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1.
Georgian Med News ; (294): 141-145, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31687967

RESUMO

General anesthesia may cause damage of the central nervous system and cognitive dysfunction in the postoperative period. A new intranasal form of Noopept (N-Phenylacetyl-L-prolylglycine ethyl ester) was developed by our team at the Department of the medical technology (Zaporizhzhia State Medical University, Ukraine). The objectives of this investigation were the study of neuroprotective action of Noopept and to prove using in the clinic for correction of amnestic and behavioral disorders after ketamine anesthesia. We discovered that the intranasal administration of noopept after ketamine anesthesia significantly decreases anxiety and excitability, raises the animal's activity, shows an intensive antiamnesic effects and increases animal's training ability. Noopept significantly exceeds piracetam and cerebrocurin according to neuroprotective effects.


Assuntos
Amnésia/tratamento farmacológico , Ketamina/efeitos adversos , Transtornos Mentais/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Amnésia/induzido quimicamente , Anestesia , Anestesia Geral , Animais , Dipeptídeos/uso terapêutico , Ketamina/administração & dosagem , Transtornos Mentais/induzido quimicamente , Resultado do Tratamento , Ucrânia
2.
J Pharm Pharmacol ; 71(10): 1565-1575, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31385305

RESUMO

OBJECTIVES: This study was designed to assess the role of caffeine on fertility parameters in testicular and epididymal tissues of scopolamine-induced model of amnesia in rats. METHODS: Adult male rats were treated with scopolamine with or without caffeine. The modulatory effects of caffeine or scopolamine on fertility parameters were assessed in rats' testicular and epididymal homogenates. KEY FINDINGS: Scopolamine-induced sperm abnormalities, reduced steroidogenic enzyme 3ß-Hydroxysteroid dehydrogenase (3ß-HSD) and 17ß-Hydroxysteroid dehydrogenase (17ß-HSD) activities and serum testosterone levels in rats' testicular tissues. Treatment with caffeine increased 3ß-HSD and 17ß-HSD as well as testosterone levels. Caffeine also reversed sperm viability, sperm motility and sperm count in testicular tissues of scopolamine-treated rats. Furthermore, scopolamine-induced oxidative damage in rats' epididymal and testicular tissues via reduction of thiol and non-protein thiol content as well as increase in reactive oxygen species (ROS) and malondialdehyde (MDA) levels. Caffeine attenuated oxidative stress in testicular and epididymal tissues of rats treated with scopolamine via increase in non-protein and protein thiol levels with concomitant reduction in ROS and MDA levels. CONCLUSION: This study revealed that caffeine (5 and 25 mg/kg) improved sperm quality, increased steroidogenic enzyme activities and attenuated oxidative damage in testis and epididymis of rats treated with scopolamine.


Assuntos
Amnésia/tratamento farmacológico , Cafeína/farmacologia , Epididimo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Espermatozoides/efeitos dos fármacos , Testículo/efeitos dos fármacos , Testosterona/metabolismo , 17-Hidroxiesteroide Desidrogenases/metabolismo , Amnésia/induzido quimicamente , Amnésia/metabolismo , Animais , Modelos Animais de Doenças , Epididimo/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Oxirredução/efeitos dos fármacos , Ratos , Ratos Wistar , Escopolamina/farmacologia , Motilidade Espermática/efeitos dos fármacos , Testículo/metabolismo
3.
Eur J Med Chem ; 182: 111613, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31437780

