic neurons characteristic of Parkinsonian brains. We also tested the neuroprotective potential of 2 commercially available BRs. Our results disclosed that 6 of the 9 BRs and analogs tested protected neuronal PC12 cells against MPP(+) toxicity. In addition, our structure-activity study suggests that the steroid B-ring and lateral chain play an important role for their neuroprotective action.     

Water extract of propolis and its main constituents, caffeoylquinic acid derivatives, exert neuroprotective effects via antioxidant actions

We investigated whether water extract of Brazilian green propolis (WEP) and its main constituents [caffeoylquinic acid derivatives (3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, chlorogenic acid) and cinnamic acid derivatives (p-coumaric acid, artepillin C, drupanin, baccharin)] exert neuroprotective effects against the retinal damage induced by oxidative stress. Additionally, their neuroprotective effects were compared with their antioxidant effects. WEP, 3,4-di-O-caffeoylquinic acid, 3,5-di-O-caffeoylquinic acid, chlorogenic acid, and p-coumaric acid (but not artepillin C, baccharin, or drupanin) concentration-dependently inhibited oxidative stress-induced neurotoxicity [achieved using L-buthionine-(S,R)-sulfoximine (BSO) to deplete glutathione in combination with glutamate to inhibit cystine uptake] in cultured retinal ganglion cells (RGC-5, a rat ganglion cell line transformed using E1A virus). At their effective concentrations against oxidative stress-induced retinal damage, WEP, 3,4-di-caffeoylquinic acid, 3,5-di-caffeoylquinic acid, and chlorogenic acid (but not cinnamic acid derivatives) inhibited lipid peroxidation (LPO) in mouse forebrain homogenates. Thus, the neuroprotective effects of WEP and caffeoylquinic acid derivatives paralleled those against LPO. These findings indicate that WEP and caffeoylquinic acid derivatives have neuroprotective effects against retinal damage in vitro, and that these effects may be partly mediated via antioxidant effects.     

Protective effect of Mori Cortex radicis extract against high glucose-induced oxidative stress in PC12 cells

ABSTRACT

This study was undertaken to investigate the neuroprotective effect of an ethanolic extract of Mori Cortex radicis (MCR) against high glucose (HG)-induced oxidative damage in PC12 cells. Cell cytotoxicity was examined using MTT and lactate dehydrogenase assays. To examine the antioxidative effects, intracellular reactive oxygen species (ROS) and malondialdehyde (MDA) levels and the activities of antioxidant enzymes were measured. The expressions of apoptosis-associated proteins were assessed. MCR was found to increase the viabilities of HG-induced PC12 cells and to inhibit ROS and MDA production and to promote antioxidative enzyme activities. Furthermore, MCR reduced apoptosis by upregulating p-Akt and Bcl-2/Bax ratio and reducing cytochrome c level. The main flavonoids in MCR were identified by HPLC to be kuwanon G and morusin. These results suggest the antioxidative effects of MCR protect against HG-induced oxidative stress and that MCR has potential therapeutic use for the prevention and treatment of diabetic neuro-degeneration.     

Quinic acid derivatives from Saussurea triangulata attenuates glutamate-induced neurotoxicity in primary cultured rat cortical cells

The leaves of Saussurea triangulata (Compositae) have been eaten with rice as a wrapping vegetable for preventing neuro-aging. However, the components responsible for the neuroprotective effects of S. triangulata still remain unidentified. In the process of investigating the neuroprotective activity of S. triangulata, we found that a methanol extract of S. triangulata exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. Three quinic acid derivatives were isolated from the n-BuOH fraction of S. triangulata. Among these three quinic acid derivatives, methyl 5-caffeoylquinic acid (3) exhibited significant neuroprotective activities against glutamate-induced toxicity exhibiting cell viability of about 50%, at concentrations ranging from 0.1 microM to 10 microM. Therefore, the neuroprotective effect of S. triangulata might be due to the inhibition of glutamate-induced toxicity by the quinic acid derivatives from S. triangulata.     

Protective Effect of Insulin on Rat Cortical Neurons in Oxidative Stress and Its Dependence on Modulation of Protein Kinase B (Akt) Activity

Clinical trials of insulin and experiments on its intranasal administration to animals suggest that this hormone can be efficient in treating human neurodegenerative and some other diseases associated with brain injury. However, the mechanism of the neuroprotective effect of intranasal insulin is far from being understood. The aim of the present work was to study the protective and antioxidative effects of insulin at various concentrations on rat brain cortical neurons under oxidative stress conditions and to estimate the contribution of protein kinase B (Akt) activity modulation to insulin-induced enhancement of neuronal viability in the rat brain cortex. The protective effect of insulin was shown to be dose-dependent within the nanomolar range (1 nM < 10 nM < 100 nM and/or 1 μM). A study of the antioxidative effect of insulin revealed the efficacy of such a low concentration as 1 nM. Immunoblot analysis showed that insulin at concentrations of 100 nM and 1 μM activates Akt both in neurons and control cells at different times after their exposure to a pro-oxidant agent. LY294002, a specific PI3K/Akt signaling pathway inhibitor, was shown to significantly reduce the protective and antioxidative effects of insulin. Insulin-induced upregulation both of Akt activity and antiapoptotic protein Bcl-2 appears to play an important role in the neuroprotective effect of insulin.     

