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Ptychopetalum olacoides, a traditional Amazonian "nerve tonic", possesses anticholinesterase activity

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Abstract

The cholinergic hypothesis of Alzheimer disease (AD) has provided the rationale for the current pharmacotherapy of this disease, in an attempt to downgrade the cognitive decline caused by cholinergic deficits. Nevertheless, the search for potent and long-acting acetylcholinesterase (AChE) inhibitors that exert minimal side effects to AD patients is still an ongoing effort. Amazonian communities use traditional remedies prepared with Ptychopetalum olacoides (PO, Olacaceae) roots for treating various central nervous system conditions, including those associated with aging. The fact that PO ethanol extract (POEE) has been found to facilitate memory retrieval in the step down procedure in young and aged mice prompt us to evaluate its effects on AChE activity in memory relevant brain areas. POEE significantly inhibited AChE activity in vitro in a dose- and time-dependent manner in rat frontal cortex, hippocampus and striatum; a significant inhibition was also found in these same brain areas of aged (14 months) mice after acute administration of POEE (100 mg/kg ip). We propose that such AChE inhibitory activity is a neurochemical correlate of a number of therapeutic properties traditionally claimed for P. olacoides, particularly those associated with cognition.

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... The traditional uses of P. olacoides have been extensively exploited by herbal industries in several American and European countries, and the native herb or its extracts are constituents of various phytomedicines supplied in the form of pills, tinctures, tablets, multivitamin supplements or compound extracts (Silva et al., 2002;Siqueira et al., 2003Siqueira et al., , 2007. The plant is also a component of the medication Catuama®, which is widely used in several parts of Brazil as a general tonic and to alleviate physical and mental fatigue (Antunes et al., 2001). ...
... The plant is also a component of the medication Catuama®, which is widely used in several parts of Brazil as a general tonic and to alleviate physical and mental fatigue (Antunes et al., 2001). The pharmacological properties of such tonics have been elucidated and discussed (Siqueira et al., 2003), while a number of experimental and clinical studies carried out on extracts of P. olacoides have validated their medicinal applications (Drewes et al., 2003;Siqueira et al., 2003Siqueira et al., , 2007Silva et al 2007). In contrast, little is known concerning the phytochemistry of the species. ...
... The plant is also a component of the medication Catuama®, which is widely used in several parts of Brazil as a general tonic and to alleviate physical and mental fatigue (Antunes et al., 2001). The pharmacological properties of such tonics have been elucidated and discussed (Siqueira et al., 2003), while a number of experimental and clinical studies carried out on extracts of P. olacoides have validated their medicinal applications (Drewes et al., 2003;Siqueira et al., 2003Siqueira et al., , 2007Silva et al 2007). In contrast, little is known concerning the phytochemistry of the species. ...
Article
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Ptychopetalum olacoides Benth., Olacaceae, popularly known as marapuama or muirapuama or miriantã, is a species native to the Amazonian region of Brazil. Extracts of the bark of the plant have been used traditionally for its stimulating and aphrodisiac properties and currently commercialised by the herbal industry as constituents in a wide range of phytomedicines. Fractionation by open column chromatography followed by preparative HPLC-UV/PAD of the stem bark and of three commercial extracts of P. olacoides allowed the isolation of three components that were common to all extracts analysed, and these were identified by NMR to be vanillic acid, protocatechuic acid and theobromine. Vanillic acid, which has been proposed as a phytochemical marker for P. olacoides, was employed as an external standard in the development and validation of a rapid qualitative and quantitative HPLC assay for the analyte. The recoveries values of the developed method were 99.02% and the LOD and LOQ values were 0.033 and 0.11 mg.L-1, respectively. The described method may be applied to the standardisation of herbs, extracts or phytomedicines commercialised as marapuama.
... Marapuama (Ptychopetalum olacoides Bentham, PO) is a medicinal plant favored by the elderly in Amazonian communities, and is used as what has now become categorized as a nootropic. We have reported that a specific Marapuama extract (POEE) possesses promnesic (da Silva et al., 2004(da Silva et al., , 2008, anti-amnesic (da Silva et al., 2009), neuroprotective (Siqueira et al., 2004) and anticholinesterase (Siqueira et al., 2003;Figueiró et al., in press) The aim of this study was to verify if POEE is also able to counteract the effects of A␤ 1-42 injection in mice. ...
... Though we had previously shown that POEE promnesic effects involve various receptors and its anticholinesterasic properties are robust enough to reverse scopolamine-induced amnesia (Siqueira et al., 2003;da Silva et al., 2008da Silva et al., , 2009, this is the first study to provide direct evidence of a protective effect for POEE against A␤-induced cognitive deficit. It is arguable that POEE attenuation of A␤-induced neurotoxicity is related to the absence of A␤-induced cognitive deficit in POEE mice. ...
... Unfortunately, due to the importance of using the very same batch of extract with which promnesic (da Silva et al., 2004) and anti-amnesic (da Silva et al., 2004) effects were shown in mouse models less directly linked to AD, complementary experiments (longer treatment and/or wider dose range) were here precluded.Given the multifactorial nature of neurodegeneration in itself (Pimplikar, 2009), and the complex interplay of factors relevant to AD susceptibility and course, the benefits of multi-functional drugs have been advocated (Youdim and Buccafusco, 2005). In this context, POEE, here shown to mitigate A␤ consequences in mice, has also been shown to be an effective brain antioxidant (Siqueira et al., 2007), to increase hippocampal cell viability after hypoxia (Siqueira et al., 2004), and to possess relevant AChE inhibitory properties in cognition-important areas (Siqueira et al., 2003;Figueiró et al., in press). ...
Article
Alzheimer's disease (AD) is expected to affect more than 22 million people worldwide by 2025, causing devastating suffering and enormous costs to families and society. AD is a multifactorial disease, with a complex pathological mosaic. In rodents, AD-like dementia can be induced by cerebral microinjection of Aβ peptide, leading to amyloid deposits, amnesia and various features of neurodegeneration. Marapuama (Ptychopetalum olacoides) is regarded as a "brain tonic" in the Amazon region and shows a nootropic profile in rodents. Because a specific extract (POEE) of Marapuama was shown to possess promnesic and anti-amnesic properties, the aim of this study was to verify if POEE is also effective against Aβ(1-42)-induced cognitive deficit in mice. Additionally, Aβ deposits (Congo red), GFAP immunoreactivity (immunohistochemistry), and neurodegenerative changes in the hippocampal pyramidal layer (Nissl) were examined as measures of Aβ(1-42)-induced neurodegeneration. CF1 mice were subjected to the experimental Alzheimer model with the Aβ(1-42) i.c.v. administration. The effects of POEE 800 mg/kg were evaluated over 14 consecutive days of treatment. The data show that 14 days of oral treatment with POEE (800 mg/kg) was effective in preventing Aβ-induced cognitive impairment, without altering the levels of BDNF and with parallel reductions in Aβ deposits and astrogliosis. CA1 hippocampus loss induced by Aβ(1-42) was also diminished in POEE-treated mice. This study offers evidence of functional and neuroprotective effects of two weeks treatment with a Ptychopetalum olacoides extract against Aβ peptide-induced neurotoxicity in mice. Given the multifactorial nature of neurodegeneration, the considerable potential for an AChE inhibitor displaying associated neuroprotective properties such as here reported warrants further clinic evaluation.
... Although some studies have cited the presence of alkaloids (Peckolt 1901;Silva 1925;Siqueira et al. 1998), this class of substances has not been properly characterized (Tang et al. 2009;Piato et al. 2010). The belief that alkaloids are present in the species may have its origin in a misinterpretation of an old study that led to the purification of crystals called "muyrapuamina" which probably correspond to β-sitosterol or other sterols already identified in the species (Steinmetz 1962;Siqueira et al. 2003). ...
... Data suggest that the pro-cholinergic activity of the extract is also important for its promnesic function. The ethanolic extract of P. olacoides roots inhibited the acetylcholinesterase activity in the frontal cortex, hippocampus, and striatum both in in vitro study (incubation of the tissue with the extract) and in ex vivo (when animals were treated with the plant and the brain removed after 2 h to evaluate enzyme activity) (Siqueira et al. 2003). Oral treatment of mice with an ethanolic extract at a dose of 300 mg/kg inhibited the acetylcholinesterase activity in the hippocampus (CA 1 and CA 3 areas) and striatum, without altering the enzyme levels, indicating that the extract does not interfere with the enzyme synthesis (Figueiró et al. 2010). ...
Chapter
The Ptychopetalum olacoides Benth. (Olacaceae) is an Amazonian tree popularly known as muirapuama or marapuama, among other names, which is used for several central nervous system related problems. The roots and occasionally the bark roots are the main medicinal parts employed and are prepared as an alcoholic infusion, tinctures, and tea. Phytochemical studies revealed that the roots contain tannins, flavonoids, and several terpenoids, while the presence of alkaloids is not clear. Most studies used ethanolic or hydroalcoholic extracts prepared with the roots of the plant. These studies indicate that the species has promising potential for treating central nervous system disorders, acting as an antidepressant, an anti-stress, a neuroprotective agent, and improving cognition. Although some herbal products contain P. olacoides in their composition, clinical studies are still needed to confirm the effects observed in pre-clinical studies.
... Another model of human declarative memory involves a natural preference displayed by rodents for novel objects: the object recognition tasks is considered a non-aversive, non-spatial type of memory, and have been shown to be very useful for assessing changes in neuronal function induced by drugs, aging, and cholinergic dysfunction (Deschaux et al., 1997; Puma et al., 1999; Lebrun et al., 2000). We have previously shown that an ethanol extract of Ptychopetalum olacoides Bentham (Olacoides), traditionally used by Amazonian communities as a " nerve tonic " (Elisabetsky and Siqueira, 1998), posses antioxidant properties in vitro (Siqueira et al., 2002) and in vivo (Siqueira et al., 2006 ), act as neuroprotector in hippocampal slices submitted to oxygen and glucose deprivation (Siqueira et al., 2004), and has anticholinesterase activity in vitro and in vivo at various relevant brain areas (Siqueira et al., 2003). Relevant to this study, it was shown that the extract specifically facilitates the retrieval of long-term memory (inhibitory avoidance) in mice; it is also noteworthy that the memory deficit observed in aging (14-month old) mice was reversed by orally given extract (da Silva et al., 2004). ...
... Therefore, the mechanism of action responsible for memory facilitation by nootropic drugs in not fully known, and may involve various neurotransmitters. Thus, the promnesic effect of POEE found in this study is coherent with its inhibitory properties for acetylcholinesterase (Siqueira et al., 2003), but also with the behavior profile so far established for this extract (Siqueira et al., 1998; da Silva et al., 2002) suggests interactions with various neurotransmitters (including noradrenaline, serotonin and dopamine). It is noteworthy that POEE is effective when administered orally to young and aged mice, concurrent with the traditional use with its alleged effects in elderly people. ...
... To date, glutamate receptor antagonists, free radical scavengers and voltage-gated channel blockers have been examined for the development of neuroprotective therapeutic agents. Because neurotoxicity mechanisms actually involve numerous interdependent processes, the development of novel drugs acting at multiple sites of the neurotoxic cascade, and/or at some crucial common step, is considered to be advantageous (Morin et al., 2001; Siqueira et al., 2003). Rat forebrain slices exposed to oxygen and glucose deprivation (OGD) have been used to model ischemic events, to investigate mechanisms of cell death and neuroprotection (Moro et al., 1998; Cárdenas et al., 2000). ...
... We have previously reported that the ethanol extract of PO roots possesses various central nervous system activities, including reversal of reserpine-induced ptosis, mild anxiogenic effect on the holeboard , and enhancement of memory retrieval in young and aged mice (Siqueira et al., 1998; Silva et al., 2002; da Silva, 2001). Additionally, we have recently reported marked free radicals scavenging activity of PO ethanol extract (POEE) in several in vitro assays (Siqueira et al., 2002), as well as a significant inhibition of acethylcholinesterase in different brain regions (Siqueira et al., 2003). Relevant to this study, it was also found that the acute (ip) administration of POEE in mice leads to significant reduction on free radical generation, lipid peroxidation and protein-bound carbonyl content, and increased activities of the antioxidant enzymes catalase and glutathione peroxidase, pertinent indexes of oxidative status in diverse brain structures (Siqueira et al., 2004). ...
