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Memory retrieval improvement by Ptychopetalum olacoides in young and aging mice
Abstract
Amazonian peoples use traditional remedies prepared with Ptychopetalum olacoides (PO) roots for treating various age-related conditions. This study shows that a single intraperitoneally (i.p.) administration of Ptychopetalum olacoides ethanol extract (POEE, 50 and 100mg/kg) improved memory retrieval in step-down inhibitory avoidance (P <or= 0.05 and P <or= 0.01, test session latency 102 [19.38-300] and 192 [91.3-300]s, respectively versus control 24.7 [12.9-89.6]), without interfering with acquisition or consolidation in adult (2.5-month-old) mice. Comparable results were obtained with POEE given p.o. at 800 and 1000mg/kg (P <or= 0.05 and P <or= 0.01, 52.7 [19.5-297.2] and 85.7 [44.4-260.4] versus control 20.5 [8-92.6]). Moreover, memory amelioration was also observed (P <or= 0.01) in aging (14 months) mice presenting memory deficit (14.95 [10.8-41]) as compared to adult (2.5 months) mice (57 [15.7-141.2]), with the extract given acutely i.p. 100 mg/kg (300 [133.1-300] versus control 14.95 [10.8-41]) or p.o. 800 mg/kg (28.4 [15.1-84.6] versus control 11.5 [7.8-23.3]). Indeed, aging mice treated with POEE (800 mg/kg, p.o.) performed as well as adult mice. Consistently with its traditional use, the data suggest that POEE facilitates memory retrieval. Although the antioxidant and acetylcholinesterase inhibitory properties previously described for this extract may be of relevance, the molecular mechanism(s) underlying the improvement in memory retrieval here reported merit further scrutiny.
... 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). Considering the different nature and composition of LTM and STM, aversive and non-aversive motivated memories, the purpose of this study was to advance the knowledge of the memory facilitating properties of POEE. ...
... The first purpose of this study was to complement our previously reported POEE facilitating effects on long-term memory retrieval (step-down inhibitory avoidance paradigm) (da Silva et al., 2004), by now examining the effects of the same extract on short-term memory in adult and aging mice. Results clearly show that POEE improves acquisition, consolidation, and retrieval of step down STM in adult mice, and reverses the retrieval deficit in aging mice. ...
... Since the pharmacokinetic of the extract is not known, an alternative interpretation of the data is that POEE treatment before training could have an effect on the early STM consolidation processes, whereas POEE treatment after training could affect consolidation but also STM retrieval processes. These results add to, and are consistent with, those previously reported (da Silva et al., 2004); however, while POEE equally influences the three memory phases in STM, it only affects LTM retrieval. While some drugs equally influence STM and LTM (e.g., scopolamine, CNQX, AP5, MCPG, muscimol), others either affect STM but not LTM (e.g., intrahippocampal SCH23390, SKF 38393, 8-OH-DPAT) or LTM but not STM (e.g., norepinephrine) (Izquierdo et al., 1998b; Vianna et al., 2000b; Schroder et al., 2003). ...
... Ptychopetalum olacoides Bentham (Olacaceae), known as Marapuama, is a medicinal plant favored by the elderly in Amazonian commu-nities (Elisabetsky and Siqueira 1998). Coherent with users' claims, this research group has established promnesic (da Silva et al. 2004 Silva et al. , 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. ...
... Therefore, although traditional claims for Marapuama-based formulas and the above mentioned data on experimental models of memory and depression constitute evidence of CNS effects, the purpose of this study was to provide conclusive data on POEE-induced AChE inhibition in brain areas relevant to cognition . Histochemical and biochemical assessments were chosen to verify the effects of orally given POEE in a dose found to ameliorate several memory types (da) and reverse age-, scopolamine-and MK801-induced amnesias (da Silva et al. 2004 Silva et al. , 2009 ) in mice. In addition, western blotting analysis was performed to verify if the AChE inhibition is associated with enzyme loss. ...
... The main contribution of this study is the conclusive proof that the anticholinesterase compound(s) present in a POEE dose that facilitates memory (da Silva et al. 2004 Silva et al. , 2008) and reverses amnesias (da Silva et al. 2009) is (are) orally effective and crosses the BBB, leading to significant AChE inhibition in cognition-relevant brain areas. 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 (Ruge and Bruder 2008). ...
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.
... 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. ...
... Additional doses, although desirable, were precluded due to the limited amount of the very same batch of extract with which the anti-amnesic effects (aging, MK-801 and scopolamine; da Silva et al., 2004Silva et al., , 2009) had been characterized. ...
... Furthermore, considering the relatively short period of treatment our results are particularly promising. 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). ...
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.
... We reported that P. olacoides standardized ethanol extract (POEE), a standardized ethanol extract obtained from P. olacoides, possesses various CNS-relevant properties, including antioxidant (Siqueira et al. 2007) and neuroprotective (Siqueira et al. 2004) activities. Regarding cognition, we showed that POEE facilitates short-term and long-term memories (inhibitory avoidance and object recognition) in adult and aged mice (da Silva et al. 2004). As a likely neurochemical correlate of POEE promnesic effects, we also reported in vitro and in vivo acetylcholinesterase inhibition for the same extract (Siqueira et al. 2003Siqueira et al. , 2007). ...
... The experiment with non-shocked animals corroborates the finding that POEE promnesic effects are not related to unspecific effects on behavior, since non-shocked animals do not exhibit increased test latencies. Based on the previously reported dose–response (10–100 mg/kg) analysis (da Silva et al. 2004), two effective doses of 50 and 100 mg/kg were selected for the present study. The chief finding of this study is that POEE reverses scop-induced amnesia, for both short-and long-term memories, in all memory phases (acquisition, consolidation, and retrieval). ...
... In fact, it suggests that POEE may induce plastic changes that positively affect the status of the memory circuit, although the chronic nature of the experiment prevents differentiating memory phases. Considering the reversal of memory deficits in 14-month-old mice (da Silva et al. 2004), and the antioxidant and neuroprotective effects previously identified for this extract, a multifaceted manysided overall effect seems to be in place. This study shows that POEE can reverse scop-and MK- 801-induced memory deficits in mice. ...
Traditional remedies prepared from Ptychopetalum olacoides (PO) are used throughout the Amazon to alleviate age-related conditions. These formulas are mainly used by elders, and alleged effects may be related to the anticholinesterase properties identified in a standardized ethanol extract of this species [P. olacoides standardized ethanol extract (POEE)].
To further characterize the potential of this extract for developing drugs useful to treat cognitive deficits, the effects of POEE on scopolamine (scop)- and MK801-induced amnesias (acquisition, consolidation, and retrieval) in mice were investigated.
Scop (3.0 mg/kg, ip) significantly impaired memory (all three phases) in the step-down inhibitory avoidance protocol. As expected, MK801 (0.1 mg/kg, ip) was amnesic regarding acquisition and consolidation, but not retrieval. POEE (100 mg/kg, ip) reversed the scop-induced impairment in all three phases of long-term and short memories, whereas only the memory consolidation deficit was reversed with MK801-induced amnesia.
This study complements previously reported promnesic properties of this plant extract and suggests that POEE may be further developed for treating conditions associated with cognitive deficits, especially those linked with cholinergic malfunction.
... 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). Considering the different nature and composition of LTM and STM, aversive and non-aversive motivated memories, the purpose of this study was to advance the knowledge of the memory facilitating properties of POEE. ...
... The first purpose of this study was to complement our previously reported POEE facilitating effects on long-term memory retrieval (step-down inhibitory avoidance paradigm) (da Silva et al., 2004), by now examining the effects of the same extract on short-term memory in adult and aging mice. Results clearly show that POEE improves acquisition, consolidation, and retrieval of step down STM in adult mice, and reverses the retrieval deficit in aging mice. ...
... Since the pharmacokinetic of the extract is not known, an alternative interpretation of the data is that POEE treatment before training could have an effect on the early STM consolidation processes, whereas POEE treatment after training could affect consolidation but also STM retrieval processes. These results add to, and are consistent with, those previously reported (da Silva et al., 2004); however, while POEE equally influences the three memory phases in STM, it only affects LTM retrieval. While some drugs equally influence STM and LTM (e.g., scopolamine, CNQX, AP5, MCPG, muscimol), others either affect STM but not LTM (e.g., intrahippocampal SCH23390, SKF 38393, 8-OH-DPAT) or LTM but not STM (e.g., norepinephrine) (Izquierdo et al., 1998b; Vianna et al., 2000b; Schroder et al., 2003). ...
Homemade remedies with Ptychopetalum olacoides (PO) roots are used by Amazonian peoples for treating various age-related conditions. We previously reported that Ptychopetalum olacoides ethanol extract significantly improved step-down inhibitory avoidance long-term memory in adult and reversed memory deficits in aging mice. Adding to previous data, this study shows that a single i.p. administration of Ptychopetalum olacoides ethanol extract (POEE 50 and 100 mg/kg) improved step-down inhibitory avoidance short-term memory (STM) 3 h after training in adult (2.5 month) mice; comparable results were obtained with POEE given p.o. at 800 mg/kg. Moreover, memory improvement was also observed in aging (14 months) mice presenting memory deficit as compared to adult mice. Furthermore, POEE (100 mg/kg) improved non-aversive memory systems in adult mice in an object recognition paradigm. Consistently with its traditional use this study add to previously reported data and reinforces that POEE facilitates memory processes. Although the acetylcholinesterase inhibitory properties described for this extract may be of relevance for improving memory processes, the molecular mechanism(s) underlying the memory improvement here reported needs further scrutiny.
... Marapuama-based remedies are employed for various conditions, including facilitating recovery from stroke, and keeping up with highly stressful psychological and/or physical circumstances [28]. A standardized ethanol extract obtained from P. olacoides (POEE) roots possesses nootropic [29], antioxidant [30,31], and neuroprotective [32] properties. The pharmacodynamic basis of POEE facilitatory effects on diverse memory types [29] includes anticholinesterase actions [33], and the involvement of dopamine D 1 and β adrenergic receptors unpublished data. ...
... A standardized ethanol extract obtained from P. olacoides (POEE) roots possesses nootropic [29], antioxidant [30,31], and neuroprotective [32] properties. The pharmacodynamic basis of POEE facilitatory effects on diverse memory types [29] includes anticholinesterase actions [33], and the involvement of dopamine D 1 and β adrenergic receptors unpublished data. ...
... Significant and consistent differences (P b 0.05) between training and test sessions were observed in all control groups, confirming memory in this paradigm. In agreement with previously reported data [29] POEE (100 mg/kg) improved (P b 0.05) acquisition ( Fig. 2A), consolidation (Fig. 2B), and retrieval (Fig. 2C) for short-term memory, as well as retrieval ( Fig. 1A and B) for long-term memory. Fig. 1 displays the effects of 5-HT antagonists on POEE-induced enhancement of LTM retrieval. ...