RESUMO

Alzheimer's disease (AD) is associated with multifactorial neuropathological conditions, which include cholinergic deficit, amyloid-beta plaques formation, loss of neuronal plasticity and neuronal death. Treating such multifactorial conditions with a single target directed approach is considered to be inadequate. Accordingly, multi-target directed ligand (MTDL) strategy has been evolved as an auspicious approach for the treatment of AD. In light of that, a library of 2-substituted benzo[d]oxazol-5-amine derivatives (29-39; 86-107) was designed using the scaffold hopping guided MTDLs strategy, synthesized and evaluated through various in-vitro and in-vivo biological studies. The optimal compound 92 exhibited potent inhibitory activities against AChE (IC50 = 0.052 ±â€¯0.010 µM), BuChE (IC50 = 1.085 ±â€¯0.035 µM), and significant amyloid-beta aggregation (20 µM) inhibition. The compound possessed better blood-brain barrier permeability (Pe = 10.80 ±â€¯0.055 × 10-6 cm s-1) in PAMPA assay and neuro protective properties (40 µM) on SH-SY5Y neuroblastoma cell lines. Furthermore, in-vivo behavioural studies were performed on Y-maze test (scopolamine-induced amnesia model) and Morris water maze test (Aß1-42 induced ICV rat model). The compound 92, at a dose of 10 mg/kg oral administration, demonstrated a substantial improvement of the cognitive and special memory impairment. In summary, both in-vitro and in-vivo investigations evidenced that compound 92 was a potential lead for the discovery of safe and effective disease-modifying agents for AD.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Aminas/farmacologia , Inibidores da Colinesterase/farmacologia , Descoberta de Drogas , Fármacos Neuroprotetores/farmacologia , Oxazóis/farmacologia , Acetilcolinesterase/metabolismo , Doença de Alzheimer/metabolismo , Aminas/síntese química , Aminas/química , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/metabolismo , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/química , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Enguias , Feminino , Cavalos , Humanos , Ligantes , Masculino , Camundongos , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/química , Oxazóis/síntese química , Oxazóis/química , Ratos , Ratos Wistar , Escopolamina , Relação Estrutura-Atividade
4.
Phytomedicine ; 63: 153007, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31301537

RESUMO

BACKGROUND: Aerial parts of Peganum harmala Linn is used as a traditional medical herb for treatment of amnesia in Uighur medicine in China. Deoxyvasicine (DVAS) is one of the chief active ingredients in P. harmala, it possesses strong acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities in vitro, but the therapeutic effect and mechanisms on amnesia in vivo are unclear. PURPOSE: The objective of this study was to investigate the improvement effect of DVAS from P. harmala in learning and memory deficits of scopolamine-induced mice and elucidate the underlying mechanisms involved. METHODS: Mice were pretreated with DVAS (5, 15 and 45 mg/kg) and huperzine-A (0.2 mg/kg) by gavage for 7 days, and subsequently were daily intraperitoneally injected with scopolamine (1 mg/kg) to induce learning and memory deficits and behavioral performance was assessed by Morris water maze. To further evaluate the potential mechanisms of DVAS in improving learning and memory capabilities, pathological change, levels of various biochemical markers and protein expressions related to cholinergic system, oxidative stress, and neuroinflammation were examined. RESULTS: The results showed that DVAS could alleviate learning and memory deficits in scopolamine-treated mice. DVAS could regulate cholinergic function by inhibiting AChE and activating choline acetyltransferase (ChAT) activities and protein expressions. DVAS could induce brain-derived neurotrophic factor and protect hippocampal pyramidal cells against neuronal damage. DVAS also enhanced antioxidant defense via increasing the antioxidant enzyme level and activity of glutathione peroxidase, and anti-inflammatory function through suppressing tumor necrosis factor-α. Additionally, DVAS could regulate the neurotransmitters by elevating acetylcholine, 5-hydroxytryptamine, γ-aminobutyric acid and reducing 5-hydroxyindole-3-acetic acid and glutamic acid. CONCLUSION: Results illustrated that DVAS may be a promising candidate compound against amnesia via restoration of cholinergic function, regulating neurotransmitters, attenuating neuroinflammation and oxidative stress.