... This species is currently included in dozens of herbal drugs or multivitamin dietary supplements available all around the world that are claimed to enhance sexual, physical and cognitive performance. We have previously reported that a specific ethanol extract (POEE) of PO roots possesses various central nervous system (CNS) activities (Siqueira et al., 1998), including mild anxiogenic effect in the hole-board test, improvement of long-term memory retrieval in the adult and aged mice step down paradigm (da Silva et al., 2002 Silva et al., , 2004), and that it inhibits AChE (in vitro and ex vivo assays, Siqueira et al., 2003 ), suggesting that improvement in cholinergic function might be a neurochemical correlate of the extract's behavioral effects. A substantial antioxidant property could be related to some of the therapeutic properties claimed to be associated with marapuama, as radical scavengers reverse the loss of spatial memory and decrease damage to brain proteins in aged gerbils and rats (Carney et al., 1991; Socci et al., 1995). ...
... Because the endogenous antioxidant defenses are not always completely effective, as is the case in normal aging and neurodegenerative diseases, it has been proposed that exogenous antioxidants could effectively restrain the cumulative effects of oxidative damage. Confirming previously reported results of in vivo and in vitro activities (da Silva et al., 2002; Siqueira et al., 1998 Siqueira et al., , 2003), this study shows that an acute treatment with POEE can improve the protective defenses against oxidative stress in specific brain areas. This is an important step toward verifying a physiologically relevant contribution. ...
... (Olacaceae) is a small tree found in the Amazon basin of Brazil. The root is the article of commerce, being known by the names 'marapuama', 'muirapuama' or 'mirantã' [186]. An alcoholic extract of the root is used widely throughout Brazil and is known further afield as an aphrodisiac, although the scientific evidence for this is not very strong. ...
... Rat hippocampal slices challenged by oxygen and glucose deprivation and treated with P. olacoides extract showed improved survival and mitochondrial activity compared to con-trols [194], implying some antioxidant effects. The same extract has been shown to have ChEI properties both in vitro [186] and in vivo in brain areas associated with cognition [195], whilst antagonism at 5HT 2A receptors also appears to be involved [196]. Thus, although some promising effects in animals have been shown, which might make P. olacoides a candidate to explore for AD treatment, RCTs are needed before any claims can be made to this effect. ...
... We have previously reported that a specific ethanol extract (POEE) of PO roots possesses various central nervous system (CNS) activities ( Siqueira et al., 1998), including mild anxiogenic effect in the hole-board test, improvement of long-term memory retrieval in the adult and aged mice step down paradigm (da Silva et al., 2002Silva et al., , 2004, and that it inhibits AChE (in vitro and ex vivo assays, Siqueira et al., 2003), suggesting that improvement in cholinergic function might be a neurochemical correlate of the extract's behavioral effects. ...
... Because the endogenous antioxidant defenses are not always completely effective, as is the case in normal aging and neurodegenerative diseases, it has been proposed that exogenous antioxidants could effectively restrain the cumulative effects of oxidative damage. Confirming previously reported results of in vivo and in vitro activities (da Silva et al., 2002;Siqueira et al., 1998Siqueira et al., , 2003, this study shows that an acute treatment with POEE can improve the protective defenses against oxidative stress in specific brain areas. This is an important step toward verifying a physiologically relevant contribution. ...
Article
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Alcohol infusions of roots from Ptychopetalum olacoides Bentham (PO; Olacaceae) have been used for treating many diseases in which free radicals are likely to be implicated. Of particular interest are the uses amongst the elderly (to ameliorate cognitive functions), and by patients recovering from pathologies associated with damage to the central nervous system (such as stroke). The aim of this study was to evaluate the antioxidant properties of a PO ethanol extract (POEE) by using various in vitro systems. POEE acted as a scavenger of nitrogen oxides as well as superoxide generated by the xanthine-xanthine oxidase system. The extract also showed a high antioxidant capacity using a luminol chemiluminescence derived from a thermolabile diazocompound. We suggest that the therapeutic effects attributed to P. olacoides could be in part associated to its oxygen free radical scavenging capacity.
... (Olacaceae) is a small tree found in the Amazon basin of Brazil. The root is the article of commerce, being known by the names 'marapuama', 'muirapuama' or 'mirantã' [186]. An alcoholic extract of the root is used widely throughout Brazil and is known further afield as an aphrodisiac, although the scientific evidence for this is not very strong. ...
... Rat hippocampal slices challenged by oxygen and glucose deprivation and treated with P. olacoides extract showed improved survival and mitochondrial activity compared to con-trols [194], implying some antioxidant effects. The same extract has been shown to have ChEI properties both in vitro [186] and in vivo in brain areas associated with cognition [195], whilst antagonism at 5HT 2A receptors also appears to be involved [196]. Thus, although some promising effects in animals have been shown, which might make P. olacoides a candidate to explore for AD treatment, RCTs are needed before any claims can be made to this effect. ...
Article
Ethnobotany encompasses the cultural uses of plants by humans, including their uses as medicines (ethnopharmacology). The reputed medicinal properties of plants have been documented for centuries in different cultures, and there are many plant species that have been traditionally used for memory disorders, which are now being explored to determine any scientific basis for their reputed uses. Plants have been a valuable source of drugs, and phytochemicals have also provided templates to develop synthetic drugs (e.g. rivastigmine, based on the chemical structure of physostigmine from Physostigma venenosum). Although drug development from botanical origin is one aim, the use of plants as herbal medicines is still popular. Scientific evidence for efficacy and safety has been explored for many species, although more research is needed, particularly to identify active phytochemicals to produce standardised herbal products. For Alzheimer's disease (AD) there are relatively few drugs available to treat symptoms, and there is a lack of successful therapies that modulate disease progression. Since two of the currently licensed drugs for AD are based on natural products (galantamine and rivastigmine), it is not surprising that many plants are now being investigated as a potential source of new therapies for AD. This review discusses those plants that have ethnobotanical uses suggestive of alleviation of AD pathology and associated symptoms, for cognitive and for behavioural and psychological symptoms of dementia (BPSD). An emphasis is placed on those plants that have shown some promising effects in clinical studies with dementia patients (e.g. Crocus sativus, Ginkgo biloba, Salvia species), but other plants and their phytochemicals showing relevant mechanistic effects for AD (e.g. Bacopa monnieri, Centella asiatica, Ptychopetalum olacoides) are also discussed.
... Coherent with users' claims, this research group has established promnesic (da Silva et al. 2004, 2007, 2008), anti-amnesic (da Silva et al. 2009) neuroprotective (Siqueira et al. 2004) and antidepressant (Piato et al. 2008) properties for a standardized ethanol extract (POEE) of Marapuama. As neurochemical correlates of these properties, antioxidant (Siqueira et al. 2007) and anticholinesterasic effects (Siqueira et al. 2003) have also been identified. A huge impediment to the development of drugs for the treatment of CNS diseases is the blood–brain barrier (BBB) (Pardridge 2009), and the extent to which a drug can readily penetrate the BBB determines its bioavailability within the CNS (Anekonda and Reddy 2005). ...
... Enzyme histochemistry is an appropriate link between biochemistry and morphology since it measures the biotransformation of a substrate by a tissue enzyme in its orthotopic localization (Meier-Ruge and Bruder 2008). Complementing the study done with intraperioteneal administration to older (14 months) mice (Siqueira et al. 2003), we here show histochemically that AChE activity is inhibited (by about 33% in hippocampus CA1, 20% in hippocampus CA3, and 17% in the striatum) in adult mice treated orally only with the dose also found to facilitate memory. ...
Article
The goal of acetylcholinesterase inhibitors (AChEIs) used to treat Alzheimer's patients is an improvement in cholinergic transmission. While currently available AChEIs have limited success, a huge impediment to the development of newer ones is access to the relevant brain areas. Promnesic, anti-amnesic and AChEI properties were identified in a standardized ethanol extract from Ptychopetalum olacoides (POEE), a medicinal plant favored by the elderly in Amazon communities. The purpose of this study was to provide conclusive evidence that orally given POEE induces AChE inhibition in brain areas relevant to cognition. Histochemistry experiments confirmed that the anticholinesterase compound(s) present in POEE are orally bioavailable, inducing meaningful AChE inhibition in the hippocampus CA1 (∼33%) and CA3 (∼20%), and striatum (∼17%). Ellman's colorimetric analysis revealed that G1 and G4 AChE isoforms activities were markedly inhibited (66 and 72%, respectively) in hippocampus and frontal cortex (50 and 63%, respectively), while G4 appeared to be selectively inhibited (72%) in the striatum. Western blotting showed that POEE did not induce significant changes in the AChE immunocontent suggesting that its synthesis is not extensively modified. This study provides definitive proof of meaningful anticholinesterase activity compatible with the observed promnesic and anti-amnesic effects of POEE in mice, reaffirming the potential of this extract for treating neurodegenerative conditions where a hypofunctioning cholinergic neurotransmission is prominent. Adequate assessment of the safety and efficacy of this extract and/or its isolated active compound(s) are warranted.
... Muira Puama (Ptychopetalum olacoides), or "potency tree" of the Olacaceae family, grows in the Amazon rainforest. The "potency tree" is used by Amazon Indians in the form of a decoction to enhance erections and sexual desire [62]. The bark and root of the plant are used to produce a medicinal tablet for ingestion. ...
Article
Since time immemorial, people have been trying to influence different aspects of their sexuality. They seek ways to increase sexual activity or sexual desire in themselves and their partners. In addition to resorting to all sorts of mystical rituals, people were looking for various effects from the use of natural raw materials. Some plant, animal, or fungal products have been shown to affect libido, sexual arousal, erectile function, orgasm or erogenous zone sensitivity. Such substances have been called "aphrodisiacs" in honor of the ancient Greek goddess of love - Aphrodite. Most often, aphrodisiacs were taken orally, but some were smoked while others applied to the genitals. In modern clinical practice, phosphodiesterase type 5 inhibitors are used. These are substances, which enhance erection and prevent detumescence in the presence of sexual arousal. Another group of drugs is selective serotonin reuptake inhibitors, which reduce sexual arousal and sexual afferent from the genitals, thus preventing the premature onset of orgasm in men and prolonging sexual intercourse. However, drugs from other pharmacological groups have not found widespread clinical application. Another issue now is a trend among people taking drugs of natural origin, therefore, all kinds of traditional aphrodisiacs are actively used to the present day. Very little is known about almost all of them. Clinical trials are in most cases limited to a few, often not randomized, studies. In this regard, it is very difficult to evaluate the adequate therapeutic and toxic doses of remedies. The situation is complicated by the fact that those few clinical studies were based on questionnaires, that is, the indicators taken into statistical calculations were extremely subjective. Moreover, it was uncertain whether all patients could adequately assess their dynamics in terms of parameters such as sexual satisfaction, or clearly distinguish between libido and sexual arousal. Since the majority of the studies were not blinded, a psychogenic influence on the results of the investigations could not be eliminated, which in the sexual area may be huge. It is worth emphasizing the toxicity of many traditional aphrodisiacs. Of course, there is a serious deficit in the spectrum of pharmacotherapy for sexual disorders. Perhaps further large, randomized, placebo-controlled trials would add some of the traditional aphrodisiacs or their modifications to the arsenal of the clinical specialist.
... It is also known in Brazil as marapuama or muirapuama [258]. The native communities have used its roots and barks as a treatment for depression, sexual dysfunction, and as a "nerve tonic" [259]. Roots are usually prepared in alcoholic infusion, but other formulations have also been employed (e.g., mixture of extracts, solutions, pills) [260]. ...