Nootropic, antioxidant, and neuroprotective properties have been shown in a standardized ethanol extract of Ptychopetalum olacoides (POEE), a medicinal plant traditionally used by the Amazonian elderly population. It has been revealed that POEE mechanisms of action include anticholinesterase effects, and involve beta-adrenergic and dopamine D(1) receptors. The purpose of this study was to verify the role of serotonin receptors in the promnesic effects of this standardized extract. The step-down task in mice and selective serotonin antagonists were used. The study reveals that POEE promnesic effects on short-term (acquisition, consolidation and retrieval) and long-term (retrieval) declarative aversive memories are increased by 5HT(2A) (but not 5HT(1A)) serotonin antagonists (spiperone and pindolol, respectively). The observed synergism between POEE and spiperone can be interpreted as the combined effects of two subeffective doses of two 5HT antagonists, or the known synergism between an acetylcholinesterase inhibitor (POEE) and a 5HT antagonist. In conclusion it is suggested that 5HT(2A) serotonin receptors are relevant for the promnesic effects of this extract, adding to its multiple mechanisms of action.
... In this study, we also observed that these behavioural deficits were considerably reversed with Muira puama. Several studies have reported the ability of MP to ameliorate central nervous system disorders like anxiety, memory loss, depression and neuronal injury [22,23,24]. These effects have been linked to its ability to inhibit acetylcholinesterase, enhance antioxidant capacity, and modulate neurotransmitters [22,23,24]. ...
... Several studies have reported the ability of MP to ameliorate central nervous system disorders like anxiety, memory loss, depression and neuronal injury [22,23,24]. These effects have been linked to its ability to inhibit acetylcholinesterase, enhance antioxidant capacity, and modulate neurotransmitters [22,23,24]. The antioxidant properties of Muira puama which were also observed in this study have been previously reported. ...
Muira puama is a plant renowned for its potent antioxidant and neuroprotective properties. The effects of ethanol extract of Muira puama on aluminium chloride-induced changes in rat behaviour and cerebral cortex histomorphology was examined in this study. Fifty male rats weighing 120-150 g each were divided into six groups: control (normal saline), Muira puama extract groups (25 mg/kg and 50 mg/kg), AlCl3 group (100 mg/kg), and AlCl3 combined with Muira puama extract groups (25 mg/kg and 50 mg/kg respectively). All treatments were administered orally for 21 days. Behaviours were assessed after the final dose of treatment. The result showed that the administration of AlCl3 was associated with decreased weight gain, behavioural alterations, and spatial working memory deficits. However, co-treatment with Muira puama was associated with increased food intake, reversal of weight loss, enhanced locomotion/self-grooming, and reduction of anxiety. Additionally, spatial working memory scores were significantly improved with Muira puama. Biochemical analysis showed reduced levels of malondialdehyde and tumour necrosis factor-alpha, and increased levels of interleukin 10 and total antioxidant capacity. Histological examination revealed neuronal preservation with Muira puama, suggesting protective effects on the cerebral cortex. These findings suggest that Muira puama extract has the ability to mitigate aluminium chloride-induced changes in rats. However, more studies would be needed to determine its suitability for use in humans.
... 3 Previous pharmacological studies have shown that the EtOH extract of P olacoides produces a series of beneficial effects on the central nervous system, consisting of neuroprotective, anti-stress, antidepressant, antioxidative, adaptogen-like activities, and inhibitory effects on acetylcholinesterase in mice. [4][5][6][7][8][9][10] As part of our ongoing research for natural products with neurotrophic activities, we have continued to investigate phytochemical constituents of the MeOH extract of the bark of P olacoides, which exhibits neurite outgrowthpromoting activity in NGF-mediated PC12 cells. [11][12][13] Further research of this plant led to the isolation of 4 new clerodane-type diterpenoids, named ptycholide V (1), 7α,20-dihydroxykolavelool (2), ptycholide VI (3), and ptycholide VII (4) (Figure 1). ...
... The extraction procedure has been reported previously. 13 The extract was separated by CC on silica gel using a linear gradient solvent system (100% n-hexane to 100% EtOAc) to give 15 fractions (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) Screening for Neurite Outgrowth-Promoting Activity PC12 (phenochromocytoma) cells were cultured in a 24-well plate at density of 8 × 10 3 cells/mL in DMEM + 10% HS, 5% FBS, 100 IU/mL penicillin, and 100 μg/mL streptomycin at 37°C under a humidified atmosphere of 95% air and 5% CO 2 for 24 h. The culture medium was then changed to DMEM + 2% HS, 1% FBS, 100 IU/mL penicillin, and 100 μg/mL streptomycin. ...
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.
... 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). ...
... Swiss albino male adult mice (CF1 strain), 14 months of age, housed with access to food and water ad libitum, and light-dark cycles of 12 h, were used. DMSO 20% or POEE 100 mg/kg body wt. were administered intraperitoneally (0.1 ml/10 g body wt.); this dose was chosen because it proved to lessen the cognitive deficit of aging animals in an inhibitory avoidance task (da Silva et al., 2004). Preparation of brain samples. ...
... 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. ...
... Swiss albino male adult mice (CF1 strain), 14 months of age, housed with access to food and water ad libitum, and light-dark cycles of 12 h, were used. DMSO 20% or POEE 100 mg/kg body wt. were administered intraperitoneally (0.1 ml/10 g body wt.); this dose was chosen because it proved to lessen the cognitive deficit of aging animals in an inhibitory avoidance task (da Silva et al., 2004). ...
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.
... We have previously reported that a specific ethanol extract (POEE) of PO roots possesses various central nervous system (CNS) activities , 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(da 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. ...
... Swiss albino male adult mice (CF1 strain), 14 months of age, housed with access to food and water ad libitum, and light-dark cycles of 12 h, were used. DMSO 20% or POEE 100 mg/kg body wt. were administered intraperitoneally (0.1 ml/10 g body wt.); this dose was chosen because it proved to lessen the cognitive deficit of aging animals in an inhibitory avoidance task (da Silva et al., 2004). ...
Ptychopetalum olacoides (PO) roots are used by Amazonian peoples to prepare traditional remedies for treating various central nervous system conditions in which free radicals are likely to be implicated. Following the identification of PO ethanol extract (POEE) free-radical scavenging properties in vitro, the aim of this study was to verify the in vivo antioxidant effect of POEE. Aging mice (14 months) were treated (i.p.) with saline, DMSO (20%) or POEE (100mg/kg body wt.), and the hippocampi, cerebral cortex, striata, hypothalamus and cerebellum dissected out 60 min later to measure antioxidant enzyme activities, free-radical production and damage to macromolecules. POEE administration reduced free-radical production in the hypothalamus, lead to significant decrease in lipid peroxidation in the cerebral cortex, striatum and hypothalamus, as well as in the carbonyl content in cerebellum and striatum. In terms of antioxidant enzymes, catalase activity was increased in the cortex, striatum, cerebellum and hippocampus, while glutathione peroxidase activity was increased in the hippocampus. This study suggests that POEE contains compounds able to improve the cellular antioxidant network efficacy in the brain, ultimately reducing the damage caused by oxidative stress.
... Ptychopetalum olacoides, known as marapuama, is a potent antioxidant Amazonian herb that is traditionally used as a brain tonic. It leads to significant memory retrieval improvement in young and aging mice and attenuated the neuroglial degeneration and cognitive impairment in mouse model of AD (da Silva et al., 2004;Figueiró et al., 2011). Banisteriopsis caapi (Malpighiaceae) one of the medical plants in South American traditional medicine showed both antioxidative and MAO inhibitory activities. ...
Neurodegenerative diseases (NDs) refer to a number of chronic progressive neurological disorders due to degradation and dysfunction of neurons. A great promise for the prevention of many NDs, herbal bioactives offer better opportunities than synthetic medical agents. However, given the low solubility and bioavailability, nanoformulation enables controlled release and therapeutic effects of natural products. In this line, the objective of this study is to evaluate the therapeutic effects of natural products and their nanostructures in several types of neurodegenerative in vitro and in vivo models. The neuroprotective potential of a number of plants and their constituents from Ayurveda, Iranian, South American, African, and Chinese medicine has been reported in NDs. Owing to the low blood–brain penetration of natural products, the effectiveness of nanoformulated forms was evaluated in NDs. The cumulative of these observations reveals that nanotechnology-based natural products hold great promise for management and treatment of NDs.
... 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. ...
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.
... Different studies have demonstrated the benefit of treatment with muirapuama on learning and memory in rodents. Acute administration of P. olacoides (50-100 mg/kg, ip or 800-1000 mg/kg, oral) improved the memory retrieval of young and old (14 months) mice in step-down avoidance inhibition test 24 h after training, without interfering with acquisition and consolidation (Da Silva et al. 2004). Further study showed a similar effect for short-term memory, evaluated 3 h after training . ...
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.
... The facilitation of learning followed by retention of learned task in normal individual is becoming an integral part in today's competitive world 12,16 . Screening of laboratory animals for avoidance behavior is a classic method for the assessment of learning and memory processes. ...
In the traditional system of medicine, the dried fruits of Trapa natans L var bispinosa (TB) have been employed clinically for their nutritional and medicinal property like nervine tonic. The effect of hydroalcoholic extract of fruits of Trapa natans L var bispinosa was investigated for its nootropic activity using various experimental paradigms of learning and memory, viz. transfer latency (TL) on elevated plus-maze, passive avoidance response (PAS), scopolamine induced amnesia (SIA) and brain acetylcholineestrase activity in albino mice. The investigation reported that TB 500 mg/kg significantly reduced the TL on 2nd and 9th day while TB 250 mg/kg was found effective on 9th day. TB 250 and 500 mg/kg significantly increased the step down latency in the PAS at acquisition and retention test. The extract also significantly attenuated the amnesic effects of scopolamine on the TL and SDL. The brain AchE levels were not altered with the pretreatment TB. In present investigation TB extract showed significant facilitatory effect on aversively motivated learning and memory in mice. moreover it attenuates the scopolamine induced memory disruption in mice.
... These treatments are often referred to as 'brain tonics'. At least one medicinal plant used as such, Ptychopetalum olacoides Benth (Olaceceae) used in the treatment of 'nerve weakness', was shown to possess memory improving and anti-amnesic effects (da Silva, 2004;da Silva, 2009). ...
During ethnopharmacological surveys, the collection of clinical data, such as patient status and progress after the use of traditional medicines, can help in the study of the effectiveness and safety of local therapeutic practices and products. At the end of an interdisciplinary research process called reverse pharmacology (also known as the ?field-to-pharmacy? or ?bedside-to-bench? approach), this information will help users of traditional medicine to make safer and more effective choices. To gather clinical data successfully, ethnopharmacologists need to be supported by an appropriate team of specialists in medicine and epidemiology. The first step is to understand why a cure is not proof of effectiveness in order to avoid misinterpretation of the clinical observations. Experience has shown that, with the bedside-to-bench approach, a treatment derived from a traditional recipe can be scientifically validated (in terms of safety and effectiveness) with a cost of less than a million euros, providing an end product that is affordable, locally available and sustainable. The end-product can take several forms: a new ?improved? phytomedicine, advice on home treatments for the target illness or a lead for conventional pharmaceutical development. In any case the major aim remains to improve quality of care in the community.