Assuntos
Alcaloides/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Quinazolinas/farmacologia , Acetilcolina/metabolismo , Amnésia/tratamento farmacológico , Animais , Antioxidantes/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Camundongos Endogâmicos C57BL , Neurotransmissores/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Peganum/química , Escopolamina/toxicidade , Sesquiterpenos/farmacologia
5.
Bull Exp Biol Med ; 167(1): 1-6, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31177445

RESUMO

Administration of 5-HT receptor antagonist to snails trained in conditioned food aversion prior to reminding of the conditioning stimulus caused amnesia. At the early period of amnesia (day 3), injections of protein synthesis inhibitor cycloheximide without reminder or reminder alone were ineffective. At the same time, injections of the inhibitor combined with reminder led to memory recovery; this effect in most animals persisted for at least 10 days. In the rest snails, aversive responses to presentations of the conditioning stimulus persisted for 2 days. Cycloheximide injection and reminder in 10 days after induction of amnesia did not affect its development or caused a transient memory recovery (2 days). We hypothesized that amnesia is an active process unfolding in time. One of mechanism of this process is reminder-induced and protein synthesis-depended reactivation of amnesia. Inhibitor of protein synthesis disturbed this reactivation and led to recovery of the initial memory of conditioned food aversion.


Assuntos
Amnésia/tratamento farmacológico , Amnésia/etiologia , Cicloeximida/uso terapêutico , Transtornos da Memória/induzido quimicamente , Memória/efeitos dos fármacos , Metiotepina/farmacologia , Inibidores da Síntese de Proteínas/uso terapêutico , Antagonistas da Serotonina/farmacologia , Animais , Caramujos
6.
J Agric Food Chem ; 67(29): 8160-8167, 2019 Jul 24.
Artigo em Inglês | MEDLINE | ID: mdl-31241932

RESUMO

An increase in the aging population has spurred recent efforts to identify diet and lifestyle changes that help prevent cognitive decline. Several epidemiological investigations and clinical studies have indicated that consuming fermented dairy products prevents cognitive decline. Some peptides from whey including ß-lactolin improve memory impairment; the intake of Camembert cheese has been shown to prevent Alzheimer's in mouse models. To elucidate the molecular mechanisms underlying these preventive effects, we screened peptides from digested casein protein for their ability to improve spatial memory in a scopolamine-induced amnesia mouse model. Administration of KEMPFPKYPVEP peptide from ß-casein at 0.5 mg/kg (54.8 ± 2.5) and 2 mg/kg (57.9 ± 3.7) improved memory impairment in the amnesia mice in comparison with control (44.9 ± 3.4; p = 0.031 and p = 0.042, respectively) and increased dopamine (5.9 ± 3.8 [control] and 12.4 ± 6.2 [KEMPFPKYPVEP peptide]) and norepinephrine (7.7 ± 0.8 [control] and 9.9 ± 2.0 [KEMPFPKYPVEP peptide]) levels in the frontal cortex (p = 0.039 and p = 0.031, respectively). Collectively, our findings suggest that peptides in fermented dairy products prevent cognitive decline and support previously reported observations.


Assuntos
Amnésia/tratamento farmacológico , Caseínas/química , Peptídeos/administração & dosagem , Amnésia/metabolismo , Amnésia/psicologia , Animais , Produtos Fermentados do Leite/análise , Modelos Animais de Doenças , Dopamina/metabolismo , Lobo Frontal/efeitos dos fármacos , Lobo Frontal/metabolismo , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Norepinefrina/metabolismo , Peptídeos/química , Escopolamina/efeitos adversos , Navegação Espacial/efeitos dos fármacos
7.
Oxid Med Cell Longev ; 2019: 3549274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31049133