Article
Full-text available
Sexual enhancers increase sexual potency, sexual pleasure, or libido. Substances increasing libido alter the concentrations of specific neurotransmitters or sex hormones in the central nervous system. Interestingly, the same pathways are involved in the mechanisms underlying many psychiatric and neurological disorders, and adverse reactions associated with the use of aphrodisiacs are strongly expected. However, sexual enhancers of plant origin have gained popularity over recent years, as natural substances are often regarded as a safer alternative to modern medications and are easily acquired without prescription. We reviewed the psychiatric and neurological adverse effects associated with the consumption of herbal aphrodisiacs Areca catechu L., Argemone Mexicana L., Citrus aurantium L., Eurycoma longifolia Jack., Lepidium meyenii Walp., Mitragyna speciosa Korth., Panax ginseng C. A. Mey, Panax quinquefolius L., Pausinystalia johimbe (K. Schum.) Pierre ex Beille, Piper methysticum G. Forst., Ptychopetalum olacoides Benth., Sceletium tortuosum (L.) N. E. Brown, Turnera diffusa Willd. ex. Schult., Voacanga africana Stapf ex Scott-Elliot, and Withania somnifera (L.) Dunal. A literature search was conducted on the PubMed, Scopus, and Web of Science databases with the aim of identifying all the relevant articles published on the issue up to June 2020. Most of the selected sexual enhancers appeared to be safe at therapeutic doses, although mild to severe adverse effects may occur in cases of overdosing or self-medication with unstandardized products. Drug interactions are more concerning, considering that herbal aphrodisiacs are likely used together with other plant extracts and/or pharmaceuticals. However, few data are available on the side effects of several plants included in this review, and more clinical studies with controlled administrations should be conducted to address this issue.
... Acetylcholinesterase inhibitory activity was assayed according to Nag and De 23 modifying the method of Ellman et al. 26 following Oh et al. 27 and Siqueira et al. 28 . Brains from 3-4 weeks old mice were washed with cold sodium phosphate buffer (0.2M, pH 8), homogenized in buffer and centrifuged at 10,000 RPM at 4 0 C. The supernatant was used as the enzyme source (AChE). ...
Research
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Both infusion and decoction of the four tea varieties were assayed for acetylcholinesterase (AChE) inhibitory property. Theaflavin and thearubigin, the two most exclusive polyphenols of black tea, were also studied for their AChE properties. The present study showed that infusion and decoction of each variety of tea inhibited AChE in a dose dependent manner. There was no significant difference in activity between the varieties. In general the activity of tea decoction was significantly higher than that of the infusion. Theaflavin and thearubigin also showed AChE inhibitory properties in a dose dependent manner. The individual tea extract had higher activity than either theaflavin or thearubigin. The present study suggests that AChE inhibitory activity of black tea could be due to theaflavin, thearubigin and other tea flavonols, phenols or some other constituents and perhaps a combination of some of the constituents acting synergistically.
... Thus, this a-muurolene compound was found to be responsible for the seperation of the treatments in PCA score plot. The a-muurolene was also reported in Ptychopetalum olacoides, a very popular tropical medicinal herb, to have vast pharmaceutical properties, such as memory enhancement (da Silva et al. 2004), antinociceptive and neuroprotective effects (Siqueira et al. 2003), antinociceptive effects (Vaz et al. 1998) and erectile dysfunction or vasorelaxant effects (Antunes et al. 2001). This compound has also been identified in juniper oil (Bailon et al. 2017) which showed antimicrobiotic properties and inhibition to Escherichia coli ATTC 25922 strain. ...
Article
Sesquiterpenes are a three-isoprene unit compounds which belong to terpenoid family of secondary metabolites. These volatile compounds are one of the major constituents of essential oils in plants and plays major roles in plant signaling of defense mechanism. The effects of methyl jasmonate (MeJA) concentrations (100 and 200 μM) on the production of sesquiterpene compounds after incubation period for 1, 3, and 6 days were investigated in Persicaria minor cell suspension culture. Headspace Solid-Phase Microextraction (HS-SPME) method was used to absorb volatile compounds from suspension cells and liquid medium. They were then analyzed through Gas Chromatography-Mass Spectrometry (GC-MS) to identify sesquiterpene compounds. Among the 15 sesquiterpene compounds identified, α- muurolene was found in significantly higher concentration in all MeJA treated cultures. The results showed that α-muurolene was detected in the suspension cells at the highest peak area of 14.17% at 100 μM MeJA treated cultures with 3-day incubation. Analysis of liquid medium of the treatments identified secretion of α-muurolene into the culture medium, with total peak area of 0.72%. These results showed that sesquiterpene production in MeJA induced P. minor suspension culture depended on the MeJA concentration and also culture incubation period. © 2018 Penerbit Universiti Kebangsaan Malaysia. All Rights Reserved.
... (Olacaceae) is a shrub or small tree widely known in Brazil as muirapuama , marapuama , marapuana and muiratã . 1 This is an endemic species to the Amazon rainforest and specially distributed in the north region of the country in Amazonas, Amapá and Pará states. 2 Preparations with the stems of P. olacoides have been used to treat "nervous weakness", fatigue, depression symptoms, tremor disorders, and sexual dysfunction. 3 The fluid root extract of this plant has been employed in phytotherapeutic formulations as Catuama®, a general tonic widely used in some regions of Brazil. 4 However, there are few data related to the phytochemical profile of this species. ...
Article
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In the present study, three flavonoids, 3-O-methylquercetin (1), 3,4'-O-dimethylquercetin (2) and 3,7-O-dimethylquercetin (3) were isolated and characterized for the first time from a methanol extract obtained from the species Ptychopetalum olacoides. The structures of compounds were identified by spectroscopic methods (1D-, 2D-NMR, MS and UV) and confirmed by comparison with the respective literature data. The cytotoxic effect of crude extract was evaluated in vitro against three human cancer cell lines. The results showed a mild cytotoxic activity (IC50 = 45.16 µg/mL) against breast cancer (MCF-7). However, crude extract did not exhibit any cytotoxic effect against normal cell human fibroblast (MRC-5).
... In young and aging mice, improvement in memory retrieval was noted following POEE administration (da Silva et al., 2004). POEE exerted AChE inhibition in hippocampus, frontal cortex and striatum of rat and mice (Siqueira et al., 2003;Figueiró et al., 2010) and decreased Aβ toxicity, Aβ deposits and astrogliosis in Aβ (1-42)-induced mice (Figueiró et al., 2011). ...
Article
Alzheimer's disease (AD) is a severe, chronic and progressive neurodegenerative disease associated with memory and cognition impairment ultimately leading to death. It is the commonest reason of dementia in elderly populations mostly affecting beyond the age of 65. The pathogenesis is indicated by accumulation of the amyloidbeta (A beta) plaques and neurofibrillary tangles (NFT) in brain tissues and hyperphosphorylation of tau protein in neurons. The main cause is considered to be the formation of reactive oxygen species (ROS) due to oxidative stress. The current treatment provides only symptomatic relief by offering temporary palliative therapy which declines the rate of cognitive impairment associated with AD. Inhibition of the enzyme acetylcholinesterase (AChE) is considered as one of the major therapeutic strategies offering only symptomatic relief and moderate
... Alguns estudos têm comprovado os benefícios de seu extrato na memória (Siqueira et al., 2003;Da Silva et al., 2004), no tratamento de isquemia cerebral e à propriedade antidepressiva (Piato et al., 2008). ...
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The popular trade of herbal drugs without quality assurance implies a health risk. This study was an interdisciplinary analysis of the herbal drugs (DVs) trade network with focus on psychoactive drug plant (DVPs) available on the Brazilian city of Diadema, and risks associated with its consumption. Methods of ethnopharmacology, such as informal interviews, semi-structured interviews and participant observation were used for the completion of the fieldwork, during which four tradesmen were selected to register the collection, handling, packaging and types of DVs marketed. We registered 63 DVs that referred to psychoactive activity (DVPs) and categorized as stimulants (67%), depressants (27%), depressants and stimulants (1%) and finally some could not be set (5%). These DVPs had their popular names, preparations and uses, used parts, contraindications, and doses recorded. Eighteen of the 63 DVPs were selected according to the study criteria, and their lots were purchased by the selected tradesmen to be examined by microbiology (61 lots) and Pharmacognosy (only 22 of those lots, related to only 8 DVPs). The results for these areas, together with query in the scientific literature concerning descriptions of adverse reactions, provided the grant for the final analysis of these DVPs in the context of pharmacovigilance. Deficiencies were observed mainly in the handling and packaging of DVs by the traders, favoring its contamination and degradation. The microbiological analysis found that 16% of DVPs analyzed showed populations of bacteria (aerobic and Enterobacteriaceae) exceeding 105 CFU/g and 31%, populations of fungi (molds and yeasts) exceeding 103 CFU/g and the presence of risk indicator microbial species in 17 DVPs, specifically in 74% of the 61 lots, in addition to aflatoxin B1 or B2 producing fungi in four of them. The results of pharmacognosy showed that 73% had failed at least one of the parameters (contaminants, characterization and chromatographic profile), 50% of the 22 lots analyzed did not match the specifications of the pharmacopoeia, 36% were contaminated by other plant organs than those permitted in the monographs and a lot contamination by insects was found. All 22 lots have been disapproved in the evaluation of the label (classification and validity) and virtually all packages were considered inadequate. In addition to data obtained from such analysis, descriptions of contraindications, adverse effects and drug interactions were found in the literature for 3 DVPs who had their identity confirmed by the Pharmacognosy (chamomile, ginkgo biloba and guarana). The results obtained here allow us to observe the priorities of sanitary adequacy of the DVs popular trade, as well as establishing a profile of quality of DVPs marketed according to the analyzed parameters. We conclude that these DVPs gather important factors that could cause damage to the consumers health, especially for some groups such as pregnant women and immunosuppressed individuals.
... is another Amazonian plant widely used as a nerve tonic, aphrodisiac and stimulant that might possess adaptogen-like properties ( Piato et al. 2010) and the anticholinesterase activity was not tested here because it had already been showed by Siqueira et al. (2003). The apparent low incidence of dementia among "quilombolas" might be related to their dietary profile, with the frequent intake of Para nuts (B. ...
... Ptychopetalum olacoides, P. uncinatum Muira puama (bark and root extracts of P. olacoides or P. uncinatum) has been used in Amazonian Brazil during highly stressful periods, to treat CNS-related ailments, neuromuscular problems, "nervous weakness", sexual debility, frigidity, impotence, and rheumatism (Schultes and Raffauf 1990;Siqueira et al. 1998;Duke et al. 2009). Consistent with these traditional uses, P. olacoides ethanol root extract has shown memory retrieval improvement in young and aging mice (da Silva et al. 2004), in-vitro acetylcholine esterase inhibitory activity (Siqueira et al. 2003), and prevention of stress-induced hypothalamic-pituitaryadrenal hyperactivity (Piato et al. 2008). In addition, Muira puama formulations have demonstrated efficacy in treating male erectile dysfunction and low libido (Waynberg 1994) and low sex drive in women (Waynberg and Brewer 2000). ...
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The purpose of this study is to use a molecular docking approach to identify potential estrogen mimics or anti-estrogens in phytochemicals found in popular dietary herbal supplements. In this study, 568 phytochemicals found in 17 of the most popular herbal supplements sold in the United States were built and docked with two isoforms of the estrogen receptor, ERα and ERβ (a total of 27 different protein crystal structures). The docking results revealed six strongly docking compounds in Echinacea, three from milk thistle (Silybum marianum), three from Gingko biloba, one from Sambucus nigra, none from maca (Lepidium meyenii), five from chaste tree (Vitex agnus-castus), two from fenugreek (Trigonella foenum-graecum), and two from Rhodiola rosea. Notably, of the most popular herbal supplements for women, there were numerous compounds that docked strongly with the estrogen receptor: Licorice (Glycyrrhiza glabra) had a total of 26 compounds strongly docking to the estrogen receptor, 15 with wild yam (Dioscorea villosa), 11 from black cohosh (Actaea racemosa), eight from muira puama (Ptychopetalum olacoides or P. uncinatum), eight from red clover (Trifolium pratense), three from damiana (Turnera aphrodisiaca or T. diffusa), and three from dong quai (Angelica sinensis). Of possible concern were the compounds from men's herbal supplements that exhibited strong docking to the estrogen receptor: Gingko biloba had three compounds, gotu kola (Centella asiatica) had two, muira puama (Ptychopetalum olacoides or P. uncinatum) had eight, and Tribulus terrestris had six compounds. This molecular docking study has revealed that almost all popular herbal supplements contain phytochemical components that may bind to the human estrogen receptor and exhibit selective estrogen receptor modulation. As such, these herbal supplements may cause unwanted side effects related to estrogenic activity.