... The mixture of ptychonal hemiacetal and ptychonal isolated from the plant has exhibited neurite outgrowth-promoting properties in NGF-mediated PC12 cells . 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). ...
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
... 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). ...
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.
... Apesar do exato mecanismo através do qual os AACR alteram a memória em ratos ainda ser desconhecido, evidências da literatura mostraram que o estresse oxidativo está associado com o déficit de memória (Bickford et al. 1999;da Silva et al. 2004;Serrano e Klann, 2004), e que a administração dos agentes antioxidantes são alternativas para melhorar tais déficits (Carney et al. 1991;Carrillo et al. 1993;Kontush, 2001;Knoll et al. 1994;Markesbery, 1997;Small, 1998). Vários estudos evidenciam que um possível mecanismo para o prejuízo, idade-dependente, na potenciação de longo prazo (LTP) através da IL-1β e ERO envolve o aumento da c-Jun N-terminal quinase (JNK) e proteínas quinases p38 ativada por mitógeno, e a diminuição no ERK resultante na inibição de liberação de glutamato (Kelly et al. , 2003Lynch, 1998;Martin et al. 2002;McGahon et al. 1999;O'Donnell et al. 2000;Vereker et al. 2000Vereker et al. , 2001. ...
... Some plants described as adaptogens improve the memory of animals in models of avoidance, as in the case of Panax ginseng C.A. Meyer, which prevented memory damage caused by scopolamine, in a model similar to the one in the present study (Hsieh et al., 2000); of Ptychopetalum olacoides Benth. (Da Silva et al., 2004), which improved the recovery of evoked memory of old mice; and ofEvolvulus alsinoides (L.) L., which also prevented the deficit caused by scopolamine in rats (Siripurapu et al., 2005). In the present study, the administration of the hydroalcoholic extract of TD at the doses of 100 and 500 mg/kg for 43 days did not inhibit the deficit induced by scopolamine, indicating that the extract might not have a cholinergic effect. ...
The objective of the present study was to assess whether Turnera diffusa Willd. ex Schult., Turneraceae, (TD), plant known in popular medicine as tonic and aphrodisiac, has other effects that are characteristic of an adaptogen substance, such as improvement of the memory and reduction of the damage caused by stress. We carried out an initial screening to detect a possible toxicity of the plant. In that phase of the study we used tests of observational screening; evaluation of acute toxicity; measurement of motor activity and motor coordination, and sleeping time induced by pentobarbital, and observed that the extract presented low toxicity and no stimulant or depressant effect on the animals. We then performed specifi c tests for the evaluation of an adaptogen effect. TD did not protect the stomach of the animals from the formation of ulcers, neither did it alter the plasmatic levels of adrenocorticotropic hormone (ACTH) and corticosterone of the animals submitted to immobilization and cold. As regards the evaluation of memory in passive avoidance, TD did not inhibit scopolamine-induced amnesia. Additionally, the hydroalcoholic extract presented low antioxidant activity in vitro. In the models used, TD produced no changes in relation to a possible adaptogen effect.
... The formula is usually drunk daily before meals, an usual dose roughly equivalent to 60 ml of a ''garrafada''. We have shown that a standardized ethanol extract of P. olacoides (POEE) is promnesic (da Silva et al. 2004) counteracts several types of amnesia (da Silva et al. 2008), and has neuroprotective (Siqueira et al. 2004), antioxidant (Siqueira et al. 2007), and antidepressant properties (Piato et al. 2008Piato et al. , 2009). Given the traditional uses of PO, the antidepressant effects identified for POEE, and the relationship between stress and depression (Sapolsky et al. 2000), the present study aimed to evaluate whether POEE counteracts stress-induced effects. ...
... The date of appearance of coat, eruption of upper incisors, eye opening and weight gain were recorded using previously reported criteria (da Silva et al., 2004;Mello et al., 1994) described in detail by Smart and Dobbing (1971). None of the interventions above interfered significantly with the adult animals' general normal behavior (e.g. ...
Aims:
The establishment of a genetic knockout murine model of glutaric acidemia type I (GAI) with complete loss of glutaryl-CoA dehydrogenase (GCDH) activity has been used to investigate the pathological mechanisms underlying neurological symptoms in this disorder. However, very little has been reported on the neurobehavior of GCDH deficient mice (Gcdh(-/-)).
Main methods:
In the present study we evaluated physical (body and weight gain) and neuromotor development (appearance of coat, upper incisor eruption, eye-opening day, motor coordination, muscular strength and climbing), as well as cognitive behavior (inhibitory avoidance) in Gcdh(-/-), as compared to wild type (WT) mice.
Key findings:
We found that Gcdh(-/-) mice did not differ in body and weight gain, appearance of coat, upper incisor eruption, motor coordination and muscular strength, but had a significant delayed eye opening, implying a mild impairment of neurodevelopment in these animals. Furthermore, the climbing behavior was significantly higher in Gcdh(-/-) as compared to WT mice, suggesting an altered dopaminergic function. Finally, Gcdh(-/-) mice presented a deficit of short- and long-term memories in the inhibitory avoidance task.
Significance:
Although it is difficult to extrapolate the present findings to the human condition, our present data are particularly interesting in view of the psychomotor/mental delay that occurs in a significant number of GAI patients with no previous history of acute encephalopathy with striatum destruction. Strict and early treatment possibly associated with novel therapies seems therefore important to prevent learning/memory disabilities in GAI patients.
... Although the exact mechanism through which BCAA alters memory in rats is still unknown, evidence from literature showed that oxidative stress is associated with memory deficits [45][46][47] and administration of antioxidant agents has been shown to improve such deficits [48][49][50][51][52][53]. It is known that metabolites accumulating in MSUD induce oxidative stress [13][14][15][16][17]. ...
Maple syrup urine disease (MSUD) is an autosomal recessive metabolic disorder resulting from deficiency of branched-chain α-keto acid dehydrogenase complex leading to branched chain amino acids (BCAA) leucine, isoleucine, and valine accumulation as well as their corresponding transaminated branched-chain α-keto acids. MSUD patients present neurological dysfunction and cognitive impairment. Here, we investigated whether acute and chronic administration of a BCAA pool causes impairment of acquisition and retention of avoidance memory in young rats. We have used two administration protocols. Acute administration consisted of three subcutaneous administrations of the BCAA pool (15.8 μL/g body weight at 1-h intervals) containing 190 mmol/L leucine, 59 mmol/L isoleucine, and 69 mmol/L valine or saline solution (0.85% NaCl; control group) in 30 days old Wistar rats. Chronic administration consisted of two subcutaneous administrations of BCAA pool for 21 days in 7 days old Wistar rats. N-acetylcysteine (NAC; 20 mg/kg) and deferoxamine (DFX; 20 mg/kg) co administration influence on behavioral parameters after chronic BCAA administration was also investigated. BCAA administration induced long-term memory impairment in the inhibitory avoidance and CMIA (continuous multiple-trials step-down inhibitory avoidance) tasks whereas with no alterations in CMIA retention memory. Inhibitory avoidance alterations were prevented by NAC and DFX. BCAA administration did not impair the neuropsychiatric state, muscle tone and strength, and autonomous function evaluated with the SHIRPA (SmithKline/Harwell/ImperialCollege/RoyalHospital/Phenotype Assessment) protocol. Taken together, our results indicate that alterations of motor activity or emotionality probably did not contribute to memory impairment after BCAA administration and NAC and DFX effects suggest that cognition impairment after BCAA administration may be caused by oxidative brain damage.
... 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]. ...
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.
... The formula is usually drunk daily before meals, an usual dose roughly equivalent to 60 ml of a ''garrafada''. We have shown that a standardized ethanol extract of P. olacoides (POEE) is promnesic (da Silva et al. 2004) counteracts several types of amnesia (da Silva et al. 2008), and has neuroprotective (Siqueira et al. 2004), antioxidant (Siqueira et al. 2007), and antidepressant properties (Piato et al. 2008Piato et al. , 2009). Given the traditional uses of PO, the antidepressant effects identified for POEE, and the relationship between stress and depression (Sapolsky et al. 2000), the present study aimed to evaluate whether POEE counteracts stress-induced effects. ...
With the recognition that high levels of sustained stress are associated with the natural course of countless illnesses, effective anti-stress agents have gained importance. Improved endurance to particularly stressful periods is one of the medicinal claims for Marapuama (Ptychopetalum olacoides Bentham, PO), a popular Amazonian herbal. The purpose of this study was to evaluate if PO possesses anti-stress properties. To this end, an extract from PO (POEE) was evaluated on anxiety and glucose levels in mice submitted to the unpredictable chronic mild stress (UCMS) paradigm. POEE did not present anxiolytic effects, but was able to prevent (p<0.01) the UCMS-induced anxiety as assessed by the light/dark test (time spent in the lit area, POEE 100 and 300mg/kg 235.9+/-20.6s and 250.4+/-17.4s, respectively, compared to DMSO 104.7+/-24.4s). Likewise, although POEE did not induce noticeable effects on glycemia, it effectively (p<0.01) prevented the UCMS-induced hyperglycemia (POEE 100 and 300mg/kg 106.4+/-6.7mg/dl and 107.3+/-3.3mg/dl, respectively, compared to DMSO 134.6+/-5.9mg/dl). Additionally, POEE (50-200mg/kg i.p. and 800mg/kg p.o.) significantly (p<0.01 and p<0.05, respectively) increased the time to hypoxia-induced convulsion (by 38%, 51%, 59% and 27%, respectively for i.p. and p.o. treatments). The data indicate that POEE counteracts some of the effects brought about by chronic stress. This study combined with the identified antioxidant and neuroprotective properties, as well as the claimed benefits associated with stressful periods suggest that Ptychopetalum olacoides (Marapuama) might possess adaptogen-like properties.
... Other species cited more frequently in this survey, which have been the object of studies supporting popular use are Ptychopetalum olacoides and Turnera diffusa. Recent studies have shown the benefits of Ptychopetalum olacoides on memory ( Siqueira et al., 2003;Da Silva et al., 2004), against cerebral ischemia ( Siqueira et al., 2004), and of Turnera diffusa on sexual performance in rats ( Arletti et al., 1999). However, none of these plants has been evaluated clinically. ...