RESUMO

Activated microglia-mediated neuroinflammation plays a key pathogenic role in neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, and ischemia. Sulforaphane is an active compound produced after conversion of glucoraphanin by the myrosinase enzyme in broccoli (Brassica oleracea var) sprouts. Dietary broccoli extract as well as sulforaphane has previously known to mitigate inflammatory conditions in aged models involving microglial activation. Here, we produced sulforaphane-enriched broccoli sprouts through the pretreatment of pulsed electric fields in order to trigger the biological role of normal broccoli against lipopolysaccharide-activated microglia. The sulforaphane-enriched broccoli sprouts showed excellent potency against neuroinflammation conditions, as evidenced by its protective effects in both 6 and 24 h of microglial activation in vitro. We further postulated the underlying mechanism of action of sulforaphane in broccoli sprouts, which was the inhibition of an inflammatory cascade via the downregulation of mitogen-activated protein kinase (MAPK) signaling. Simultaneously, sulforaphane-enriched broccoli sprouts inhibited the LPS-induced activation of the NF-κB signaling pathway and the secretions of inflammatory proteins (iNOS, COX-2, TNF-α, IL-6, IL-1ß, PGE2, etc.), which are responsible for the inflammatory cascades in both acute and chronic inflammation. It also upregulated the expression of Nrf2 and HO-1 in normal and activated microglia followed by the lowered neuronal apoptosis induced by activated microglia. Based on these results, it may exhibit anti-inflammatory effects via the NF-κB and Nrf2 pathways. Interestingly, sulforaphane-enriched broccoli sprouts improved the scopolamine-induced memory impairment in mice through Nrf2 activation, inhibiting neuronal apoptosis particularly through inhibition of caspase-3 activation which could lead to the neuroprotection against neurodegenerative disorders. The present study suggests that sulforaphane-enriched broccoli sprouts might be a potential nutraceutical with antineuroinflammatory and neuroprotective activities.


Assuntos
Amnésia , Brassica/química , Heme Oxigenase-1/metabolismo , Isotiocianatos , Fator 2 Relacionado a NF-E2/metabolismo , Escopolamina/efeitos adversos , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Amnésia/metabolismo , Amnésia/patologia , Animais , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Isotiocianatos/química , Isotiocianatos/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Microglia/metabolismo , Microglia/patologia , Escopolamina/farmacologia
8.
Food Funct ; 10(5): 2439-2449, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-30968880

RESUMO

The peptide derived from Anchovy hydrolysates, Pro-Ala-Tyr-Cys-Ser (PAYCS), was reported to display a neuroprotective effect in vitro in our previous study. The in vivo memory improving effects of PAYCS were investigated in this study. Prior to the scopolamine-induced amnesia mice trial, the stability of PAYCS during digestion was detected and the digestive products were identified. The results showed that PAYCS was susceptible to proteolytic degradation after incubation with pepsin and pancreatin and Pro-Ala-Tyr (PAY) was released and survived during the simulated GI digestion. The results of scopolamine-induced amnesia model trials showed that PAYCS and PAY treatment exhibited cognitive improvement effects in the behavioral tests and different pathways were determined. The results indicated that only PAYCS facilitated cholinergic activity by up-regulating the amount of acetylcholine (Ach) and acetylcholine receptor (AChR). Additionally, both PAYCS and PAY enhanced the superoxide dismutase (SOD) activity. Furthermore, PAYCS was found to be beneficial for the expression of the nuclear factor (erythroid-derived2)-like 2 protein (Nrf2), brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB). This indicated that PAYCS could regulate the oxidative stress by activating the Nrf2/antioxidant response elements (Nrf2/ARE) pathway. In our study, we demonstrated that the memory improving effects conferred by PAYCS on amnesia mice were linked to the attenuation of the cholinergic system and the activation of Nrf2/ARE and BDNF/CREB signaling.