... Acetylcholinesterase inhibitory property was measured modifying the method of Ellman et al. (18) following Oh et al. (19) and Siqueira et al. (20). AChE from electric eel was used for assay. ...
... Acetylcholinesterase inhibitory activity was assayed according to Nag and De 23 modifying the method of Ellman et al. 26 following Oh et al. 27 and Siqueira et al. 28 . Brains from 3-4 weeks old mice were washed with cold sodium phosphate buffer (0.2M, pH 8), homogenized in buffer and centrifuged at 10,000 RPM at 4 0 C. The supernatant was used as the enzyme source (AChE). ...
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Both infusion and decoction of the four tea varieties were assayed for acetylcholinesterase (AChE) inhibitory property. Theaflavin and thearubigin, the two most exclusive polyphenols of black tea, were also studied for their AChE properties. The present study showed that infusion and decoction of each variety of tea inhibited AChE in a dose dependent manner. There was no significant difference in activity between the varieties. In general the activity of tea decoction was significantly higher than that of the infusion. Theaflavin and thearubigin also showed AChE inhibitory properties in a dose dependent manner. The individual tea extract had higher activity than either theaflavin or thearubigin. The present study suggests that AChE inhibitory activity of black tea could be due to theaflavin, thearubigin and other tea flavonols, phenols or some other constituents and perhaps a combination of some of the constituents acting synergistically.
... Several studies have provided evidence of the effects of this plant drug on the central nervous system. Initially it was found to show effects as an anxiogenic (Silva et al., 2002), anticholinesterase (Siqueira et al., 2003), neuroprotective (Siqueira et al., 2004), facilitation of memory recovery in young and old mice (Silva et al., 2004), antioxidant (Siqueira et al., 2007), antidepressant (Paiva et al., 1998;Piato et al., 2009), and anti-stress (Piato et al., 2010). Its aphrodisiac potential has not been confi rmed experimentally or clinically, although some of its effects, such as antidepressant and antioxidant activity, may improve sexual performance (Feldman et al., 1994). ...
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Croton echioides Baill., Euphorbiaceae, is a small tree found in Bahia, Northeastern Brazil. Its stem bark has been widely sold as an aphrodisiac and tonic, as a substitute for the roots of Ptychopetalum olacoides Benth. Olacaceae, the Amazon Muira Puama or Marapuama, and C. echioides is characterized as the "Northeastern Marapuama". This contribution describes a morphoanatomical analysis and pharmacognostic study of stem bark of this species. The stem has a thick cortex with compound starch grains and laticifers; a sclerenchymatic sheath which consists of brachysclereids with large crystals externally to the phloem, and abundant fiber in the secondary xylem, as the main features of the species. The data obtained for water content (9.26±0.07%), water-soluble extractives (3.92±0.19%), total ash (1.24±0.06%) and acid-insoluble ash (0.16±0.01%), together with the chromatographic profile obtained by TLC, contribute to the quality control and standardization for the plant drug. The pharmacological screening indicated LD50 values above 500 mg/kg orally and equal to 500 mg/kg by the i.p. route, as well as some stimulant potential, depending on the dose.
... Acorus calamus -asarone, -asrone, eugenol Antioxidative, anticholinesterase [13] Adhatoda vasica Vasicine, vasicol, vasicinol, arachidic, cerotic, linoleic, oleic acids Anticholinesterase [10] Bacopa monnieri Bacoside, brahmin, herpestine, d-mannitol, luteolin, apigenin Anticholinesterase [14] Brassica species Brassicasterol, sinapic acid, sinapine Anti-inflammatory, neuroprotective, anticholinesterase [15][16][17] Buddleja salviifolia Phenols, flavonoids, proanthocyanidins Antioxidative, anticholinesterase [18] Chamaecrista mimosoides Phenols, flavonoids, proanthocyanidins Antioxidative, anticholinesterase [18] Corydalis species AChE inhibition [19] Corydalis ternate Protopine Anticholinesterase, antiamnesic [20] Cymbopogon schoenanthus Piperitone, 2-carene Antioxidative, anticholinesterase, antimicrobial [21] Ferula assafoetida Cadinene, eremophilene Anti-COX-1 [10] Ginkgo biloba Ginkgetin, ginkoglides-A, B Anticholinesterase [14] Myricaria elegans Crude extract Anticholinesterase, antilipooxygenase [22] Nardostachys jatamansi Angelicin, -eudesmol, calarene, calarenol, elemol, nardol, oroselol Antioxidative, anticholinesterase [13] Origanum ehrenbergii Carvacrol, thymol Antioxidative, anti-inflammatory [23] Origanum syriacum Carvacrol, thymol Antioxidative, anti-inflammatory, anticholinesterase [23] Peganum harmala Norharmane, harmine, harmalol Anticholinesterase [10] Piper nigrum Piperine Antioxidative, anticholinesterase [11] Ptychopetalum olacoides Lupeol, , -pinene Anticholinesterase [24] Salvia lavandulaefolia Essential oil, terpenes Anticholinesterase [25] Salvia miltiorrhiza Diterpenoid Anticholinesterase [26] Salvia miltiorrhiza Terpenes, tanshinones Anticholinesterase [26,27] Salvia officinalis Polyphenols Antioxidative, anticholinesterase [28,29] Salvia plebeian Essential oil Antioxidative [30] Salvia tiliifolia Phenols, flavonoids, proanthocyanidins Antioxidative, inhibition of cholinesterase [18] Salvia triloba Rosmarinic acid, ferulic acid, luteolin, quercetin Antioxidative, anticholinesterase [11] Schotia brachypetala (root) Phenols, flavonoids, proanthocyanidins Antioxidative, anticholinesterase [18] Schotia brachypetala (bark) Phenols, flavonoids, proanthocyanidins Antioxidative, anticholinesterase [18] Syzygium aromaticum Eugenol, trans--caryophyllene, -humulene Anti-COX-1 [10] Tabernaemontana divaricata Voafinidine, lupeol, -amyrin, -sitosterol Anticholinesterase [31] Terminalia chebula Penta-O-galloyl--D-glucose Anticholinesterase [32] Zingiber officinale Gingerol, shogaol, zingerone Anti-COX-1 [10] such as AD, PD, Huntington's, and others share common features at cellular and subcellular levels as well as sharing mostly common molecular signaling pathways that may lead to apoptosis, necroptosis, and inflammation. Overall phytochemicals provide promising alternatives to current therapies for neurodegenerative disorders. ...
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Neurodegenerative diseases are characterized by protein aggregates and inflammation as well as oxidative stress in the central nervous system (CNS). Multiple biological processes are linked to neurodegenerative diseases such as depletion or insufficient synthesis of neurotransmitters, oxidative stress, abnormal ubiquitination. Furthermore, damaging of blood brain barrier (BBB) in the CNS also leads to various CNS-related diseases. Even though synthetic drugs are used for the management of Alzheimer's disease, Parkinson's disease, autism, and many other chronic illnesses, they are not without side effects. The attentions of researchers have been inclined towards the phytochemicals, many of which have minimal side effects. Phytochemicals are promising therapeutic agents because many phytochemicals have anti-inflammatory, antioxidative as well as anticholinesterase activities. Various drugs of either synthetic or natural origin applied in the treatment of brain disorders need to cross the BBB before they can be used. This paper covers various researches related to phytochemicals used in the management of neurodegenerative disorders.
... The experimental conditions were validated with huperzine A (0.5 mg/kg), which inhibited the enzyme in all brain regions (64% in cortex and 47.5% in hippocampus) (p < 0.05). As already reported, DMSO was devoid of effect (p > 0.05) (Siqueira et al. 2003), with no significant differences when compared to saline-treated groups. HQAE inhibited enzyme activity in the cortex, at all doses tested (Fig. 1A), achieving 50.4, ...
Article
Huperzine A, a Lycopodium alkaloid produced by Chinese folk herb Huperzia serrata (Lycopodiaceae), has been shown to be a promising agent for the treatment of Alzheimer's disease due to its potent acetylcholinesterase (AChE) activity, as well its efficacy in the treatment of memory of aged patients. Thus, the effects of two Huperzia species of habitats in Brazil (H. quadrifariata and H. reflexa) with described in vitro AChE inhibition activities were studied and their effects on mice brain AChE inhibition were determined after a single intraperitoneal (i.p.) injection. The alkaloid extracts were administered to mice in various doses (10, 1 and 0.5mg/kg) and acetylcholinesterase activity was measured post mortem in two brain areas using the Ellman's colorimetric method. The AChE activity was found to be significantly reduced in both the cortex and hippocampus, although this activity was less potent than that of reference inhibitor huperzine A (0.5mg/kg). Thus, it appears that H. quadrifariata and H. reflexa alkaloid extracts, shown to inhibit acetylcholinesterase in vitro, also have very potent in vivo effects, suggesting that the Huperzia species may still constitute a promising source of compounds with pharmaceutical interest for Alzheimer's disease.
... The competitive/noncompetitive mode of inhibition, as suggested by the Lineweaver-Burk plots, indicates that active alkaloids in extracts are able to interact with both the enzyme active center and the enzyme-substrate complex. Interestingly, compounds with notorious efficacy for the symptomatic treatment of AD, such as tacrine galanthamine and donepezil, are also of the mixed type of inhibition Khalid et al., 2005), as well as some plant extracts with reported neuroprotective effects (Siqueira et al., 2003). ...
Article
The study was aimed at evaluating medicinal and therapeutic potentials of two Lycopodiaceae species, Lycopodium clavatum (L.) and Lycopodium thyoides (Humb. & Bonpl. ex Willd), both used in South American folk medicine for central nervous system conditions. Alkaloid extracts were evaluated for chemical characterization, acetylcholinesterase and antioxidant activities. The alkaloid extracts obtained by alkaline extraction were determined for each species by GC/MS examination. The evaluation of the anticholinesterase and the antioxidant activities of the extracts were tested by determining in vitro and ex vivo models. Effects on acetylcholinesterase (AChE) were tested in vitro using rat brain homogenates and ex vivo after a single administration (25, 10 and 1mg/kg i.p.) of the alkaloid extracts in mice. The in vitro antioxidant effects were tested for the 2-deoxyribose degradation, nitric oxide (NO) interaction, 2,2-diphenyl-1-picryl hydrazyl (DPPH) radical scavenging activity and total reactive antioxidant potential (TRAP). After an acute administration (25 and 10mg/kg i.p.) of the extracts in middle-aged (12 months) mice, the antioxidant effects were estimated through the thiobarbituric acid reactive substances test (TBARS), and the antioxidant enzymes activities for catalase (CAT) and superoxide dismutase (SOD) were measured. AChE activity was inhibited in vitro by the alkaloid-enriched extracts of both Lycopodium species in a dose and time-dependent manner in rat cortex, striatum and hippocampus. A significant inhibition was also observed in areas of the brain after acute administration of extracts, as well as decreased lipid peroxidation and increased CAT activity in the cortex, hippocampus and cerebellum. A moderate antioxidant activity was observed in vitro for the extracts. Chemically, the main alkaloids found for the two species were lycopodine and acetyldihidrolycopodine. This study showed that the biological properties of the folk medicinal plants Lycopodium clavatum and Lycopodium thyoides include AChE inhibitory activity and antioxidant effects, two possible mechanisms of action in Alzheimer's related processes.
... The roots and bark of the species are known as Marapuama or Muirapuama and have been used as a neuromuscular tonic for the treatment of chronic rheumatism, sexual impotency, and central nervous system disorders [2]. Previous pharmacological studies have indicated that the EtOH extract of P. olacoides produces a series of beneficial effects on the central nervous system in mice [3][4][5][6][7]. As part of our ongoing project to search for natural products with neurotrophic properties [8][9][10][11][12], we have continued to explore bioactive diterpenoids from the MeOH extract of the bark of P. olacoides, which exhibited neurite outgrowth-promoting activity in NGF-mediated PC12 cells [13,14]. ...