In a survey, from Brazilian books, we searched plants that are in popular use for purposes resembling those of an adaptogen. This study focused on 24 books by authors from diverse regions in the country, resulting in a total of 1317 citations of uses related to a possible adaptogen effect from approximately 766 plants. Only species native to Brazil, cited in at least four books, were selected, resulting a total of 33 species, belonging to 24 families. Of these, four species have been studied previously in relation to effects that are considered as part of an adaptogen effect (anti-stress, memory enhancement, increased physical and/or sexual performance): Heteropterys aphrodisiaca (Malpighiaceae), Paullinia cupana (Sapindaceae), Ptychopetalum olacoides (Olacaceae), and Turnera diffusa (Turneraceae). Three others--Pfaffia glomerata, Pfaffia paniculata (Amaranthaceae), and Trichilia catigua (Meliaceae)--have also been the object of pharmacological studies that support their use as a possible adaptogen, but they are listed in less than four books. The overall results obtained in the present review of Brazilian folk literature reveals that Brazil is rich in plants with potential adaptogen-like effect, but lacks pharmacological studies (mostly clinical ones) to confirm these therapeutic properties.
... Another reason why adaptogens are commonly used is to improve the cognitive functions. It is a known fact that aging leads to a loss of neurons which, in turn, leads to a progressive reduction of the cognitive functions, a fact that can be observed experimentally in old animals and prevented or improved by the admin-istration of some plants (Petkov et al., 1993;Galvão et al., 2002;Da Silva et al., 2004;Marques et al., 2004). However, there was no improvement in the T-maze learning time of the old animals treated with B. trimera or D. rugosa extracts when compared with old controls. ...
Baccharis trimera (Asteraceae) and Davilla rugosa (Dilleniaceae) are used popularly as tonics, aphrodisiacs and for stomach ailments, among other uses. Hydroalcohol extracts of the aerial parts of both plants were investigated with regard to their chemical constitution and their pharmacological activity in tests that evaluate adaptogen activity. Alkaloids, flavonoids, saponins, polyphenols/tannins and coumarins were identified in both extracts, while lignans were found only in the extract of Davilla rugosa. This extract presented also a marked antioxidant activity and exerted a moderate antiulcer effect in rats submitted to cold immobilization stress. It did not, however, inhibit the increase in the levels of ACTH and corticosterone induced by stress. Moreover, the Davilla rugosa did not improve the physical performance of mice submitted to forced exercise and the learning time of old rats in the T-maze, neither did it reduce the blood viscosity of the old animals. Conversely, the Baccharis trimera extract only presented a moderate antioxidant activity, without any positive effect on the other tests. These results point to the absence of an adaptogen activity of Baccharis trimera, with some effects that could be related to such an activity as regards the Davilla rugosa.
... The plant material is usually prepared in cachaç a (a distilled spirit obtained from sugar cane) or wine, and drunk daily before meals. Coherently with traditional claims, antidepressant (Piato et al., submitted), neuroprotective (Siqueira et al., 2004), antioxidant (Siqueira et al., 2007), and memory facilitating effects (da Silva et al., 2004) were identified with a standardized PO ethanol extract (POEE). We have established that POEE (intraperitoneally or orally administered to mice) significantly and dose-dependently decreases immobility in the tail suspension and forced swimming tests, apparently through effects on D 1 dopamine and -noradrenergic receptors (Piato et al., submitted). ...
ETHNOPHARMACOLOGY RELEVANCE: Ptychopetalum olacoides Bentham (PO) (Olacaceae), known as Marapuama, is regarded as a "nerve tonic" in the Amazon. Traditional uses include states of lassitude with noticeable lack of desire/motivation, and to manage particularly stressful (physical and/or psychological) circumstances. Suggestive of antidepressant activity, we have established that a specific PO ethanol extract (POEE) significantly decreases immobility in the tail suspension and forced swimming tests.
The aim of this study was to verify the effects of POEE in the unpredictable chronic mild stress (UCMS) depression model in mice, given the construct and face values of the UCMS as an experimental model of depression and the traditional use of this species.
Over 6 weeks BALB/c mice were subjected to the UCMS protocol. The effects of POEE (50, 100, 300mg/kg, p.o.) and imipramine (20mg/kg, i.p.) were evaluated in relation to coat state, splash-test grooming, and corticosterone levels.
The coat state degradation, decreased grooming and increased serum corticosterone induced by UCMS were prevented by POEE and imipramine treatments.
In addition to supporting traditional claims and previously reported antidepressant properties for POEE, this study shows that POEE prevents stress-induced HPA hyperactivity.
Background
Guettarda viburnoides Cham. & Schltdl., “veludinho do campo”, is used in the Brazilian Amazon for its effects on the central nervous system (CNS) as a “brain tonic”; however, scientific evidence is needed to elucidate its ethnobotanical uses.
Objective
This study evaluated the neurobehavioural effects of an ethanolic extract of G. viburnoides (EEGV). Molecular docking, microchemical and morphoanatomical features of the species were investigated.
Methods
EEGV was investigated by UHPLC‒MS/MS and dereplication and molecular network were investigated using platforms available for natural product chemistry. For the in vivo assay, EEGV was administered to mice orally (3, 30 or 100 mg/kg). The effect of EEGV on spatial memory was measured using the Morris water maze test in mice with scopolamine-induced amnesia. The depression- and anxiety-like effects were assessed by forced swimming, tail suspension, marble burying and elevated plus maze tests. The AChE inhibition was evaluated in the brains of treated mice and molecular docking simulations were carried out with the main constituents. The leaves and stems of G. viburnoides were analysed via optical microscopy, scanning electron microscopy and energy dispersive X-ray spectroscopy.
Results
Secoxyloganin, grandifloroside, hyperin/or isoquercitrin, uncaric acid and ursolic acid were identified by UHPLC‒MS/MS. Molecular networking by three flavonoids, three triterpenes, two coumarins, two iridoids, and one phenolic acid. EEGV reversed these scopolamineinduced effects. In the forced swim and tail suspension test, EEGV (30 and 100 mg/kg) significantly reduced the immobility time. EEGV significantly reduced the number of buried marbles, while in the elevated plus maze test, no changes were observed compared to the Sco group. AChE activity was altered in the hippocampus. Studies of the molecular coupling of iridoid glycosides (grandifloroside and secoxyloganin) and flavonoid hyperin with AChE revealed significant interactions, corroborating the activity indicated by the inhibition assay.
Conclusions
These results might be in accordance with medicinal use for neuroprotetor effects and important microchemical and micromorphological data that support the identification and quality control of G. viburnoides.
Alzheimer's disease (AD) is increasingly becoming a major public health concern in our society. While many studies have explored the use of natural polyketides, alkaloids, and other chemical components in AD treatment, there is an urgent need to clarify the concept of multi-target treatment for AD. This study focuses on using network pharmacology approach to elucidate how secondary metabolites from Dictyostelium discoideum affect AD through multi-target or indirect mechanisms. The secondary metabolites produced by D. discoideum during their development were obtained from literature sources and PubChem. Disease targets were selected using GeneCards, DisGeNET, and CTD databases, while compound-based targets were identified through Swiss target prediction and Venn diagrams were used to find intersections between these targets. A network depicting the interplay among disease, drugs, active ingredients, and key target proteins (PPI network) was formed utilizing the STRING (Protein-Protein Interaction Networks Functional Enrichment Analysis) database. To anticipate the function and mechanism of the screened compounds, GO and KEGG enrichment analyses were conducted and visually presented using graphs and bubble charts. After the screening phase, the top interacting targets in the PPI network and the compound with the most active target were chosen for subsequent molecular docking and molecular dynamic simulation studies. This study identified nearly 50 potential targeting genes for each of the screened compounds and revealed multiple signaling pathways. Among these pathways, the inflammatory pathway stood out. COX-2, a receptor associated with neuroinflammation, showed differential expression in various stages of AD, particularly in pyramidal neurons during the early stages of the disease. This increase in COX-2 expression is likely induce by higher levels of IL-1, which is associated with neuritic plaques and microglial cells in AD. Molecular docking investigations demonstrated a strong binding interaction between the terpene compound PQA-11 and the neuroinflammatory receptor COX2, with a substantial binding affinity of −8.4 kcal/mol. Subsequently, a thorough analysis of the docked complex (COX2-PQA11) through Molecular Dynamics Simulation showed lower RMSD, minimal RMSF fluctuations, and a reduced total energy of −291.35 kJ/mol compared to the standard drug. These findings suggest that the therapeutic effect of PQA-11 operates through the inflammatory pathway, laying the groundwork for further in-depth research into the role of secondary metabolites in AD treatment.
Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to study the effect of boldine on the learning and memory of the Swiss albino male young and aged mice. Boldine (1.5, 3 and 6mg/kg, po) and physostigmine salicylate (0.1mg/kg, ip) were administered to separate groups of mice for 7 successive days. Morris water maze was utilized as a behavioural model to study the effect of drugs on learning and memory of mice. Boldine and physostigmine significantly improved learning and memory of young as well as aged mice, as indicated by decrease in escape latency time during training session and increase in time spent in target quadrant during retrieval session. No significant effect on locomotor activities of mice was observed due to drug treatments. Memory-enhancing activity of boldine (3mg/kg) was found to be comparable to physostigmine. Boldine significantly reversed scopolamine-, sodium nitrite- and aging-induced amnesia in mice. Moreover, boldine attenuated oxidative stress, as shown by a significant decrease in brain malondialdehyde as well as brain nitrite levels and a significant increase in brain GSH level of young as well as aged mice. Brain acetylcholinesterase activity was also significantly inhibited by boldine in young as well as aged mice. In conclusion boldine administered for 7 successive days exhibited significant improvement of learning and memory of young and aged mice possibly through inhibition of brain acetylcholinesterase activity and alleviation of brain oxidative stress.
The effect of hydroalcoholic extract of fruits of Trapa bispinosa (TB) was investigated for its
nootropic activity using various experimental paradigms of learning and memory, viz. transfer
latency (TL) on elevated plus-maze, passive avoidance response (PAS) and object recognition test.
The investigation reported that TB 500 mg/kg significantly reduced the TL on 2nd and 9th day while
TB 250 mg/kg was found effective on 9th day. TB 250 and 500mg/kg significantly increased the
step down latency in the PAS at acquisition and retention test. Moreover the TB (250 & 500mg/kg)
increased discrimination index in the object recognition test indicating nootropic activity. To
conclude TB extract showed significant facilitatory effect on aversively motivated learning and
memory in mice as well as improvement of memory in absence of cognitive deficit.
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.
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.