Assuntos
Amnésia/tratamento farmacológico , Amnésia/psicologia , Proteínas de Peixes/química , Trato Gastrointestinal/metabolismo , Peptídeos/administração & dosagem , Peptídeos/química , Acetilcolina/metabolismo , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Amnésia/etiologia , Amnésia/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Feminino , Peixes , Humanos , Masculino , Memória/efeitos dos fármacos , Camundongos , Fármacos Neuroprotetores/administração & dosagem , Peptídeos/metabolismo , Escopolamina/efeitos adversos
9.
Neurochem Res ; 44(7): 1665-1677, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30949934

RESUMO

Dementia is considered as the frequent cause of neurodegenerative mental disorder such as Alzheimer's disease (AD) amongst elderly people. Free radicals as well as cholinergic deficit neurons within nucleus basalis magnocellularis demonstrated to attribute with aggregation of ß amyloid which further acts as an essential hallmark in AD. Various phenolic phytoconstituents exists in Trianthema portulastrum (TP) leaves have been reported as active against various neurological disorders. The current investigation was undertaken to evaluate the antiamnesic potential of butanol fraction of TP hydroethanolic extract (BFTP) by utilizing rodent models of elevated plus maze (EPM) and Hebbs William Maze (HWM) along with in vitro and in vivo antioxidant as well as acetylcholinesterase (AChE) inhibition studies. Molecular docking studies were also performed for evaluation of molecular interaction of existed phenolic compounds in BFTP. In vitro antioxidant study revealed concentration dependant strong ability of BFTP to inhibit free radicals. In vitro AChE inhibition study showed competitive type of inhibition kinetics. BFTP significantly reversed (p < 0.005 versus scopolamine) the damaging effect of scopolamine by reducing TL (Transfer Latency) and TRC (Time taken to recognize the reward chamber) in the EPM and HWM, respectively. BFTP also contributed towards increased (p < 0.005 versus scopolamine) enzymatic antioxidant as well as hippocampal acetylcholine (ACh) levels. Histological studies also supported the results as BFTP pretreated mice significantly reversed the scopolamine induced histological changes in hippocampal region. Docking studies confirmed chlorogenic acid has the most significant binding affinity towards AChE. This research finding concludes that BFTP could be a beneficial agent for management of cognition and behavioral disorders associated with AD.


Assuntos
Aizoaceae/química , Doença de Alzheimer/tratamento farmacológico , Amnésia/tratamento farmacológico , Nootrópicos/uso terapêutico , Fenóis/uso terapêutico , Extratos Vegetais/uso terapêutico , Acetilcolinesterase/química , Acetilcolinesterase/metabolismo , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Amnésia/patologia , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Catalase/metabolismo , Domínio Catalítico , Inibidores da Colinesterase/uso terapêutico , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Glutationa Peroxidase/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Simulação de Acoplamento Molecular , Folhas de Planta/química , Escopolamina , Superóxido Dismutase/metabolismo
10.
Oxid Med Cell Longev ; 2019: 8636835, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30911351

RESUMO

Ginkgo ketoester tablets (GT) and donepezil were a clinically used combination for the treatment of Alzheimer's disease (AD). The aim of the study was undertaken to investigate the antiamnesic effects of the two drugs alone and in combination through in vivo models of the Morris water maze along with in vitro antioxidants, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). The potential mechanisms were speculated by the activities of acetylcholine (ACh), AChE, superoxide dismutase (SOD), and malondialdehyde (MDA) and the protein expression of brain-derived neurotrophic factor (BDNF) and tyrosine protein kinase B (TrkB). The combination group showed a concentration-dependent inhibition of cholinesterase and antioxidation. As far as its mechanism was concerned, the combination of two drugs exerted excellent effects on oxidative stress, cholinergic pathway damage, and inactivation of the BDNF-TrkB signaling pathway. Additionally, to elucidate the binding mechanism of GT active ingredients into the structure of AChE, the results of molecular docking studies indicated that hydrogen and/or hydrophobic bonds might play an important role in their binding process. Thus, the combination of drugs could treat AD perfectly and further verify the scientific rationality of clinical medication.