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Eight new clerodane type diterpenoids, named 7-oxo-kolavelool (1), 7alpha-hydroxykolavelool (2), 6alpha,7alpha-dihydroxykolavenol (3), 12-oxo-hardwickiic acid (4), ptycholide I (5), ptycholide II (6), ptycholide III (7), and ptycholide IV (8) were isolated from the MeOH extract of the bark of a Brazilian medicinal plant, Ptychopetalum olacoides. The structures of 1-8 were elucidated by analyzing spectroscopic data and by comparing their NMR data with those of the previously reported compounds kolavelool (la), kolavenol (3a), hardwickiic acid (4a), and ptychonolide (5a). Compounds 5 and 6 existed as a 1:1 mixture of inseparable epimers at C-15.
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A phytochemical component investigation of the bark of Ptychopetalum olacoides led to the isolation of 4 new clerodane-type diterpenoids, namely, ptycholide V (1), 7α,20-dihydroxykolavelool (2), ptycholide VI (3), and ptycholide VII (4). Their structures were elucidated by extensive spectroscopic data and comparison of NMR data with that obtained for known compounds.
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Alzheimer's disease (AD), is the most common type of dementia primarily affecting the later years of life. Its prevalence is likely to increase in any aging population and will be a major burden on healthcare system by the mid of the century. Despite scientific and technological breakthroughs in the last 50 years, that have expanded our understanding of the disease on a system, cellular and molecular level, therapies that could stop or slow the progression of the disease are still unavailable. The Food and Drug Administration (FDA), has approved acetylcholinesterase (AChE) inhibitors (donepezil, galantamine, tacrine and rivastigmine) and glutamate receptor antagonist (memantine) for the treatment of AD. In this review we summarize the studies reporting phytocompounds and extracts from medicinal plants that show AChE inhibitory activities and could be of potential benefit in AD. Future research directions are suggested and recommendations made to expand the use of medicinal plants and their formulations to prevent, mitigate and treat AD.
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Common name: Silver wattle, French mimosa.
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Inhibitors of acetylcholinesterase (AChE) are used in the treatment of Alzheimer's disease. Initial screening revealed that the edible flowers of N. pubescens inhibited AChE. This finding motivated us to identify the contributory bioactive metabolite(s) responsible for inhibition AChE using Gas Chromatography ‐ Mass Spectrometry based metabolomics and chemometric approach. The metabolite levels as well as AChE inhibitory activity varied in different flower samples collected from different districts of West Bengal in the monsoon season. Different multivariate analyses differentiated the extracts with low activity (< 45% inhibition) from that of higher activities (> 45% inhibition). Chemometric analysis revealed gallic acid, a previously reported metabolite, to be one of the contributors significantly related to the inhibition of AChE by the flower extracts. Kaempferol, although negatively correlated, inhibited AChE. A probable synergistic action of metabolites is suggested for the AChE inhibitory property of N. pubescens flower extracts. Practical applications Nymphaea pubescens flower is edible in different countries. The flowers also have different medicinal properties. Acetylcholinesterase inhibitors are used in the treatment of Alzheimer's disease. As the flower extracts of this plant inhibited acetylcholinesterase, although the activity of the flower extracts varied with locality of collection. The level of metabolites also varied. A detailed study was made to identify the active constituents. Gallic acid and kaempferol were found to have high acetylcholinesterase inhibitory activities. The study suggested that consumption of this edible part of the plant may have beneficiary effect on memory function.
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Chapter
Alzheimer’s disease (AD) is progressive neurodegenerative disorder and identified as a major health concern globally. Individuals with AD and their care givers are affected in personal, emotional, financial, and social levels. Due to its significant impact and heavy burden on the individual, the patients’ families, and society, it is highly needed to search for cost effective, long-time retention therapeutic targets. In recent decades, there are lots of research conducted the possible benefit of natural products and their active components on AD and other neurodegenerative disease, which are discussed here.
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The supplementary material provides four schematic diagrams (Supplementary Figures S1-S4) with an overview about current state-of-the-art technologies in protemics that are currently widely applied in TCM such as 2DE proteomics, SILAC proteomics, iTRAQ or TMT proteomics, and label-free quantitative proteomics. In addition, a Supplementary Table S1 provides an overview of AD-related studies using TCM or TCM-derived traditional medicines.
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Acetylcholinesterase inhibitors have been extensively used for the symptomatic treatment of Alzheimer's disease. Methanolic extracts of Ayurvedic herbal drug Triphala and the ingredient fruits Terminalia chebula, Terminalia bellirica, and Emblica officinalis were assayed to study their acetylcholinesterase inhibitory properties. All the extracts inhibited the enzyme activity in a dose dependent manner. Gallic acid and ellagic acid, the phenolic acids present in all the fruits, also inhibited the enzyme acetylcholinesterase.
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Abstract Alzheimer's disease (AD) is a progressively neurodegenerative disease that eventually leads to the irreversible loss of neurons and intellectual abilities, including cognition and memory. AD has become the most common cause of dementia in aged people, and the ill-defined pathogenesis of AD is seriously impeding the current drug discovery against this disease. To date, there is still a lack of etiologically therapeutic drugs for AD, although some symptomatic treatments have been successfully developed. The β-amyloid (Aβ)-induced neurodegeneration is determined as the main pathogenesis of AD, and by targeting the regulation of Aβ in production inhibition or clearance promotion, many active agents have been designed potentially for AD treatment, but no drug has yet been approved in clinical use. Actually, AD has a complex pathogenic mechanism that involves multiple aberrant signaling genes and pathways, and the idea of 'single target' for anti-AD drug research is thus full of challenges. Recently, with a deep understanding of AD pathogeneses and the development of advanced pharmacological techniques, 'multiple target'-based strategy has been widely applied for the drug discovery against this disease, and many promising results have been achieved. Here, we review the recent multitarget strategies for the drug discovery in the treatment of AD by focusing on the involvement of Aβ regulation.
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Alzheimer’s disease (AD) is a progressive, neurodegenerative pathology that primarily affects the elderly population, and is estimated to account for 50-60% of dementia cases in persons over 65 years of age. The main symptoms associated with AD involve cognitive dysfunction, primarily memory loss. Other features associated with the later stages of AD include language defi cits, depression, behavioural problems including agitation, mood disturbances and psychosis. One of the most promising approaches for treating this disease is to enhance the acetylcholine level in the brain using acetylcholinesterase (AChE) inhibitors. The present work reviews the literature on plants and plant-derived compounds inhibitors of enzyme acetylcholinesterase. The review refers to 309 plant extracts and 260 compounds isolated from plants, which are classifi ed in appropriate chemical groups and model tested, and cites their activity. For this purpose 175 references were consulted.
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The steps involved in the development of formulations containing 5% of the commercial extract of Trichilia catigua Adr. Juss and Ptychopetalum olacoides Bentham are reported. Fourteen formulations were developed in order to obtain macroscopically stable emulsions with varying apparent viscosities, pH values compatiblcwith the skin and appropriate organoleptic characteristics, through Preliminary and Accelerated Stability Assays. These emulsions were separated into two groups, one of fluid emulsions and the other of more viscous emulsions. After evaluation, eight formulations were considered suitable to be subjected to the Preliminary Stability Assay. On the basis of this assay, five formulations were selected for the Accelerated Stability Assay, in which they were exposed to storage conditions, light and extreme temperatures. Two of the fluid emulsions were selected as having adequate stability characteristics. These were composed of self- emulsifying waxes and 0.3% (w/w) of xanthan gum, but only one of them contained soya lecithin.
Article
Objective To further characterize the acetylcholinesterase inhibitors (AChE-Is) pattern of Ptychopetalum olacoides ethanol extract (POEE) on the cytosolic globular monomer (G1) and membrane bound globular tetramer (G4) AChE isoforms in brain areas relevant for cognition.Methods The G1 and G4 AChE isoforms were prepared according to the reported methods and the determination of AChE activity used was adapted from colorimetric method.ResultsPOEE mostly inhibited G1 in hippocampus (75%), and G4 in frontal cortex (58%) and striatum (75%) (P < 0.05). Kinetic analysis indicated that POEE-induced AChE inhibition in hippocampus was of a competitive nature for G1 but uncompetitive for G4.Conclusion Considering the high density of cholinergic projection to the cortex and striatum, and the usefulness of conserving cytosolic acetylcholine to replenish synaptic vesicles in a highly active cognition site such as hippocampus, we argue that this could be a desirable profile for a clinically relevant AChE-I.
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Alzheimer's disease (AD) is a chronic neurodegenerative disorder and is the most common cause of progressive dementia in aging. Research on AD therapy has been partly successful in terms of developing symptomatic treatments, but there have been a number of failures with regard to developing disease-modifying therapies. The pathogenesis of AD remains unclear and the present one-drug, one-target paradigm for anti-AD treatment appears to be clinically unsuccessful. In many countries, traditional herbal medicines are used to prevent or treat neurodegenerative disorders, and some have been developed as nutraceuticals or functional foods. This review briefly introduces progress in the development of anti-AD treatments and then focuses on recent advances in the research, characteristics, and development of herbal medicines. Because AD arises via multiple pathological or neurotoxic pathways, herbal medicines have the potential to be developed into optimum pharmaceuticals and nutraceuticals for AD because of their multi-function, multi-target characteristics.
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Alzheimer's disease (AD), a common neurodegenerative disease, is characterized by low levels in the brain of the neurotransmitter, acetylcholine (ACh). Clinical treatment of this disease is palliative and relies mostly on enhancing cholinergic function by stimulation of cholinergic receptors or prolonging the availability of ACh released into the neuronal synaptic cleft by use of agents which restore or improve the levels of acetylcholine. Inhibition of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE), enzymes which breakdown acetylcholine, are considered as a promising strategy for the treatment of AD. A potential source of AChE and BChE inhibitors is provided by the abundance of plants in nature, and natural products continue to provide useful drugs and templates for the development of other compounds. The present work constitutes a review of the literature on 123 species of medicinal plants that have been tested for AChE inhibitory activity and 42 plant species which have been tested for BChE inhibitory activity. The plant species listed are potential cholinesterase inhibitors and may aid researchers in their study of natural products which may be useful in the treatment of AD.
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Abstract Although herbal/natural remedies have been, and are still being used, in the treatment of chronic degenerative diseases, little is known about basic principles –or theory- to combine these components and attain synergistic, gene modulating, as well as clinical health improving effects, in circulatory diseases -such as diabetes- and other chronic degenerative diseases. This chapter is divided into six sections. Section 2 reviews the background which gives origin and establishes the Systemic Theory and Systemic Medicine. The section also provides the general precepts to structure Circulat -a complex herbal formulation- for the treatment of circulatory chronic degenerative diseases. Section 3 is an outline of an investigation into the aforementioned formulation’s role and capability to modulate various gene expression levels -in cultured human fibroblasts- including those associated with diabetes. On the other hand, Section 4 presents a review of Circulat´s clinical properties through a Diabetic Foot management Study. An abbreviated limited Phase 2 GSPECT evaluated Chronic Ischemic Disease –another circulatory chronic disease- study is presented in Section 5. Finally, Section 6 provides some conclusions concerning the use of a complex herbal formulation as well as some reflections on the future design of such compositions.
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In Italy most herbal products are sold as food supplements and are subject only to food law. A list of about 1200 plants authorised for use in food supplements has been compiled by the Italian Ministry of Health. In order to review and possibly improve the Ministry's list an ad hoc working group of Istituto Superiore di Sanità was requested to provide a technical and scientific opinion on plant safety. The listed plants were evaluated on the basis of their use in food, therapeutic activity, human toxicity and in no-alimentary fields. Toxicity was also assessed and plant limitations to use in food supplements were defined.