Maple syrup urine disease (MSUD) is an inborn metabolism error caused by a deficiency of branched-chain α-keto acid dehydrogenase complex activity. This blockage leads to an accumulation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine, as well as their corresponding α-keto and α-hydroxy acids. Previous reports suggest that MSUD patients are at high risk for chronic neuropsychiatric problems. Therefore, in this study, we assessed variables that suggest depressive-like symptoms (anhedonia as measured by sucrose intake, immobility during the forced swimming test and body and adrenal gland weight) in rats submitted to chronic administration of BCAA during development. Furthermore, we determined if these parameters were sensitive to imipramine and N-acetylcysteine/deferoxamine (NAC/DFX). Our results demonstrated that animals subjected to chronic administration of branched-chain amino acids showed a decrease in sucrose intake without significant changes in body weight. We also observed an increase in adrenal gland weight and immobility time during the forced swimming test. However, treatment with imipramine and NAC/DFX reversed these changes in the behavioral tasks. In conclusion, this study demonstrates a link between MSUD and depression in rats. Moreover, this investigation reveals that the antidepressant action of NAC/DFX and imipramine might be associated with their capability to maintain pro-/anti-oxidative homeostasis.
In Brazil, many plants are used as tonic, fortifier, aphrodisiac, anti-stress, among other uses that are similar to the indications of an adaptogen. In general, such plants are used unspecifically, in situations of stress and fatigue, in the recovery after a previous pathological or debilitating state, or simply aiming at the maintenance of a healthy state. This article discusses the popular terms employed in the Brazilian folk medicine for the plants with this profile, their particularities and limitations. The article also discusses the possible mechanisms of action of an adaptogen and compares the main Brazilian plants used for that purpose: guarana (Paullinia cupana Kunth, family Sapindaceae), muirapuama (Ptychopetalum olacoides Benth., Olacaceae), catuaba (Anemopaegma arvense (Vell.) Stellfeld & J.F. Souza, Bignoniaceae, and Trichilia catigua A. Juss., Meliaceae), nó-decachorro (Heteropterys aphrodisiaca O. Mach, Malpighiaceae), damiana (Turnera diffusa Willd. ex Schult., Turneraceae) and pfaffia or Brazilian ginseng (Pfaffia sp, Amaranthaceae).
Hyperornithinemia is the biochemical hallmark of hyperornithinemia-hyperammonemia-homocitrullinuria (HHH) syndrome, an inherited metabolic disease clinically characterized by mental retardation whose pathogenesis is still poorly known. In the present work, we produced a chemical animal model of hyperornithinemia induced by a subcutaneous injection of saline-buffered Orn (2-5 μmol/g body weight) to rats. High brain Orn concentrations were achieved, indicating that Orn is permeable to the blood brain barrier. We then investigated the effect of early chronic postnatal administration of Orn on physical development and on the performance of adult rats in the open field, the Morris water maze and in the step down inhibitory avoidance tasks. Chronic Orn treatment had no effect on the appearance of coat, eye opening or upper incisor eruption, nor on the free-fall righting reflex and on the adult rat performance in the Morris water maze and in the inhibitory avoidance tasks, suggesting that physical development, aversive and spatial localization were not changed by Orn. However, Orn-treated rats did not habituate to the open field apparatus, implying a deficit of learning/memory. Motor activity was the same for Orn- and saline- injected animals. We also verified that Orn subcutaneous injections provoked lipid peroxidation in the brain, as determined by a significant increase of thiobarbituric acid-reactive substances levels. Our results indicate that chronic early postnatal hyperornithinemia may impair the central nervous system, causing minor disabilities which result in specific learning deficiencies.
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.
Inhibitory effects of intravenously or orally administered antioxidants on the anthralin-derived radical generated in skin (mainly in the epidermis) of living mice by ultraviolet-A (UVA) irradiation were estimated. Anthralin was applied to the dorsal skin of living mice and the mice were then exposed to UVA. The EPR signal intensity in skin tissue strips obtained from mice after anthralin-UVA treatment was measured by an X-band EPR spectrometer. Several common antioxidants such as ascorbate, glutathione and Trolox (a vitamin E analogue) intravenously administered to mice reduced anthralin-derived radical generation. Trolox showed the most prolonged and powerful effect. Intravenous injection of a clinically used cerebral neuroprotective drug, Edarabone (Radicut), also showed depletion for the anthralin-derived radical. Oral administration of a commercialized nutritional supplement (a cocktail of 17 herbals and vitamins) also attenuated the anthralin-derived radical. The anthralin-UVA treatment model for antioxidant activity in the epidermis is a potentially feasible method to estimate activity of antioxidants in the body.
From the MeOH extract of Ptychopetalum olacoides, which is used in Brazilian folk medicine for the treatment of chronic degenerative conditions of the nervous system, four novel clerodane-type diterpenoids named 6alpha,7alpha-dihydroxyannonene (1), 7alpha,20-dihydroxyannonene (2), 7alpha-hydroxysolidagolactone I (3), and ptycho-6alpha,7alpha-diol (4) were isolated by bioassay-directed fractionation using NGF-differentiated PC12 cells. The structures of 1-4 were established by extensive NMR spectroscopic analyses and chemical conversion. Compounds 1 and 2 significantly enhanced NGF-mediated neurite outgrowth in PC12 cells at concentrations ranging from 0.1 to 50.0 microM for 1 and 0.1 to 30.0 microM for 2, whereas 3 and 4 had no morphological effect on NGF-mediated PC12 cells in the same concentration range. The structure-activity relationship of these compounds is also discussed.
High concentrations of ethylmalonic acid (EMA) are found in tissues and biological fluids of patients affected by ethylmalonic encephalopathy (EE), as well as by deficiency of short-chain acyl-CoA dehydrogenase (SCAD) activity and other illnesses characterized by developmental delay and other neurological and muscular symptoms. The pathophysiological mechanisms responsible for the brain damage in these patients are virtually unknown. However, they may be due to the neurotoxic actions of EMA. Therefore, in the present work we investigated whether chronic exposure of EMA during early development (from 5th to 28th day of life) could alter the behavioral performance of adult rats in the Morris water maze (MWM) and elevated plus maze tasks. Control rats were treated with saline in the same volumes. We observed that adult rats pretreated with EMA presented impairment in the learning and memory in water maze task spending significantly less time in the training quadrant. However, chronic EMA administration did not affect rat performance in the elevated plus maze tasks, suggesting that anxiety-like behavior was not changed by EMA. We also evaluated the in vitro effect of EMA on lipoperoxidation and on creatine kinase (CK) activity in rat hippocampus and observed that this metabolite induced lipid peroxidation and diminished creatine kinase activity. The results provide evidence that early chronic EMA treatment induces long-lasting spatial behavioral deficit that may be possibly related to a secondary bioenergetics dysfunction and/or increase of free radical production caused by this organic acid.
Four new clerodane-type diterpenoids, ptychonolide (1), 20-O-methylptychonal acetal (2), and an equilibrium mixture of ptychonal hemiacetal (3) and ptychonal (4), were isolated from the MeOH extract of the bark of a Brazilian plant, Ptychopetalum olacoides. The structure of 1 was elucidated as a clerodane-type diterpenoid on the basis of spectroscopic data, whereas 2 was assigned to an acetal derivative of 1. Compounds 3 and 4 existed as an equilibrium mixture. A mixture of compounds 3 and 4 was found to exhibit neurite outgrowth-promoting activities on NGF-mediated PC12 cells at concentrations ranging from 0.1 to 10.0 microM.
Western medical science lacks a solid philosophical and theoretical approach to disease cognition and therapeutics. My first two articles provided a framework for a humane medicine based on Modern Biophysics. Its precepts encompass modern therapeutics and CAM. Modern Biophysics and its concepts are presently missing in medicine, whether orthodox or CAM, albeit they probably provide the long sought explanation that bridges the abyss between East and West. Key points that differentiate Systemic from other systems' approaches are 'Intelligence', 'Energy' and the objective 'to survive'. The General System Theory (GST) took a forward step by proposing a departure from the mechanistic biological concept-of analyzing parts and processes in isolation-and brought us towards an organismic model. GST examines the system's components and results of their interaction. However, GST still does not go far enough. GST assumes 'Self-Organization' as a spontaneous phenomenon, ignoring a causative entity or central controller to all systems: Intelligence. It also neglects 'Survive' as the directional motivation common to any living system, and scarcely assigns 'Energy' its true inherent value. These three parameters, Intelligence, Energy and Survive, are vital variables to be considered, in our human quest, if we are to achieve a unified theory of life.
The aim of this study was to investigate the effects of intrastriatal injection of hypoxanthine, a metabolite accumulated in Lesch-Nyhan disease, on rats' performance in the Morris water maze tasks, along with the monoamine content in striatum of rats. Male adult Wistar rats were divided in two groups: (1) saline-injected and (2) hypoxanthine-injected group. Seven days after solutions infusion, animals were trained in the Morris Water Maze or were sacrificed for evaluation of the striatal monoamine content. Results show that hypoxanthine administration caused impairment on spatial navigation in the acquisition phase in reference memory task in the Morris Water Maze, as well as in the latency to cross over the platform location in probe trial, when compared to the saline group (control). Hypoxanthine also altered rat performance in the working memory. Although striatal dopamine metabolites content did not change, treated animals showed a reduction of tissue levels of serotonin (5-HT) and 5- hydroxyl-indoleacetic acid (5-HIAA). These results show that intra-striatal hypoxanthine administration provoked impairment of spatial learning/memory in rats without affecting striatal dopaminergic system, although serotonergic pathways seem to have been affected.
Although there are normal cognitive changes that take place as a person becomes older, ageing in humans is generally associated with a deterioration of cognitive performance, in particular of learning and memory. There are a number of herbal medicines that are reported to improve brain function and intelligence. In the present study, the ameliorating effects of an essential oil extracted from Acori graminei rhizoma on learning and memory in aged, dysmnesia rats and mice were determined using the step-down passive avoidance test and Y maze. Oral administration of the essential oil (0.02, 0.04 and 0.08 g kg(-1)) to rats for 30 days and to mice for 15 days improved the latency and number of errors in aged, dysmnesia rats and mice. The cerebral neurotransmitters in aged rats given the essential oil (0.02, 0.04, 0.08 g kg(-1)) for 30 days were also investigated, and increased levels of norepinephrine, dopamine and serotonin, and decreased levels of acetylcholinesterase activity were found. The results suggest that the essential oil improves cognitive function in aged animals possibly by increasing norepinephrine, dopamine and serotonin relative levels, and by decreasing the activity of acetylcholinesterase in the cerebra.
Glutaric acidemia type I (GA I) is an autosomal recessive metabolic disorder caused by glutaryl-CoA dehydrogenase deficiency leading to predominant accumulation of glutaric acid (GA), and to a lesser extent of 3-hydroxyglutaric acid (3HG) in body fluids and tissues. The clinical manifestations of GA I are predominantly neurological. Although the pathophysiological mechanisms responsible for the brain damage of this disease are virtually unknown, they are thought to be due to the neurotoxic actions of GA and 3HG. Therefore, in the present work we investigated whether chronic exposure of GA (5 micromol g of body weight(-1), twice per day), the major metabolite accumulating in GA I, during early development (from the 5th to the 28th day of life) could alter the cognitive performance of adult rats in the Morris water maze, open field and elevated plus maze tasks. Control rats were treated with saline in the same volumes. GA administration provoked an impairment of spatial performance in the water maze since adult rats pretreated with GA were not able to remember the previous location of the platform spending significantly less time in the training quadrant. In contrast, GA chronic administration did not affect rat performance in the open field and elevated plus maze tasks, indicating that motor activity and anxiety was not changed by GA. The results provide evidence that early chronic GA treatment induces long-lasting spatial behavioral deficit.