Assuntos
Amnésia/tratamento farmacológico , Donepezila/uso terapêutico , Ginkgo biloba/química , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/uso terapêutico , Acetilcolina/metabolismo , Acetilcolinesterase , Amnésia/patologia , Animais , Benzotiazóis/química , Compostos de Bifenilo/química , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inibidores da Colinesterase/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Donepezila/farmacologia , Quimioterapia Combinada , Ginkgolídeos/química , Ligantes , Malondialdeído/metabolismo , Camundongos Endogâmicos ICR , Simulação de Acoplamento Molecular , Picratos/química , Extratos Vegetais/farmacologia , Receptor trkB/metabolismo , Escopolamina , Ácidos Sulfônicos/química , Superóxido Dismutase/metabolismo , Comprimidos
11.
Phytomedicine ; 58: 152889, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30901660

RESUMO

BACKGROUND: Agathisflavone, a biflavonoid isolated from Schinus polygamus (Cav.) Cabrera leaves been reported to promote various biological activities such as anti-inflammatory properties, promoting cognition and preventing cancer, antioxidant and antiapoptotic activities. PURPOSE: Here, we tested the hypothesis whether anxiety, amnesia, and brain oxidative stress induced by scopolamine could be counteracted in zebrafish model by agathisflavone and tried to ascertain the underlying mechanism. METHODS: Agathisflavone (1, 3 and 5 µg/l) was administered by immersion to zebrafish once daily for 8 days period. Anxiety and memory impairment were induced with scopolamine (100 µM) and measured with the novel tank diving test (NTT) and the Y-maze test. Zebrafish were divided into seven groups (n = 20/group): first group - control, second group - scopolamine (100 µM), the third, fourth and fifth group - agathisflavone treatment groups (FAB, 1 µg/l, 3 µg/l, and 5 µg/l), the sixth group - imipramine (IMP, 20 mg/l, as the positive control in NTT test), and the seventh group - donepezil group (DP, 10 mg/l, as the positive control in Y-maze test). The identification of the agathisflavone was done by spectroscopy, and the structure of the compound was confirmed by (-) Electrospray Ionisation Mass Spectrometry (ESI-MS). The brain oxidative status and acetylcholinesterase (AChE) activity were also investigated. RESULTS: Agathisflavone from Schinus polygamus (Cav.) Cabrera leaves was identified. Also, we demonstrated that agathisflavone significantly reversed scopolamine-induced behavioral score alteration in the NTT and Y-maze tests. Consequently, agathisflavone promoted inhibition of AChE activity and restored the brain antioxidant status. CONCLUSION: Our results demonstrate that agathisflavone promotes brain antioxidant action and ameliorates scopolamine-induced anxiety and memory deficits in zebrafish.


Assuntos
Anacardiaceae/química , Antioxidantes/farmacologia , Biflavonoides/farmacologia , Encéfalo/efeitos dos fármacos , Transtornos da Memória/prevenção & controle , Escopolamina/toxicidade , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Animais , Biflavonoides/isolamento & purificação , Encéfalo/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Masculino , Transtornos da Memória/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Folhas de Planta/química , Peixe-Zebra
12.
Nutrients ; 11(2)2019 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-30736353

RESUMO

Tryptophan-tyrosine (WY)-related peptides including the ß-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, ß-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline.


Assuntos
Amnésia/tratamento farmacológico , Dipeptídeos/farmacologia , Dopamina/metabolismo , Memória/efeitos dos fármacos , Triptofano/farmacologia , Tirosina/farmacologia , Amnésia/induzido quimicamente , Animais , Modelos Animais de Doenças , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Escopolamina
13.
Metab Brain Dis ; 34(1): 173-181, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30406376

RESUMO

The present study was designed to evaluate the effects of matrine (MAT) on scopolamine (SCOP)-induced learning and memory impairment. After successive oral administration of MAT to mice for three days at doses of 0.4, 2, and 10 mg/kg, we assessed improvements in learning and memory and investigated the mechanism of action of SCOP-induced amnesia. Donepezil at a dose of 3 mg/kg was used as a standard memory enhancer. MAT significantly improved SCOP-induced learning and memory impairment in novel object recognition and Y-maze tests at doses of 0.4, 2, and 10 mg/kg. Furthermore, MAT inhibited acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activities and decreased oxidative stress in the brain, as evidenced by increased total antioxidant capacity, total superoxide dismutase levels, and catalase activities as well as decreased malondialdehyde levels. Additionally, there was a significant negative correlation between the percentage of spontaneous alternation in the Y maze and AChE activity in the cortex and hippocampus. MAT ameliorated SCOP-induced amnesia by the inhibition of both AChE/BuChE activities and oxidative stress. This study provides further evidence to encourage the development of MAT as a drug for the prevention or treatment of Alzheimer's disease.