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O presente estudo apresenta etapas de desenvolvimento de emulsões cosméticas, contendo 5% do extrato comercial de Trichilia catigua Adr. Juss (e) Ptychopetalum olacoides Bentham. Desenvolveramse 14 formulações-teste e avaliou-se a obtenção de emulsões macroscopicamente estáveis, com valores de viscosidade aparente variados, pH compatível com o da pele e características organolépticas adequadas, por meio dos Testes de Estabilidade Preliminar e Acelerada. Estas formulações foram divididas em dois grupos: um com emulsões fluidas e outro com emulsões mais viscosas. Após análise, oito formulações-teste foram consideradas aptas para serem submetidas ao Teste de Estabilidade Preliminar. Após os ensaios, cinco formulações-teste foram selecionadas para o Teste de Estabilidade Acelerada. Os ensaios foram conduzidos em condições de armazenamento, de luminosidade e de temperatura extremas. Ao final do estudo, duas formulações-teste foram consideradas aprovadas por apresentarem os perfis mais estáveis durante o estudo, sendo ambas, emulsões fluidas constituídas de ceras auto-emulsionantes e 0,3% p/p de um polímero natural, e uma delas adicionada também de 2,0% lecitina de soja. Palavras-chave: estabilidade de emulsões cosméticas; desenvolvimento de emulsões; Trichilia catigua Adr. Juss (e) Ptychopetalum olacoides Bentham
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Roots of Ptychopetalum olacoides Bentham (Olacaceae), known as Marapuama, are prepared in alcoholic infusion for treating “nervous weakness” by Amazonian Caboclos. “Nervous weakness” can be described as a syndrome having several symptoms, among which the following are emphasized: lassitude, depression, sexual impotence and tremors. Based on ethnopharmacological data, we have considered the hypothesis that PO may have psychopharmacological effects, by interacting with different neurotransmitter systems: (i) the dopaminergic system, considering its use as an appetite modulator and to counteract tremors, as well as for its alleged sexual arousing properties; (ii) the noradrenergic system, again for its use against tremors and/or depression; and/or (iii) the serotonergic system, also related to depression and sexual arousal. This paper reports that P. olacoides hydroalcoholic extract potentiated yohimbine-induced lethality, rever sed reserpine-induced ptosis and prevented apomorphine-induced stereotypy. The data indicates that P. olacoides has central nervous system effects and supports the hypothesis of its interaction with dopaminergic and/or noradrenergic systems.
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Oxygen free radicals and oxidative events have been implicated as playing a role in bringing about the changes in cellular function that occur during aging. Brain readily undergoes oxidative damage, so it is important to determine if aging-induced changes in brain may be associated with oxidative events. Previously we demonstrated that brain damage caused by an ischemia/reperfusion insult involved oxidative events. In addition, pretreatment with the spin-trapping compound N-tert-butyl-alpha-phenylnitrone (PBN) diminished the increase in oxidized protein and the loss of glutamine synthetase (GS) activity that accompanied ischemia/reperfusion injury in brain. We report here that aged gerbils had a significantly higher level of oxidized protein as assessed by carbonyl residues and decreased GS and neutral protease activities as compared to young adult gerbils. We also found that chronic treatment with the spin-trapping compound PBN caused a decrease in the level of oxidized protein and an increase in both GS and neutral protease activity in aged Mongolian gerbil brain. In contrast to aged gerbils, PBN treatment of young adult gerbils had no significant effect on brain oxidized protein content or GS activity. Male gerbils, young adults (3 months of age) and retired breeders (15-18 months of age), were treated with PBN for 14 days with twice daily dosages of 32 mg/kg. If PBN administration was ceased after 2 weeks, the significantly decreased level of oxidized protein and increased GS and neutral protease activities in old gerbils changed in a monotonic fashion back to the levels observed in aged gerbils prior to PBN administration. We also report that old gerbils make more errors than young animals and that older gerbils treated with PBN made fewer errors in a radial arm maze test for temporal and spatial memory than the untreated aged controls. These data can be interpreted to indicate that oxidation of cellular proteins may be a critical determinant of brain function. Moreover, it also implies that there is an age-related increase in vulnerability of tissue to oxidation that can be modified by free radical trapping compounds.
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Aged memory-impaired (AI) and unimpaired (AU) 24-25-month-old Long-Evans rats were used to investigate the integrity of various cholinergic markers during normal aging and to establish if alterations can possibly relate to cognitive disabilities. AI and AU rats were classified on the basis of their performance in the Morris swim maze task. Choline acetyltransferase activity (ChAT) was not differentially altered in various cortical and hippocampal areas between these two groups. Similarly, quantitative receptor autoradiography did not reveal significant differences in 3H-pirenzepine/muscarinic M1 and 3H-hemicholinium-3/high-affinity choline uptake binding sites in AI versus AU rats. In contrast, 3H-AF-DX 384/putative muscarinic M2 binding was significantly increased in certain cortical and hippocampal areas of the age-impaired animals. These increments were correlated with decreased in vivo acetylcholine (ACh) release capacity in the AI rats. Most interestingly, the muscarinic M2 antagonist BIBN-99 reversed, in a dose-dependent manner, the impaired ACh release as well as the cognitive deficits observed in the AI group. Similarly, BIBN-99 reversed scopolamine-induced amnesia in young animals. The efficacy of BIBN-99 likely relates to its antagonistic properties on negative muscarinic M2 autoreceptors that are apparently increased in the AI animals, leading to altered ACh release. Taken together, these findings strengthen the role of ACh in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic functions, such as Alzheimer's disease.
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Alcohol infusions of roots of Ptychopetalum olacoides Benth. (PO), known as Marapuama or Muirapuama, are used in the Brazilian Amazon as a 'nerve tonic'. Over the years PO has been found increasingly in phytoformulations and regarded as a stimulant, claimed to enhance physical and mental performances. This study determined that a P. olacoides ethanol extract (30, 100 and 300 mg/kg) decreased exploratory behaviour in the hole-board test, without interfering with locomotion or motor coordination (rota-rod test). The data are comparable to that obtained with pentylenetetrazol (40 mg/kg), suggesting an anxiogenic effect of P. olacoides.
Conference Paper
Nature has been a source of medicinal agents for thousands of years, and an impressive number of modern drugs have been isolated from natural sources, many based on their use in traditional medicine. In the past century, however, an increasing role has been played by microorganisms in the production of antibiotics and other drugs for the treatment of some serious diseases. Advances in the description of the human genome, as well as the genomes of pathogenic microbes and parasites, is permitting the determination of the structures of many proteins associated with disease processes. With the development of new molecular targets based on these proteins, there is an increasing demand for novel molecular diversity for screening. Natural products will play a crucial role in meeting this demand through the continued investigation of world's biodiversity, much of which remains unexplored. With less than 1% of the microbial world currently known, advances in procedures for microbial cultivation and the extraction of nucleic acids from environmental samples from soil and marine habitats, will provide access to a vast untapped reservoir of genetic and metabolic diversity. The same holds true for nucleic acids isolated from symbiotic and endophytic microbes associated with terrestrial and marine macroorganisms. By use of combinatorial chemical and biosynthetic technology, novel natural product leads will be optimized on the basis of their biological activities to yield effective chemotherapeutic and other bioactive agents. The investigation of these resources requires multi-disciplinary, national, and international collaboration in the discovery and development process.
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Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer’s disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer’s Disease Assessment Scale — Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer’s disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer’s disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer’s disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with a n incidence ranging between 7 to 30% For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.
Article
Der lipophile Inhaltsstoff von Muira puama wurde als Lupeol identifiziert. Eine Methode zur Gehaltsbestimmung, die auf der Farbreaktion mit Chlorsulfonsäure beruht, wurde ausgearbeitet und eine Reihe von Drogen untersucht. Lupeol fand sich in der Rinde, nicht aber im Holz. Von 7 Drogen war nur eine lupeolreich. Sie stammte wahrscheinlich von Ptychopetalum olacoides, die lupeolarmen Drogen aber von Ptychopetalum uncinatum. The Lipophile Constituent of Muira Puama The lipophile constituent of Muira puama was identified as lupeol. A method, based on the colour reaction with chlorosulphonic acid, has been elaborated to determine the content. A series of drugs was analysed. Lupeol was found in the bark but not in the wood. Only one of 7 drugs was rich in lupeol. This drug probably originated from Ptychopetalum olacoides, the drugs containing only a minimum of lupeol from Ptychopetalum uncinatum.
Article
Die Droge Muira puama enthält 0,4 bis 0,5% eines Estergemisches, das zu 2/3 aus dem Behensäureester eines α-Sterols besteht. Für das α-Sterol wird eine Konstitutionsformel vorgeschlagen. 1/3 der Säurekomponente besteht aus den nächsten Homologen der Behensäure. — In geringer Menge findet man frei und gebunden als Steroid auch β-Sitosterin.Muira puama contains 0,4 to 0,5% of an ester mixture, consisting of up to 2/3 of the behenic acid ester from an α-sterol. For this α-sterol a molecular formula is proposed. 1/3 of the acid component consists of the next homologues of behenic acid. — The steroid β-sitosterol, free and bound, is found in a small quantity also.
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A photometric method for determining acetylcholinesterase activity of tissue extracts, homogenates, cell suspensions, etc., has been described. The enzyme activity is measured by following the increase of yellow color produced from thiocholine when it reacts with dithiobisnitrobenzoate ion. It is based on coupling of these reactions: The latter reaction is rapid and the assay is sensitive (i.e. a 10 μ1 sample of blood is adequate). The use of a recorder has been most helpful, but is not essential. The method has been used to study the enzyme in human erythrocytes and homogenates of rat brain, kidney, lungs, liver and muscle tissue. Kinetic constants determined by this system for erythrocyte eholinesterase are presented. The data obtained with acetylthiocholine as substrate are similar to those with acetylcholine.
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A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Article
Following the discovery of a new series of 1-benzyl-4-[2-(N-benzoyl-N-methylamino)ethyl]piperidine (2) derivatives with a potent anti-acetylcholinesterase (anti-AChE) activity, we extended the structure-activity relationships (SAR) to rigid analogues (4) and 1-benzyl-4-[2-(N-benzoyl-N-phenylamino)ethyl]piperidine derivatives (3). Introduction of a phenyl group on the nitrogen atom of the amide moieties resulted in enhanced activity. The rigid analogue containing isoindolone (9) was found to exhibit potent anti-AChE activity comparable to that of 2. Furthermore, replacement of the isoindolone with other heterobicyclic ring systems was examined. Among the compounds prepared in these series, 1-benzyl-4-[2-[4-(benzoylamino)phthalimido]ethyl]piperidine hydrochloride (19) (IC50 = 1.2 nM) is one of the most potent inhibitors of AChE. Compound 19 showed a definite selectivity to AChE over the BuChE (about 34700-fold) and, at dosages of 10-50 mg/kg, exerted a dose-dependent inhibitory effect on AChE in rat brain.
Article
Previous studies in this laboratory showed an age-related decline of acetylcholinesterase (AChE) activity in the cerebral cortex of rats. In the present study the age-related differences in enzymatic activity were evaluated in terms of individual molecular forms. Extracts containing total, soluble and membrane-bound AChE were analyzed both by ultracentrifugation in sucrose gradient and by non-denaturing gradient polyacrylamide gel electrophoresis. By ultracentrifugation two molecular forms, namely 10S and 4S (corresponding to tetrameric-G4 and monomeric-G1 forms, respectively) were separated in extracts of total and soluble AChE, while only 10S forms were present in extracts of membrane-bound AChE. Electrophoresis of soluble AChE extracts revealed slowly- and fast-migrating bands, grouped in two clusters of at least three bands each; membrane-bound AChE contained only a single slowly-migrating band. Electrophoresis of the single forms isolated by ultracentrifugation showed that slowly- and fast-migrating bands corresponded to G4 and G1 forms, respectively. Therefore, in soluble AChE no one-to-one relationship between charge- and size-isomers was observed; on the contrary, such relationship has been shown for membrane-bound AChE. This implies that soluble G4 forms and membrane-bound-G4 forms are electrophoretically different, being heterogeneous the former and homogeneous the latter. The age-related decline of total AChE, accompanied by a decrease of G4/G1 ratio, depended mainly on a decrease of membrane-bound AChE while soluble AChE and its G4/G1 ratio was unchanged. The qualitative pattern of charge isomers was not modified by aging.
Article
The stereoselectivities and mechanisms of the inhibition of rat cortical acetylcholinesterase by the enantiomers of huperzine A were determined. (-)-Huperzine A was the more potent enantiomer with a Ki value of 8 nM. (+)-Huperzine A inhibited the enzyme 38-fold less potently with a Ki value of 300 nM. Racemic huperzine A was about two-fold less potent than the more active isomer, (-)-huperzine A. The mechanism of inhibition of acetylcholinesterase for all three drugs was of the mixed linear competitive type.