Current characteristics and perspectives of Brazilian demographic and epide- miological transition processes are analyzed. Results from the 1991, 1993, 1995 and 1996 censuses, new population projections and recent studies on socioeco- nomic and health profiles of elderly people of S. Paulo, Rio de Janeiro and Belo Horizonte are discussed. In 1995, estimated life expectancy at birth in Brazil was already over 67 years. The number of individuals aged 60 years and older - in 1995, 8.3%, of the total population - is expected to duplicate and probably stabi- lize by the year 2050. Yet lacking coverage and quality, health services are al- ready burdened with degenerative diseases and mental disorders, frequent out- patient appointments, high hospital bed occupation and high costs. Functional impairment and self-reported diseases are related to poverty among the elderly,
A collection of traditional medicine substances have been used as tonics or stimulants by indigenous people of Brazil for thousands of years. Since such substances may represent a source of potentially active drugs for treating various mental diseases, natural products used by the Caboclos, a population native to the Amazon, were reviewed. Special attention has been paid to Chaunochiton kappleri (Sagot ex Engler) Ducke, a species observed in the upland rain forests and savanna forests in the Brazilian portion of Amazonia. This plant, considered highly effective, is used as treatment for "nerve weakness," a traditional syndrome that resembles depressive disorders.
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.
Ptychopetalum olacoides (Olacaceae) is a popular Amazonian medicinal plant in Brazil claimed to be aphrodisiac and to cure male impotence. In the present study, we have evaluated the hydroalcohol extract prepared from stem bark on the behaviour in mice using forced swimming-induced immobility and open field as test models. The plant extract was found to possess both motor depressant and stimulant properties depending on the test model used. While it diminished locomotor activity in the open field test, it caused a reduction of immobility time in the forced swimming test. Also, these effects were found to be similar to those produced by clonidine, an α2-adrenoceptor agonist and were abolished by yohimbine, an α2-adrenergic antagonist. The findings obtained suggest a clonidine-like effect of P. olacoides bark extract. © 1998 John Wiley & Sons, Ltd.
Context.
—EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior.
Depression in the elderly is nowadays a predominant health care problem, mainly due to the progressive aging of the population. It results from psychosocial stress, polypathology, as well as some biochemical changes which occur in the aged brain and can lead to cognitive impairments, increased symptoms from medical illness, higher utilization of health care services and increased rates of suicide and nonsuicide mortality. Therefore, it is very important to make an early diagnosis and a suitable pharmacological treatment, not only for resolving the acute episode, but also for preventing relapse and enhancing the quality of life. Age-related changes in pharmacokinetics and in pharmacodynamics have to be kept into account before prescribing an antidepressant therapy in an old patient. In this paper some of the most important and tolerated drugs in the elderly are reviewed. Tricyclic antidepressants have to be used carefully for their important side effects. Nortriptyline, amytriptiline, clomipramine and desipramine as well, seem to be the best tolerated tricyclics in old people. Second generation antidepressants are preferred for the elderly and those patients with heart disease as they have milder side effects and are less toxic in overdose and include the so called atypicals, such as selective serotonin reuptake inhibitors, serotonin noradrenalene reuptake inhibitors and noradrenaline reuptake inhibitors. Monoamine oxidase (MAO) inhibitors are useful drugs in resistant forms of depression in which the above mentioned drugs have no efficacy; the last generation drugs (reversible MAO inhibitors), such as meclobemide, seem to be very successful. Mood stabilizing drugs are widely used for preventing recurrences of depression and for preventing and treating bipolar illness. They include lithium, which is sometimes used especially to prevent recurrence of depression, even if its use is limited in old patients for its side effects, the anticonvulsants carbamazepine and valproic acid. Putative last generation mood stabilizing drugs include the dihydropyridine L-type calcium channel blockers and the anticonvulsants phenytoin, lamotrigine, gabapentin and topiramate, which have unique mechanisms of action and also merit further systematic study. Psychotherapy is often used as an adjunct to pharmacotherapy, while electroconvulsant therapy is used only in the elderly patients with severe depression, high risk of suicide or drug resistant forms.
Many epileptic patients suffer from cognitive impairments; both the underlying pathology and antiepileptic drug therapy can cause such deficits. Phenytoin, one of the widely used anticonvulsants, is known to adversely affect cognitive function. A reputed Indian nootropic plant Bacopa monniera (BM) was evaluated alone and in combination with phenytoin for its effect on (a) passive-avoidance (PA) task; (b) maximal electroshock seizures; and (c) locomotor activity in mice. Phenytoin (PHT, 25 mg/kg po×14 days) adversely affected cognitive function in the PA task. BM extract (40 mg/kg×7 days), given along with phenytoin in the second week of the two-week regimen, significantly reversed PHT-induced impairment. Both acquisition and retention of memory showed improvement without affecting its anticonvulsant activity. The observed cognitive effects of PHT and BM were found to be independent of motor stimulation. The results provide evidence for potential corrective effect of BM in cognitive deficit associated with PHT therapy.
The potentiating effect of low doses of σ ligands on the N-methyl-d-aspartate (NMDA)-induced excitation of pyramidal CA3 dorsal hippocampal neurons has recently been reported. In the present study, we investigated behavioral effects relevant to these findings in the experimental amnesia induced by the non-competitive NMDA antagonist, dizocilpine (MK-801), in mice. At doses below 1 mg/kg s.c., the σ ligands, 1,3-di-(2-tolyl)guanidine (DTG), (+)-SKF 10,047, and (+)-pentazocine, but not their (−)-isomers, significantly decreased MK-801 (100 μg/kg s.c.)-induced impairment of spontaneous alternation performances in 8-min sessions of a Y-maze exploration, an index of spatial working memory, without affecting the concomitant hyperlocomotion. The effect of DTG (100 μg/kg s.c.) was completely antagonized by the simultaneous administration of BMY 14802 (10 mg/kg i.p.) and NE-100 (1 mg/kg i.p.), two putative σ antagonists, which had no effect by themselves. In long-term memory tests (step-down and step-through types of passive avoidance, elevated plus-maze), DTG exhibited a significant attenuation of MK-801-induced amnesia, at doses of 10 and 100 μg/kg s.c. In all tests of short- and long-term memory, the effects exhibited by the σ ligands tested had a bell-shaped curve; no effect was seen at 1 mg/kg. DTG did not affect the impairment of alternation induced by CPP (5 mg/kg i.p.): the modulation may selectively target the blockade of NMDA receptor-associated ion channels. Moreover, DTG (1–1000 μg/kg) did not affect the impairment induced by scopolamine (1 mg/kg i.p.) or diazepam (4 mg/kg i.p.), but significantly prevented the impairment induced by mecamylamine (10 mg/kg i.p.). These results suggest that the potentiating effect of σ ligands on NMDA receptor-mediated glutamatergic neurotransmission, already demonstrated electrophysiologically, may have some relevance to learning and memory processes in the hippocampus. A similar modulation may also affect cholinergic nicotinic systems.
The effect of diazepam on retention of an inhibitory avoidance task was investigated in mice. In Experiment 1, animals were trained in this task, and tested for retention 24 h later. The mice received, 20 min after training, an IP injection of either diazepam (2 mg/kg) or saline; half of the mice in each treatment group were exposed, 40 min after avoidance training (and 20 min after the injections) to a Y maze. Exposure to the Y maze disrupted retention of the avoidance task in the saline-treated animals, and enhanced it in the diazepam-treated mice. Retention of habituation to the Y maze was impaired in the diazepam group. The effect can be explained by an interaction of the drug with the Y maze, by which exposure to the Y maze became facilitatory, instead of deleterious, to retention of the avoidance task. This may or may not be related to anterograde amnesia for the Y maze; and may be related to effects of diazepam seen in clinical practice. In Experiment 2, diazepam was given prior to, instead of after, inhibitory avoidance training; it caused anterograde amnesia for this task, which was not reversed by pre-test diazepam, and was therefore not due to state dependency. In conclusion, the effect of diazepam on inhibitory avoidance learning depends on the time at which the drug is given. A pretraining injection causes amnesia, whereas a post-training injection, while ineffective per se, may facilitate retention of the task when it is followed by exposure to a habituation procedure.
Rats were trained in a step-down inhibitory avoidance task using a 25 X 25-cm platform and either a 0.3- or a 0.8-mA training footshock. Immediately after training retrieval was good in all animals; but at 24 h there was a decline in the group trained with 0.3-mA footshock. This decline was not observed in animals submitted to an immediate retrieval test and then tested again at 24 h. Thus, the immediate retrieval test apparently served the purpose of a rehearsal. A considerable degree of activity (rearing, ambulation, sticking the head out of the platform) was observed in test sessions. Activity scores were lower in the animals trained with the 0.8-mA footshock. The amount of activity, however, was unrelated to retrieval performance (i.e., to test session step-down latency).
This review focuses on age-related memory loss and its neurobiological correlates. A considerable body of evidence indicates that performance on tests of learning and memory declines with increasing age. Performance decrements have been documented in both human and animal studies employing tests of short- and long-term memory. In reviewing this voluminous literature, we have attempted to identify the critical factors accounting for the task-selective nature of these deficits. Important variables include task complexity, attention, and situational pacing requirements. Neurobiological changes associated with aging appear to be specific to particular anatomical regions and neurotransmitter systems. Most experimental interest has been directed toward the role of dopamine and acetylcholine in relation to memory deficits associated with aging. Norepinephrine has frequently been implicated in processes related to memory, including arousal, attention, and neural plasticity. In view of the role of norepinephrine in memory-related functions, we suggest that noradrenergic involvement in age-related memory dysfunction should receive more serious consideration.