Antioxidative activities of novel diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter

A new series of diphenylalkyl piperazine derivatives with high affinities for the dopamine transporter (DAT), which were modified at both the diphenylalkyl moiety and the phenyl ring in the phenylamino moiety of 1-[4,4-bis(4-fluorophenyl)butyl]-4-[2-hydroxy-3-(phenylamino)propyl]piperazine 1, was evaluated for their inhibitory activities against auto-oxidative lipid peroxidation in canine brain homogenates. Some of these were approximately equivalent in activity to alpha-tocopherol as a potent antioxidant with IC(50) values of low micromolar order, and the 4-hydroxyphenyl derivative 11 showed the most potent antioxidative activity with an IC(50) value of 0.32 microM, exhibiting approximately 5-fold more potent activity than alpha-tocopherol. The structure-activity relationship (SAR) studies of the antioxidative activity of these derivatives are presented.     

Synthesis and biological evaluation of 21-arylidenepregnenolone derivatives as neuroprotective agents

A series of 21-arylidenepregnenolone derivatives and their corresponding epoxides were synthesized. The neuroprotective effects of these steroidal compounds against amyloid-β(25-35) (Aβ(25-35))- and hydrogen peroxide (H(2)O(2))-induced neurotoxicity in PC12 cells, and oxygen-glucose deprivation (OGD)-induced neurotoxicity in SH-SY5Y cells were evaluated. The bioassay results indicated that several 3β-pregn-21-benzylidene-20-one derivatives displayed potent in vitro neuroprotective effects in different screening models, for example, compounds 2b, 3a, 3b, and 3s showing significant activities against Aβ(25-35)-induced neurotoxicity in PC12 cells, 2b showing significant activities against H(2)O(2)-induced neurotoxicity in PC12 cells, and 2g, 3b, and 3e showing potent protection against OGD insult. The results suggested that introduction of an arylidene group into steroidal nucleus played an important role in neuroprotective activity, while the formation of epoxy group at C-5,6 could be also important for the neuroprotective activity in some degree. The pharmacological data reported here are helpful for the design of novel steroidal neuroprotective candidates.     

Synthesis and biological evaluation of 3-carbamate smilagenin derivatives as potential neuroprotective agents

Studies indicated that smilagenin, isolated from Anemarrhena asphodeloides Bunge, could improve cognitive impairment and exhibit neuroprotective activity. On the basis of the structure of smilagenin, a series of derivatives were synthesized and evaluated for their neuroprotective effects of H₂O₂-induced, oxygen glucose deprivation-induced neurotoxicity in SH-SY5Y cells and LPS-induced NO production in RAW264.7 cells. Structure activity relationship of derivatives revealed that benzyl-substituted piperazine formate derivatives showed the potent neuroprotective activity such as A12. These findings may provide new insights for the development of neuroprotective agents against Alzheimer’s disease.     

Novel semisynthetic spin-labeled derivatives of podophyllotoxin with cytotoxic and antioxidative activity

A series of novel spin-labeled podophyllotoxin derivatives were synthesized by reacting the corresponding N-(1-oxyl-2,2,6,6-tetramethyl-4-piperidinyloxy carbonyl)-amino acids with 4β-amino-4′-demethylepipodophyllotoxin. The synthesized derivatives 12a–g were evaluated for the partition coefficients, cytotoxicities in vitro against three tumor cell lines (A-549, HL-60, and RPMI-8226) and antioxidative activities in tissues of SD rats by the TBA method. The vast majority of target compounds have shown superior or comparable activities against A-549, HL-60, and RPMI-8226 compared to VP-16, and they have shown more significant antioxidative activities and superior water solubility than VP-16.     

Quinic acid derivatives from Saussurea triangulata attenuates glutamate-induced neurotoxicity in primary cultured rat cortical cells

The leaves of Saussurea triangulata (Compositae) have been eaten with rice as a wrapping vegetable for preventing neuro-aging. However, the components responsible for the neuroprotective effects of S. triangulata still remain unidentified. In the process of investigating the neuroprotective activity of S. triangulata, we found that a methanol extract of S. triangulata exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. Three quinic acid derivatives were isolated from the n-BuOH fraction of S. triangulata. Among these three quinic acid derivatives, methyl 5-caffeoylquinic acid (3) exhibited significant neuroprotective activities against glutamate-induced toxicity exhibiting cell viability of about 50%, at concentrations ranging from 0.1 μM to 10 μM. Therefore, the neuroprotective effect of S. triangulata might be due to the inhibition of glutamate-induced toxicity by the quinic acid derivatives from S. triangulata.     