Article
To assess the relative importance of binding to enzyme-substrate complex (E.S) and to acetylenzyme (EA), noncompetitive inhibition has been studied in hydrolysis by acetylcholinesterase (AcChE) of cationic and uncharged substrates - acetylcholine (AcCh), 3,3-dimethylbutyl acetate, n-butyl acetate, 2-(methylammonio)ethyl acetate, 2- (N,N-diethyl-N-n-butylammonio)ethyl acetate (DEBAAc) and 2-(methylsulfonyl)ethyl acetate. For the N-trimethyl quaternary ions related to AcCh, tetramethylammonium ion, choline and choline ethyl ether, noncompetitive inhibition (Ki(nonc) is more favorable with the slower substrates than with AcCh, i.e., when E.S greater than EA, and is attributed to formation of enzyme-substrate-inhibitor complexes, E.S.I'. Noncompetitive inhibition by tetraethyl-, tert-butyl- and isopropylammonium ions, and acetamidocholine and its lower dimethyl analogue, is also attributed to E.S.I' complexes. Peripheral binding of these inhibitors decreases acylation more than deacylation. Some tertiary dimethylamonio ions have more favorable Ki(nonc) values with AcCh, decreasing deacylation more than acylation. The substrate DEBAAc is a more effective noncompetitive than competitive inhibitor in hydrolysis of AcCh, indicating that it binds more strongly in a peripheral site than in the active site of the free enzyme. In its hydrolysis by AcChE, it acts as its own noncompetitive inhibitor, by this non-productive binding. Formation of E.S.I' complexes is a general characteristic of hydrolysis by AcChE and decrease in rates at high concentrations of AcCh and related substrates is attributed to peripheral regulatory site binding, formation of E.S.S' complexes, rather than to binding to the acetylenzyme.
Article
The effects of physostigmine, tacrine and NIK-247 on scopolamine-induced impairment of a passive avoidance response were examined in rats. In addition, we investigated possible peripheral side-effects: miosis and salivation, and central side-effects: hypothermia and tremor which are mediated by cholinergic activation. Intraperitoneal injection of physostigmine reversed scopolamine-induced amnesia at a dose of 0.03 mg/kg. Antiamnesic effects of oral administration of tacrine and NIK-247 were observed at doses of 0.3 and 0.1-0.3 mg/kg, respectively. Intraperitoneal injection of physostigmine induced miosis, salivation, hypothermia and tremor at doses > or = 0.1, 0.3, 0.3 and 1 mg/kg, respectively. Oral administration of tacrine (at doses > or = 0.3 mg/kg) and NIK-247 (at doses > or = 3 mg/kg) produced miosis. Tacrine (at doses > or = 1 mg/kg) and NIK-247 (at doses > or = 3 mg/kg) produced hypersalivation. Hypothermia and tremor were observed after administration of tacrine (at doses > or = 10 mg/kg) and NIK-247 (30 mg/kg). The antiamnesic dose of physostigmine was 1/30-1/3 of doses with central or peripheral side-effects. The dose ratio of tacrine was 1/30-1; that of NIK-247 was 1/300-1/10. These results indicate that NIK-247 has higher safety and greater selectivity for cognitive functions than physostigmine or tacrine.
Article
To characterize the hepatic effects of tacrine treatment in patients with Alzheimer's disease. Controlled trials of tacrine therapy consisting of two blinded, parallel-group trials; three blinded, enrichment-design trials; and their respective open-label extensions. Multicenter clinical trials in the United States, France, and Canada. A total of 2446 men and women at least 50 years of age with a diagnosis of probable Alzheimer's disease of mild to moderate severity and in good health without significant hepatic, cardiovascular, or renal disease. Administration of tacrine vs placebo, with weekly measurement of serum hepatic enzymes. Incidence, maximum severity, and timing of event for serum alanine aminotransferase (ALT) elevation. Among the 2446 patients who received tacrine in clinical trials, ALT levels greater than the upper limit of normal (ULN) occurred on at least one occasion in 1203 patients (49%), ALT levels greater than three times the ULN occurred in 621 patients (25%), and ALT levels greater than 20 times the ULN occurred in 40 patients (2%). The elevated ALT levels were generally asymptomatic and occurred more frequently in women than men. The mean time from initiation of tacrine treatment to first ALT level greater than three times the ULN was 50 days, and 90% of all initial ALT levels greater than three times the ULN occurred during the first 12 weeks of treatment. Of 145 patients who discontinued tacrine treatment because of an ALT level greater than three times the ULN and were rechallenged, 127 (88%) were able to resume long-term therapy with the drug. In all instances, discontinuing tacrine completely reversed elevations in ALT levels, and no deaths related to hepatotoxicity occurred. These data suggest that the potential for serious hepatic toxicity can be reduced through careful monitoring of ALT levels in patients who may benefit from tacrine therapy.
Article
Age-dependent changes in central nervous system (CNS) cholinergic synaptic transmission were studied in three age groups of Sprague-Dawley and Fischer 344 rats: 1- to 2-month-old, 8- to 10-month-old, and 18- to 23-month-old. Utilizing intracellular recording techniques and the in vitro hippocampal slice preparation, we report an age-related decline in central cholinergic transmission as a function of age. Slow excitatory postsynaptic potentials (slow EPSPs) were reduced approximately 60% in aged (18- to 23-month-old) compared to younger (1- to 2-month-old) animals. The response of the postsynaptic membrane to the muscarinic agonist, carbachol (0.3 microM), was also reduced with age. These changes were not accompanied by a global decline in muscarinic receptor function since two additional measures of cholinergic function were not changed with age. Both presynaptic inhibition of fast excitatory synaptic transmission and postsynaptic inhibition of the afterhyperpolarization (AHP) following a train of spikes were not changed during aging. Our results suggest that a primary functional decline in central cholinergic mechanisms during aging may be a specific reduction in central cholinergic synaptic transmission.
Article
Cognitive deterioration is a characteristic symptom of Alzheimer's disease. This deterioration is notably associated with structural changes and subsequent cell death which occur, primarily, in acetylcholine-producing neurons, progressively damaging cholinergic neurotransmission. We have reported previously that excess acetylcholinesterase (AChE) alters structural features of neuromuscular junctions in transgenic Xenopus tadpoles. However, the potential of cholinergic imbalance to induce progressive decline of memory and learning in mammals has not been explored. To approach the molecular mechanisms underlying the progressive memory deficiencies associated with impaired cholinergic neurotransmission, we created transgenic mice that express human AChE in brain neurons. With enzyme levels up to two-fold higher than in control mice, transgenic mice displayed an age-independent resistance to the hypothermic effects of the AChE inhibitor, paraoxon. In addition to this improved scavenging capacity for anti-AChEs, however, these transgenic mice also resisted muscarinic, nicotinic and serotonergic agonists, indicating that secondary pharmacological changes had occurred. The transgenic mice also developed progressive learning and memory impairments, although their locomotor activities and open-field behaviour remained similar to those of matched control mice. By six months of age, transgenic mice lost their ability to respond to training in a spatial learning water maze test, whereas they performed normally in this test at the age of four weeks. This animal model is therefore suitable for investigating the transcriptional changes associated with cognitive deterioration and for testing drugs that may attenuate progressive damage. We conclude that upsetting cholinergic balance may by itself cause progressive memory decline in mammals, suggesting that congenital and/or acquired changes in this vulnerable balance may contribute to the physiopathology of Alzheimer's disease.
Article
This study evaluated the efficacy and safety of donepezil in patients with mild to moderately severe Alzheimer's disease, and examined the relationships between plasma donepezil concentration, red blood cell acetylcholinesterase (AChE) activity and clinical response. The trial was of a multicenter, double-blind, parallel-group design and patients were randomised to once-daily treatment with either donepezil (1, 3 or 5 mg) or placebo. The 12-week double-blind phase was followed by a 2-week single-blind placebo washout. 161 patients (55-85 years of age) entered the study and 141 completed treatment. Patients treated with donepezil showed dose-related improvements in the Alzheimer's Disease Assessment Scale-cognitive subscale score (ADAS-cog) and in MMSF scores. The improvements in ADAS-cog were statistically significantly greater with donepezil 5 mg/day than with placebo. There was a 50% reduction in the percentage of patients showing clinical decline with donepezil at 5 mg/day (11%) relative to placebo (20%). In addition, a statistically significant correlation between plasma concentrations of donepezil and AChE inhibition was demonstrated. A plateau of inhibition (76-84%) was reached at plasma donepezil concentrations > 50 ng/ml. The correlation between plasma drug concentrations and ADAS-cog (p = 0.014), MMSE (p = 0.023) and patient quality of life scores, assessed by the patient (p = 0.037) were also statistically significant, as was the correlation between AChE inhibition and change in ADAS-cog (p = 0.008). The incidence of treatment-emergent adverse events with all three dosages of donepezil (64-68%) was comparable to that observed with placebo (65%). Donepezil had no clinically significant effect on vital signs, haematology or clinical biochemistry tests. Importantly, donepezil was not associated with any hepatotoxicity, as observed with acridine-based cholinesterase inhibitors.
Article
To find a new compound with antiamnesic activity, we screened 29 natural products for their abilities to inhibit acetylcholinesterase and reverse scopolamine-induced amnesia. Among the plants tested Evodia rutaecarpa Bentham showed a strong inhibitory effect on acetylcholinesterase in vitro and an anti-amnesic effect in vivo. By sequential fractionation of E. rutaecarpa, the active component was finally identified as dehydroevodiamine hydrochloride (DHED). DHED inhibited acetylcholinesterase activity in a dose-dependent and non-competitive manner. The IC50 value of DHED is 37.8 microM. A single administration of DHED to rats (6.25 mg/kg) significantly reversed the scopolamine-induced memory impairment in a passive avoidance test. The antiamnesic effect of DHED was more potent than that of tacrine which is the only drug for Alzheimer's disease approved by FDA. This potent antiamnesic effect of DHED was thought to be due to the combined effects of acetylcholinesterase inhibition and the known cerebral blood flow enhancement. These results indicate that DHED has novel anti-cholinesterase and antiamnesic activities and might have therapeutic potential in various disorders including Alzheimer's disease.
Article
During ageing, basal forebrain cholinergic neurons are prone to degeneration for unknown reasons. In this study we morphometrically evaluated the retrograde labelling of basal forebrain neurons obtained after injection of FluoroGold into multiple sites in the cerebral neocortex in aged (24–33 months) as compared with young adult (four to six months) male Sprague–Dawley rats. In addition, we looked for differences in the distribution of degenerative changes in topographic subdivisions of the basal forebrain cholinergic complex of neurons identified by immunohistochemical detection of the cholinergic markers choline acetyltransferase or low-affinity neurotrophin receptor. After injection of FluoroGold into the cerebral neocortex, the number of retrogradely labelled neurons in the horizontal diagonal band/substantia innominata and basal nucleus was significantly lower in aged rats, by 41% and 48%, respectively. In aged rats injected with FluoroGold, as well as in non-injected aged rats, the numbers of neurons immunoreactive for choline acetyltransferase and low-affinity neurotrophin receptor were significantly lower, by 23–27% in the basal forebrain system as a whole, with no significant difference in the degree of decline amongst different subdivisions (i.e. medial septum, diagonal band, substantia innominata and basal nucleus). The ratios of the number of neurons labelled with Fluoro Gold as compared with the number of neurons immunoreactive for either cholinergic marker were significantly lower in aged rats, by 32–37%, indicating that the decline in the number of neurons retrogradely transporting tracer was greater than the decline in the number of immunoreactive neurons in aged animals. Immunoreactive as well as retrogradely labelled neurons showed a significant shrinkage of cell surface area of 6–13% in different subdivisions of the basal forebrain cholinergic system in aged rats.
Article
This chapter focuses on the cholinergic drug resistance and impaired spatial learning in transgenic mice overexpressing human brain acetylcholinesterase. Appropriate functioning of the cholinergic synapse requires a precise balance of its elements. Important contributors toward this balance are the acetylcholine (ACh) synthesizing enzyme choline acetyltransferase, the hydrolyzing enzyme acetylcholinesterase (AChE), and ACh receptors. Balanced cholinergic neurotransmission is disrupted in several pathological situations. Expression of human AChE under control of the authentic human promoter and first intron is observed in central nervous system neurons of transgenic mice. This expression changed responses to hypothermia-inducing drugs acting on cholinergic and probably serotonergic receptors. In addition, it created a progressive spatial learning and memory impairment. In contrast, the open field behavior of these transgenic animals remained normal. These findings suggest that subtle alterations in the cholinergic balance may cause physiologically observable changes and contribute by itself to the memory deterioration in at least a part of the patients with cholinergic deficits.