In the present study the effect of nicotine on naloxone-induced jumping behaviour in morphine-dependent mice was examined. In addition, the modulatory role of dopaminergic, adrenergic and cholinergic mechanisms upon the effect of nicotine were investigated. Animals were rendered dependent on morphine by subcutaneous (s.c.) injections of morphine sulfate 3 times a day for 3 days, and jumping behaviour was induced by intraperitoneal (i.p.) administration of naloxone 2 h after the tenth injection of morphine sulfate on day 4. Nicotine (0.001-2 mg/kg s.c.) caused a significant decrease in withdrawal jumping behaviour in morphine-dependent mice. The effect of nicotine was blocked by the central nicotinic antagonist mecamylamine (0.01-0.1 mg/kg i.p.) but not by the peripheral nicotinic antagonist hexamethonium (0.01 and 0.1 mg/kg i.p.) nor the muscarinic receptor antagonist atropine (2.5-10 mg/kg i.p.). The dopamine receptor antagonist SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5- phenyl-1H-3-benzazepine-7-ol maleate) (0.01-0.5 mg/kg s.c.) reduced the response induced by nicotine. The dopamine receptor antagonist sulpiride (25 and 50 mg/kg s.c.) and the adrenoceptor antagonists phenoxybenzamine (5 and 10 mg/kg i.p.) and propranolol (5 and 10 mg/kg i.p.) were without an effect. The results indicate that the effect of nicotine on naloxone-induced jumping is mediated by central nicotinic receptors.
The effect of nicotine was tested on retrieval 24 h after training on a passive avoidance task. Intraperitoneal (i.p.) injection of nicotine (0.25-1.5 mg/kg) increased the step-down latency in mice dose dependently. Pretreatment with the nicotinic receptor antagonist mecamylamine (0.5-1 mg/kg) decreased, whereas pretreatment with the dopamine D1 receptor antagonist SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol maleate) (0.01, 0.05 and 0.1 mg/kg) and the beta-adrenoreceptor antagonist propranolol (10 mg/kg) increased the nicotine response. The dopamine receptor D2 receptor antagonist sulpiride (5-10 mg/kg), the anti-muscarinic agent atropine (2.5-10 mg/kg), the peripheral nicotinic receptor antagonist hexamethonium (0.01-0.5 mg/kg), the alpha-adrenoceptor antagonist phenoxybenzamine (1 and 10 mg/kg) and the peripheral dopamine D2 receptor antagonist domperidone (5 and 10 mg/kg) did not change the response induced by nicotine. Single administration of the antagonists did not cause response; however, a high dose of domperidone (10 mg/kg) and propranolol alone increased the step-down latencies. It may be concluded that a nicotinic receptor mechanism is involved in the nicotine-induced improvement of memory retrieval.
Mice that ingested a suspension of guarana (Paullinia cupana, Sapindaceae) in a dose of 0.3 mg/ml showed a significant increase in physical capacity when subjected to a stressful situation such as forced swimming after 100 and 200 days of treatment. Such an effect, however, was not obtained with a concentration of 3.0 mg/ml, nor with the ingestion of a suspension of ginseng 5.0 mg/ml, nor of a solution of caffeine 0.1 mg/ml. Guarana, both after a single (3.0 and 30 mg/kg) or chronic administrations (0.3 mg/ml), was able to partially reverse the amnesic effect of scopolamine as measured through a passive avoidance test in mice and rats, indicating a positive effect on memory acquisition. However, no effect was observed when an active avoidance task was used in rats, even after 20 days of guarana administration. There was also a tendency of rats treated with 0.3 mg/ml of guarana to better maintain the memory of a Lashley III maze path. The animals had the same average lifespan, indicating a low toxicity of guarana, even after 23 months of treatment.
In young adult rats with scopolamine-induced cognitive impairment, choline acetyltransferase activity was increased in the medial septum, but not in the diagonal band, caudate and hippocampus, 30 min after the injection of ginsenosides Rg1 or Re. Rb1 and Rd had no effect on choline acetyltransferase activity. Aged rats showed a smaller number of initial correct responses in the radial-arm maze and a lower choline acetyltransferase activity in the medial septum, diagonal band, caudate and hippocampus than did young adult rats. Repeated i.p. injections of Rg1 increased the number of initial correct responses and the activity of choline acetyltransferase in the medial septum, but not in the diagonal band, caudate and hippocampus, in aged rats. These results suggest that Rg1 and Re may contribute the ameliorative effects through an increase of choline acetyltransferase activity in the medial septum.
EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior.
To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia.
A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study.
Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions.
Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks.
Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC).
From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events.
EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI.
Neuroscience is witnessing growing interest in understanding brain mechanisms of memory formation for emotionally arousing events, a development closely related to renewed interest in the concept of memory consolidation. Extensive research in animals implicates stress hormones and the amygdaloid complex as key, interacting modulators of memory consolidation for emotional events. Considerable evidence suggests that the amygdala is not a site of long-term explicit or declarative memory storage, but serves to influence memory-storage processes in other brain regions, such as the hippocampus, striatum and neocortex. Human-subject studies confirm the prediction of animal work that the amygdala is involved with the formation of enhanced declarative memory for emotionally arousing events.
The effects of treatment with anxiogenic or anxiolytic agents and exposure to acute restraint stress on emotional behavior in mice were examined using an automatic hole-board apparatus. Changes in the emotional state of mice were evaluated in terms of changes in exploratory activity, i.e., total locomotor activity, numbers and duration of rearing and head-dipping, and latency to the first head-dipping. The typical benzodiazepine anxiolytics diazepam (0.05-0.5 mg/kg, i.p.) and chlordiazepoxide (0.5-4 mg/kg, i.p.) dose-dependently increased the number and duration of head-dips at doses that did not produce sedation. In contrast with these anxiolytics, the typical anxiogenic drugs N-methyl-beta-carboline-3-carboxamide (FG7142, 0.125-10 mg/kg, i.p.) and methyl-beta-carboline-3-carboxylate (beta-CCM, 0.1-2 mg/kg, i.p.) decreased both the number and duration of head-dips, and increased the latency to head-dipping. Moreover, decreases in the number and duration of head-dips, and an increase in the latency to head-dipping, were also observed in animals that were exposed to acute restraint stress. These effects of acute restraint stress were suppressed by treatment with diazepam at a dose that alone did not produce significant behavioral effects (0.1 mg/kg, i.p.). In addition, non-benzodiazepine anxiolytic flesinoxan (0.1 mg/kg, i.p.), a 5-HT1A receptor agonist, also had an effect on the restraint stress-induced decrease in head-dipping behavior. The present study shows that the changes in several exploratory behaviors could be objectively measured using our automatic hole-board apparatus. Therefore, this system can serve as a useful tool for evaluating the changes in various emotional states of animals. Moreover, we also found that treatment with anxiolytics or anxiogenics and exposure to acute restraint stress affected head-dipping behavior. These results suggest that changes in head-dipping behavior in the hole-board test may reflect the anxiogenic and/or anxiolytic state of animals.
The Chinese tree Ginkgo biloba or “maiden hair tree” is extensively cultivated for the exploitation of the medicinal properties of its leaves. From these, a well-defined extract designated “EGb 761” has been developed, which was commercialized initially as Tanakan, Tebonin and Rokin; a similar product, Kaveri (LI 3170), also exists. The major therapeutic applications for these products are “cerebral insufficiency”, other cerebral disorders, neurosensory problems and peripheral circulatory disturbances. Four primary concepts of action have been proposed to explain the pharmacotherapeutic benefits of EGb761; these are: vasoregulatory, cognition-enhancing, stress-alleviating, and gene-regulatory. These actions are believed to be realized through the principal active ingredients, flavonoids and the terpenoids ginkgolides and bilobalide acting simultaneously in concert, combination and synergy, so-called polyvalent action.
It has been proposed that EGb761 may improve the memory of healthy volunteers, and in an assessment meta-analysis of forty clinical studies, it was reported that Ginkgo was able to improve the twelve different symptoms comprising ‘cerebral insufficiency’, all of which are manifest in the elderly. These were supported in a second major study, using LI1370. However, in both instances, the evidence was largely based upon the results of self-assessment questionnaires. Latterly, in a large double blind study of men and women with the diagnosis of uncomplicated dementia who were administered Ginkgo for a year, a further positive outcome was claimed. In this study, patients were tested using ADAS-cog, GERRI and CGIC.
It is suggested that whilst these different outcomes are compatible with (but do not affirm) a clinical benefit resulting from the use of Ginkgo, the application of a more objective system of assessment would be able to provide firm proof. It is proposed, therefore, that an objective, computer-based testing system for assessment of clinical improvement in volunteers and patients administered Ginkgo (such as CANTAB) would provide the convincing evidence currently being sought by patients, carers, physicians, legislators and the pharmaceutical industry.
The effect of a standardized extract of Bacopa monniera Linn. was assessed on rat brain frontal cortical, striatal and hippocampal superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPX) activities, following administration for 7, 14 or 21 days. The effects induced by this extract (bacoside A content 82% +/- 0.5%), administered in doses of 5 and 10 mg/kg, orally, were compared with the effects induced by (-) deprenyl (2 mg/kg, p. o.) administered for the same time periods. Bacopa monniera (BM) induced a dose-related increase in SOD, CAT and GPX activities, in all the brain regions investigated, after 14 and 21 days of drug administration. On the contrary, deprenyl induced an increase in SOD, CAT and GPX activities in the frontal cortex and striatum, but not in the hippocampus, after treatment for 14 or 21 days. The results suggest that BM, like deprenyl, exhibits a significant antioxidant effect after subchronic administration which, unlike the latter, extends to the hippocampus as well. The results suggest that the increase in oxidative free radical scavenging activity by BM may explain, at least in part, the cognition- facilitating action of BM, recorded in Ayurvedic texts, and demonstrated experimentally and clinically.
Crocus sativus L., commonly known as saffron, is used in folk medicine for various purposes. Modern pharmacological studies have demonstrated that saffron extracts have antitumour effects, radical scavenger properties or hypolipaemic effects. Among the constituents of saffron extract, crocetin is mainly responsible for these pharmacological activities. In addition, recent behavioural and electrophysiological studies have demonstrated that saffron extract affects learning and memory in experimental animals. Saffron extract improved ethanol-induced impairments of learning behaviours in mice, and prevented ethanol-induced inhibition of hippocampal long-term potentiation, a form of activity-dependent synaptic plasticity that may underly learning and memory. This effect of saffron extract is attributed to crocin (crocetin di-gentiobiose ester), but not crocetin. Saffron extract or its active constituents, crocetin and crocin, could be useful as a treatment for neurodegenerative disorders accompanying memory impairment.