Protective effects of pinostilbene,a resveratrol methylated derivative,against 6-hydroxydopamine-induced neurotoxicity in SH-SY5Y cells

Resveratrol (3,4′,5-trans-trihydroxystilbene) is a phytoalexin with emerging lines of evidence supporting its beneficial effects on cardiovascular systems and inhibition of carcinogenesis. It has also been reported that certain methylated resveratrol derivatives are more effective than resveratrol in the prevention/treatment of cancer. However, little is known about the impact of resveratrol and its derivatives on the development of Parkinson's disease. In this study, we compared the neuroprotective effects of resveratrol with four methylated (fully or partially) resveratrol derivatives against parkinsonian mimetic 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in SH-SY5Y cells. Release of lactate dehydrogenase and activity of caspase-3 triggered by 6-OHDA were significantly reduced by resveratrol and one of the methylated derivatives, pinostilbene (3,4′-dihydroxy-5-methoxystilbene), in a dose-dependent manner. In addition, pinostilbene exerted a potent neuroprotective effect with a wider effective concentration range than resveratrol. By using high-performance liquid chromatography, we found that uptake of pinostilbene into SH-SY5Y cells was significantly higher than that of resveratrol. Enhanced bioavailability may thus be a major factor contributing to the neuroprotective activity of pinostilbene. Moreover, Western blot analysis demonstrated that pinostilbene markedly attenuated the phosphorylation of JNK and c-Jun triggered by 6-OHDA. Besides, mammalian target of rapamycin kinase may be an intracellular target accounting for the neuroprotective effects of pinostilbene. Our findings demonstrate the potential of methylated stilbenes in neuroprotection and provide important information for further research in this field.     

New promising antioxidants based on 2,6-dimethylphenol

Three new sulfur-containing derivatives of 2,6-dimethylphenol were synthesized. Their antioxidative activity, mutagenicity, and genotoxicity were examined by bacterial tests and by calculating the dominant lethal mutations in murine embryonic cells. It was shown that all the compounds synthesized have a marked antioxidative effect and have no genotoxic and mutagenic properties. One of the antioxidants, 4-(3-dodecylthiopropyl)-2,6-dimethylphenol, increases the survival of cells of both the wild-type Escherichia coli strain and bacterial strains defective in the genes of repair enzymes and has a more distinct antioxidative effect than the classic antioxidants α-tocopherol and trolox, increasing the survival of cells devoid of repair enzymes.     

Free Radical Scavenging Activity and Neuroprotective Potentials of D138, One Cu(II)/Zn(II) Schiff-Base Complex Derived from N,N′-bis(2-Hydroxynaphthylmethylidene)-1,3-propanediamine

There is increasing evidence that free radicals play an important role in neuronal damages induced by diabetes mellitus or cerebral ischemia insults. Antioxidants with free radical scavenging activities have been shown to be beneficial and neuroprotective for these pathological conditions. Here, we report free radical scavenging activity and neuroprotective potential of D138, one copper(II)/zinc(II) Schiff-base complex derived from N,N′-2(2-hydroxynaphthylmethylidene)-1,3-propanediamine. The data from three in vitro assays, 2,2-diphenyl-1-picrylhydrazyl assay, nitro blue tetrazolium assay and hydroxyl radical scavenging assay, indicated that D138 presented a potent free radical scavenging activity. The neuroprotective and antioxidative effects of D138 were further evaluated in vivo using bilateral common carotid artery occlusion (BCCAO) mouse model and streptozotocin (STZ) diabetic mouse model. Our results indicated that treatment of D138 significantly ameliorated the hippocampal neuronal damage and the oxidative stress levels in these animal models. Moreover, D138 also reversed the behavioral deficiencies induced by BCCAO or STZ, as assessed by Y-maze test and fear conditioning test. In conclusion, all these findings support that D138 exerts free radical scavenging and neuroprotective activities and has the potentials to be a potent therapeutic candidate for brain oxidative damage induced by cerebral ischemia or diabetes mellitus.     

Dopamine Promotes the Survival of Embryonic Striatal Cells: Involvement of Superoxide and Endogenous NADPH Oxidase

The dopaminergic system appears early in mammalian brain development, and a neurodevelopmental role for dopamine (DA) has been suggested. In the present study, we found that DA markedly promoted the survival of embryonic striatal cells in cultures. The failure of DA receptor antagonists to block this survival-promoting effect and the capability of S-apomorphine, which is devoid of DA receptor agonist activity but possesses antioxidative activity as R-apomorphine and DA, to completely mimic this effect suggested that DA receptor activation was not required in the survival-promoting effect elicited by DA, and its antioxidative activity might be involved. Moreover, it was found that mRNA of NADPH oxidase was expressed in the embryonic striatum. Furthermore, DPI or apocynin, NADPH oxidase inhibitors, promoted the survival of embryonic striatal cells. Addition of either DA or DPI into striatal cell cultures decreased the superoxide level. These results indicate that the mechanisms underlying the neuroprotective effects of DA were likely associated with its antioxidative activity. NADPH oxidase might contribute, at least in part, to ROS generation.