Article
The effects of huperzine A on memory impairments induced by scopolamine were evaluated using a radial maze task and inhibition of cholinesterase in vitro compared with the effects of E2020 and tacrine. Scopolamine (0.2 mg kg-1) significantly impaired spatial memory in rats. Huperzine A (0.1-0.4 mg kg-1, p.o.), E2020 (0.5-1.0 mg kg-1, p.o.) and tacrine (1.0-2.0 mg kg-1, p.o.) could reverse these scopolamine-induced memory deficits. The ratios of huperzine A, E2020 and tacrine for butyrylcholinesterase:acetylcholinesterase determined by a colourimetric method were 884.57, 489.05, and 0.80, respectively. The results demonstrated that huperzine A was the most selective acetylcholinterase inhibitor, and improved the working memory deficit induced by scopolamine significantly better than did E2020 or tacrine, suggesting it may be a promising agent for clinical therapy of cognitive impairment in patients with Alzheimer's Disease.
Article
A variety of neuropsychiatric symptoms occur in Alzheimer's disease (AD) including agitation, psychosis, depression, apathy, disinhibition, anxiety, purposeless behavior, and disorders of sleep and appetite. Neuropsychiatric symptoms have been related to cholinergic deficiency and improve after treatment with cholinomimetic agents. Cholinergic drugs are unique among psychotropic agents in exerting disease-specific and broad-spectrum effects. These observations provide the basis for the cholinergic hypothesis of the neuropsychiatric symptoms of AD, suggesting that the cholinergic deficit of AD contributes to the neuropsychiatric symptoms of AD and that cholinomimetic therapy ameliorates the behavioral disturbances accompanying AD.
Article
Comparative effects of cholinesterase inhibitors (ChEI) huperzine A with E2020 and tacrine on the radial maze performance in ethylcholine mustard aziridinium ion (AF64A)-treated rat and inhibition of cholinesterase activity were studied. The intracerebroventricular (i.c.v.) injection of AF64A (3 nmol/side) caused significant impairment in the rat's ability to fulfill the partially baited maze paradigm. Oral huperzine A (0.5-0.8 mg/kg), E2020 (1.0-2.0 mg/kg), and tacrine (8.0 mg/kg) effectively reversed AF64A-induced working memory deficit. The doses that improved AF64A-induced memory deficit were correlated to about 25-30% (huperzine A) and less than 10% (E2020, tacrine) inhibition of acetylcholinesterase (AChE) activity in the cortex and hippocampus. Huperzine A, E2020 and tacrine all produced dose-dependent inhibition of brain AChE following i.c.v. and oral administration. Oral huperzine A exhibited higher efficacy on the inhibition of AChE in the cortex and hippocampus than those of E2020 and tacrine. Tacrine was more effective in inhibiting plasma butyrylcholinesterase (BuChE) than it was brain AChE. Conversely, the BuChE activity was less affected by huperzine A and E2020. The results showed that huperzine A had high bioavailability and more selective inhibition on AChE activity in cortex and hippocampus. Huperzine A fits more closely with the established criteria for an ideal AChE inhibitor to be used in clinical studies.
Article
Cholinesterase inhibitors are currently the most established treatment strategy in Alzheimer's disease. The treatment effect appears mainly to be symptomatic. Effects on progression of the disease following long term treatment, and possible neuroprotective effects, have been investigated. Delay until nursing home placement has been reported. Three cholinesterase inhibitors, tacrine, donepezil and rivastigmine, are in clinical use. Other cholinesterase inhibitors, such as galantamine (galanthamine), metrifonate, physostigmine, eptastigmine, are currently under clinical evaluation. So far the efficacy appears to be comparable between the various cholinesterase inhibitors; treatment for up to 6 months has produced an improvement in Alzheimer's Disease Assessment Scale -- Cognitive Subscale score (ADAS-cog) of between 1.8 and 4.9 in patients with Alzheimer's disease. Tacrine, donepezil, galantamine and physostigmine are reversible inhibitors of acetylcholinesterase and butyrylcholinesterase, while metrifonate is considered to be an irreversible inhibitor and rivastigmine a pseudoirreversible inhibitor. Tacrine and physostigmine have lower bioavailability, 17 to 37% and 3 to 8%, respectively, than the other cholinesterase inhibitors such as rivastigmine, galantamine and donepezil (40 to 100%). The elimination half-life is considerably longer for donepezil (70 to 80h) in comparison to most of the other cholinesterase inhibitors (0.3 to 12h). Donepezil is therefore administered once daily in comparison to rivastigmine which is administered twice daily and tacrine which is administered 4 times daily. Simultaneous food intake lowers the plasma concentration of tacrine and reduces the adverse effects of rivastigmine. Drugs like theophylline and cimetidine have been reported to change the pharmacokinetics of tacrine and donepezil. In contrast, concomitant medication with various drugs with rivastigmine does not seem to cause any drug interactions in patients with Alzheimer's disease. Tacrine, donepezil and galantamine are metabolised via the cytochrome P450 (CYP) liver enzymes. Active metabolites are known for tacrine and galantamine. Rivastigmine is not metabolised via CYP enzymes, but via esterases and is excreted in the urine. Tacrine is associated with hepatotoxicity while other cholinesterase inhibitors seem devoid this adverse effect. Increased liver enzyme values have been observed in 49% of patients with Alzheimer's disease treated with tacrine. Rechallenge with tacrine reduces the incidence of elevated liver enzyme levels. Peripheral cholinergic adverse effects are common for the cholinesterase inhibitors, with an incidence ranging between 7 to 30%. For some cholinesterase inhibitors, such as rivastigmine, the cholinergic adverse effects such as nausea, vomiting, dizziness, diarrhoea and abdominal pain can be reduced by slowing the rate of dose titration.
Article
The in vitro and in vivo effects of the novel acetylcholinesterase inhibitors donepezil and NXX-066 have been compared to tacrine. Using purified acetylcholinesterase from electric eel both tacrine and donepezil were shown to be reversible mixed type inhibitors, binding to a similar site on the enzyme. In contrast, NXX-066 was an irreversible non-competitive inhibitor. All three compounds were potent inhibitors of rat brain acetylcholinesterase (IC50 [nM]; tacrine: 125 +/- 23; NXX-066: 148 +/- 15; donepezil: 33 +/- 12). Tacrine was also a potent butyrylcholinesterase inhibitor. Donepezil and tacrine displaced [3H]pirenzepine binding in rat brain homogenates (IC50 values [microM]; tacrine: 0.7; donepezil: 0.5) but NXX-066 was around 80 times less potent at this M1-muscarinic site. Studies of carbachol stimulated increases in [Ca2+]i in neuroblastoma cells demonstrated that both donepezil and tacrine were M1 antagonists. Ligand binding suggested little activity of likely pharmacological significance with any of the drugs at other neurotransmitter sites. Intraperitoneal administration of the compounds to rats produced dose dependent increases in salivation and tremor (ED50 [micromol/kg]; tacrine: 15, NXX-066: 35, donepezil: 6) with NXX-066 having the most sustained effect on tremor. Following oral administration, NXX-066 had the slowest onset but the greatest duration of action. The relative potency also changed, tacrine having low potency (ED50 [micromol/kg]; tacrine: 200, NXX-066: 30, donepezil: 50). Salivation was severe only in tacrine treated animals. Using in vivo microdialysis in cerebral cortex, both NXX-066 and tacrine were found to produce a marked (at least 30-fold) increase in extracellular acetylcholine which remained elevated for more than 2 h after tacrine and 4 h after NXX-066.
Article
Alzheimer's disease is associated with a specific pattern of pathological changes in the brain that result in neurodegeneration and the progressive development of dementia. Pathological hallmarks common to the disease include beta-amyloid plaques, dystrophic neurites associated with plaques and neurofibrillary tangles within nerve cell bodies. The exact relationship between these pathological features has been elusive, although it is clear that beta-amyloid plaques precede neurofibrillary tangles in neocortical areas. Examination of the brains of individuals in the preclinical stage of the disease have shown that the earliest form of neuronal pathology associated with beta-amyloid plaques resembles the cellular changes that follow structural injury to axons. Thus, the development of beta-amyloid plaques in the brain may cause physical damage to axons, and the abnormally prolonged stimulation of the neuronal response to this kind of injury ultimately results in the profound cytoskeletal alterations that underlie neurofibrillary pathology and neurodegeneration. Therapeutically, inhibition of the neuronal reaction to physical trauma may be a useful neuroprotective strategy in the earliest stages of Alzheimer's disease.
Article
N-tert-butyl-alpha-phenylnitrone (PBN), a widely used nitrone-based free radical trap was recently shown to prevent acetylcholinesterase (AChE) inhibitors induced muscle fasciculations and brain seizures while being ineffective against glutamergic or cholinergic receptor agonist induced seizures. In the present study we compared the effects on AChE activity of four free radical spin traps PBN, alpha-(4-pyridil-1)-N-tert-butyl nitrone (POBN), N-tert-butyl-alpha-(2-sulfophenyl)-nitrone (S-PBN) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO). The kinetics of AChE inhibition were studied in vitro using a spectrophotometric kinetic assay with AChE from rat brain, diaphragm, electric eel and mouse brain. Spin trapping compounds S-PBN and DEPMPO, in concentrations up to 3 mM did not inhibit hydrolysis of ACh, while PBN and POBN inhibited hydrolysis of ACh in a reversible and concentration-dependent manner. Double reciprocal plots of the reaction velocity against varying ACh concentrations at each inhibitor concentration were linear and generally indicated mixed type inhibition. PBN was the most potent inhibitor of mouse AChE with Ki and Ki' of 0.58 and 2.99 mM, respectively, and the weakest inhibitor of electric eel AChE. In contrast, POBN showed the highest affinity for electric eel enzyme, with Ki and Ki' values of 1.065 and 3.15 mM, respectively. These findings suggest that the effect of PBN and POBN on AChE activity does not depend on trapping of damaging reactive oxygen and that in addition to their antioxidant action other pharmacological effects of these compounds should be considered when neuroprotective actions of PBN or POBN are investigated.
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Siqueira IR, Fochesatto C, Torres ILS, da Silva AL, Nunes DS, Elisabetsky E, Netto CA. Antioxidant activities of the ethanol extract from Ptycho-petalum olacoides in mice brain. Pharmacol Biochem Behav 2003 [sub-mitted for publication]. Snape MF, Misra A, Murray TK, de Souza RJ, Williams JL, Cross AJ, et al. A comparative study in rats of the in vitro and in vivo pharmacology of I.R. Siqueira et al. / Pharmacology, Biochemistry and Behavior 75 (2003) 645–650 the acetylcolinesterase inhibitors tacrine, donepezil and NXX-066. Neu-ropharmacology 1999;38:181 – 93.
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Facilitating effects of Ptychopetalum olacoides Bentham (Marapuama) on memory retrieval in young and old mice Reduced retrograde labelling with fluorescent tracer accompanies neu-ronal atrophy of basal forebrain cholinergic neurons in aged rats
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da Silva AL, Bardini S, Netto CA, Nunes DS, Elisabetsky E. Facilitating effects of Ptychopetalum olacoides Bentham (Marapuama) on memory retrieval in young and old mice. Braz J Med Biol Res 2002b [submitted for publication]. De Lacalle S, Cooper JD, Svendsen CN, Dunnett SB, Sofroniew MV. Reduced retrograde labelling with fluorescent tracer accompanies neu-ronal atrophy of basal forebrain cholinergic neurons in aged rats. Neuro-science 1996;75:19 – 27.
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AChE activity over a range of substrate concentrations (50 to 250 mM) from striatum samples, in the absence or presence of POEE
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Lineweaver – Burk plots of AChE activity over a range of substrate concentrations (50 to 250 mM) from striatum samples, in the absence or presence of POEE (125, 190 and 250 mg/ml).
Facilitating effects of Ptychopetalum olacoides Bentham (Marapuama) on memory retrieval in young and old mice
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Pharmacopées traditionnelles en Guyane. Editions de L'Orstom