Rats were trained in one-trial step-down inhibitory avoidance and tested either 3 h or 31 days later. Ten minutes prior to the retention test, through indwelling cannulae placed in the CA1 region of the dorsal hippocampus, they received 0.5 microl infusions of: saline, a vehicle (2% dimethylsulfoxide in saline), the glutamate NMDA receptor blocker, aminophosphonopentanoic acid (AP5) (5.0 microg), the AMPA/kainate receptor blocker, cyanonitroquinoxaline dione (CNQX) (0.25 or 1.25 microg), the metabotropic receptor antagonist, methylcarboxyphenylglycine (MCPG) (0.5 or 2.5 microg), the inhibitor of calcium/calmodulin-dependent protein kinase II (KN62) (3.5 microg), the inhibitor of cAMP-dependent protein kinase (PKA), Rp-cAMPs (0.1 or 0.5 microg), the stimulant of the same enzyme, Sp-cAMPs (0.1 or 0.5 microg), or the inhibitor of the mitogen-activated protein kinase (MAPK) kinase, PD098059 (10 or 50 microM). CNQX, KN62 and PD098059 were dissolved in the vehicle; the other drugs were dissolved in saline. All these drugs, at the same doses, had been previously found to affect short- and long-term memory formation of this task. Retrieval measured 3 h after training (short-term memory) was blocked by CNQX and MCPG, and was unaffected by all the other drugs. In contrast, retrieval measured at 31 days was blocked by MCPG, Rp-cAMPs and PD098059, enhanced by Sp-cAMPs, and unaffected by CNQX, AP5 or KN62. The results indicate that, in CA1, glutamate metabotropic receptors are necessary for the retrieval of both short- and long-term memory; AMPA/kainate receptors are necessary for short-term but not long-term memory retrieval, and NMDA receptors are uninvolved in retrieval. Both the PKA and MAPK signalling pathways are required for the retrieval of long-term but not short-term memory.
Effects of hippocampal lesions and aging on spatial learning and memory and ameliorating effects of red ginseng on learning deficits were investigated in the following two experiments: performance of young rats with selective hippocampal lesions with red ginseng by mouth (p.o.; Experiment 1) and aged rats with red ginseng (p.o.; Experiment 2) in the spatial tasks was compared with that of sham-operated or intact young rats. Each rat in these two behavioral experiments was tested with the three types of spatial-learning tasks (distance movement task, DMT; random-reward place search task, RRPST; and place-learning task, PLT) in a circular open field using intracranial self-stimulation as reward. The results in the DMT and RRPST tasks indicated that motivational and motor activity of young rats with hippocampal lesions with and without ginseng were not significantly different from that of sham-operated young rats in Experiment 1. However, young rats with hippocampal lesions displayed significant deficits in the PLT task. Treatment with red ginseng significantly ameliorated place-navigation deficits in young rats with hippocampal lesions on the PLT task. Similarly, red ginseng improved performance of aged rats on the PLT task in Experiment 2. The results, along with previous studies showing significant effects of red ginseng on the central nervous system, suggest that red ginseng ameliorates learning and memory deficits through effects on the central nervous system, partly through effects on the hippocampal formation.
The loss of cognitive (particularly mnemonic) abilities constitutes a prominent symptom of Alzheimer's disease (AD). These cognitive symptoms occur in close relation to the slowing of the electroencephalogram (EEG), and it is likely that the inability of cortical circuits to maintain an activated state contributes to the behavioral disorganization in AD. The 'cholinergic hypothesis' of AD suggests that many of the cognitive and EEG symptoms are related to the atrophy of basal forebrain cholinergic neurons, which innervate the neocortex and hippocampus, among others. However, data from behavioral and electrophysiological studies in rats suggest that selective reductions in cholinergic transmission result in relatively small mnemonic impairments, and only a partial reduction in EEG activation. Thus, cholinergic atrophy alone may not be sufficient to cause the marked changes in cognition and cortical activity typical of AD. Cholinergic deficits do, however, make neural circuits susceptible to additional neurodegenerative processes. In rats, lowered serotonergic or noradrenergic activity alone often produces only minor impairments in learning/memory tasks and does not block EEG activation. The same monoaminergic deficits, however, result in severe behavioral impairments, and reduce or abolish EEG activation when they occur in a brain already affected by lowered cholinergic activity. There is an abundance of evidence that monoamines are reduced in AD. These degenerative processes, when occurring in a neural environment compromised by cholinergic atrophy, may then contribute to the disturbances in cortical processing and cognition/behavior in AD. A prediction derived from this theory is that an enhancement of monoaminergic functions may have beneficial effects on behavior and cortical activity. Preliminary experiments support this idea: combined cholinergic-monoaminergic stimulation can be more effective in reversing behavioral (Morris water maze) impairments and EEG slowing in rats with multiple neurotransmitter deficiencies than cholinergic enhancement alone. Thus, a stimulation of monoaminergic activity, in conjunction with cholinergic therapies, may provide an effective treatment option for AD.
It is rare to see a day pass in which we are not told through some popular medium that the population is becoming older. Along with this information comes the "new" revelation that as we enter the next millennium there will be increases in age-associated diseases (e.g., cancer, cardiovascular disease) including the most devastating of these, which involve the nervous system (e.g., Alzheimer's disease [AD] and Parkinson's disease [PD]). It is estimated that within the next 50 years approximately 30% of the population will be aged 65 years or older. Of those between 75 and 84 years of age, 6 million will exhibit some form of AD symptoms, and of those older than 85 years, over 12 million will have some form of dementia associated with AD. What appears more ominous is that many cognitive changes occur even in the absence of specific age-related neurodegenerative diseases. Common components thought to contribute to the manifestation of these disorders and normal age-related declines in brain performance are increased susceptibility to long-term effects of oxidative stress (OS) and inflammatory insults. Unless some means is found to reduce these age-related decrements in neuronal function, health care costs will continue to rise exponentially. Thus, it is extremely important to explore methods to retard or reverse age-related neuronal deficits as well as their subsequent, behavioral manifestations. Fortunately, the growth of knowledge in the biochemistry of cell viability has opened new avenues of research focused at identifying new therapeutic agents that could potentially disrupt the perpetual cycle of events involved in the decrements associated with these detrimental processes. In this regard, a new role in which certain dietary components may play important roles in alleviating certain disorders are beginning to receive increased attention, in particular those involving phytochemicals found in fruits and vegetables.
It has been known for years that systemic administration of the stress hormones, adrenocorticotrophin (ACTH), lysine-vasopressin, adrenaline, or beta-endorphin, enhances retrieval of aversive behaviours acquired one or a few days before. Here we show that the pre-test i.p. injection of the hormones in rats can also enhance retrieval when given months after the original training. The effectiveness of the treatments changed with time. When animals were tested 3 months after training the hormones enhanced retrieval only at doses five times higher than those needed 1 day after training. Between 6 and 9 months from training the hormones either lost their effect (vasopressin, beta-endorphin) or actually inhibited retrieval (ACTH, adrenaline). The effects of the hormones cannot be explained by a decrease in locomotor activity: none of the treatments had such an effect, as measured in an open field. However, when the animals were tested between 12 and 19 months after training, the hormones once again became as effective as they had been 1 day after training. This was so in spite of the fact that control retention levels became very low with age, probably as a result of extinction. The oscillation of the sensitivity of retrieval to the hormones does not appear to depend on changes in anxiety levels with ageing or to effects of the hormones on locomotor activity.
It is well established that glucocorticoid hormones, secreted by the adrenal cortex after a stressful event, influence cognitive performance. Some studies have found glucocorticoid-induced memory enhancement. However, many studies have reported impairing effects of glucocorticoids on memory function. This paper reviews recent findings from this laboratory on the acute effects of glucocorticoids in rats on specific memory phases, i.e., memory consolidation and memory retrieval. The evidence suggests that the consequences of glucocorticoid activation on cognition depend largely on the different memory phases investigated. Posttraining activation of glucocorticoid-sensitive pathways involving glucocorticoid receptors enhances memory consolidation in a pattern highly similar to that previously described for adrenal catecholamines. Also, similar to catecholamine effects on memory consolidation, glucocorticoid influences on memory consolidation depend on noradrenergic activation of the basolateral complex of the amygdala and interactions with other brain regions. By contrast, memory retrieval processes are usually impaired with high circulating levels of glucocorticoids or following infusions of glucocorticoid receptor agonists into the hippocampus. The hypothesis is proposed that these apparently dual effects of glucocorticoids on memory consolidation and memory retrieval might be related and that the basolateral complex of the amygdala is a key structure in a memory-modulatory system that regulates, in concert with other brain regions, stress and glucocorticoid effects on both memory consolidation and memory retrieval.
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.
Traditional Amazo-nian nerve tonics as antidepressant agents: Chaunochiton kappleri: a case study
- E Elisabetsky
- W Figueiredo
- G Oliveira
Elisabetsky, E., Figueiredo, W., Oliveira, G., 1992. Traditional Amazo-nian nerve tonics as antidepressant agents: Chaunochiton kappleri: a case study. Journal of Herbs Spices and Medicinal Plants 1, 125– 161
Therapeutic value of Gingko biloba in reducing symptoms of decline in mental function Anxio-genic effects of Marapuama (Ptychopetalum olacoides)
- Curtis
- P Prior
- D Vere
- P Fray
Curtis-Prior, P., Vere, D., Fray, P., 1999. Therapeutic value of Gingko biloba in reducing symptoms of decline in mental function. Journal of Pharmacy and Pharmacology 51, 535–541. da Silva, A.L., Bardini, S., Nunes, D.S., Elisabetsky, E., 2001. Anxio-genic effects of Marapuama (Ptychopetalum olacoides). Phytotherapy Research 15, 422–425
From indigenous disease concepts to laboratory work hypothesis: the case of “nerve tonics” from the Brazilian Amazon. International Foundation for Science
- E Elisabetsky
Elisabetsky E., 1987. From indigenous disease concepts to laboratory work hypothesis: the case of “nerve tonics” from the Brazilian Ama-zon. International Foundation for Science, Provisional Report Series, IFS, Stockholm, Sweden 19, S-11438
Is there a psychopharmacological meaning for traditional tonics? Plants for food and medicine
- E Elisabetsky
- I R Siqueira
Elisabetsky, E., Siqueira, I.R., 1998a. Is there a psychopharmacological meaning for traditional tonics? In: Prendergast, H.D.V., Etkin, N.L., Harris, D.R., Houghton, P.J. (Eds.), Plants for food and medicine. Royal Botanic Gardens, Kew, pp. 372–385.
Anxiogenic effects of Marapuama (Ptychopetalum olacoides)
- A L Da Silva
- S Bardini
- D S Nunes
- E Elisabetsky
da Silva, A.L., Bardini, S., Nunes, D.S., Elisabetsky, E., 2001. Anxiogenic effects of Marapuama (Ptychopetalum olacoides). Phytotherapy
Research 15, 422–425.
Mechanisms of emotional arousal and lasting declarative memory
- Cahill
Cahill, L., McGaugh, J.L., 1998. Mechanisms of emotional arousal and
lasting declarative memory. Trends in Neurosciences 21, 294–299.
Anxiogenic effects of Marapuama (Ptychopetalum olacoides)
- da Silva
Is there a psychopharmacological meaning for traditional tonics?
- Elisabetsky
Stress hormones enhaced retrieval of fear conditioning acquired either one day or many months before
- Izquierdo
Behaviour evidence for modulation role of σ ligands in memory process. I. Attenuation of dizocilpine (MK-801)-induced amnesia
- Maurice
Effects of Ptychopetalum olacoides extract on mouse behaviour in forced swimming and open field test
- Paiva