Assuntos
Alcaloides/uso terapêutico , Amnésia/tratamento farmacológico , Antioxidantes/uso terapêutico , Inibidores da Colinesterase/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Quinolizinas/uso terapêutico , Alcaloides/farmacologia , Amnésia/induzido quimicamente , Amnésia/metabolismo , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Inibidores da Colinesterase/farmacologia , Masculino , Malondialdeído/metabolismo , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos ICR , Fármacos Neuroprotetores/farmacologia , Quinolizinas/farmacologia , Escopolamina , Superóxido Dismutase/metabolismo
14.
Mini Rev Med Chem ; 19(1): 72-78, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30009706

RESUMO

BACKGROUND: Currently, there is no conclusive cure for Alzheimer's disease (AD) and existing treatments mainly offer symptomatic relief. Dysfunction of the cholinergic system plays an important role in the pathogenesis of AD. Tacrine (1, 2, 3, 4-tetrahydroacridin-9-amine, III) was the first approved agent for the palliative therapy of AD but its use is associated with some complications. Development of novel multi target derivatives of Tacrine with lower complications is strongly warranted. In this study, new aminobenzothiazole (1-5, with many useful biological and pharmacological properties) analogues (IV-VIII) were synthesized by changing of amine moiety of III. Then, the effects of these new compounds on learning and memory impairment in scopolamine-induced model of amnesia were studied and the outcomes were compared with control and Tacrine groups in rat. MATERIAL AND METHODS: The rats received Tacrine or its derivatives (IV-VIII) i.p. for two weeks at a dose of 10 mg/kg. For induction of amnesia, scopolamine at a dose of 1 mg/kg was daily administered i.p. started on day-8 till the end of the study. Behavioral experiments including Y-maze, novel object recognition (discrimination) and passive avoidance paradigms were conducted at week 2. RESULTS: Data analysis showed that some Tacrine derivatives, especially VII with 2-amino, 6-nitrobenzothiazole moiety, could markedly and significantly improve alternation score, discrimination ratio and step through latency compared to control and Tacrine groups. CONCLUSION: These findings indicated that some of these derivatives (especially compounds VI and VII) are capable to mitigate learning and memory deficits in scopolamine-induced model of amnesia in rats and may have potential benefit in management of patients with AD.


Assuntos
Amnésia/tratamento farmacológico , Benzotiazóis/química , Benzotiazóis/uso terapêutico , Nootrópicos/química , Nootrópicos/uso terapêutico , Tacrina/análogos & derivados , Tacrina/uso terapêutico , Doença de Alzheimer/tratamento farmacológico , Aminação , Animais , Benzotiazóis/administração & dosagem , Aprendizagem/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Nootrópicos/administração & dosagem , Ratos , Ratos Wistar , Escopolamina , Tacrina/administração & dosagem
15.
Behav Brain Res ; 357-358: 98-103, 2019 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-29330003

RESUMO

Previously the effects (0.01-3.0 mg/kg) of post-training SB-699551 (a 5-HT5A receptor antagonist) were reported in the associative learning task of autoshaping, showing that SB-699551 (0.1 mg/kg) decreased lever-press conditioned responses (CR) during short-term (STM; 1.5-h) or (3.0 mg/kg) long-term memory (LTM; 24-h); relative to the vehicle animals. Moreover, as pro-cognitive efficacy of SB-699551 was reported in the ketamine-model of schizophrenia. Hence, firstly aiming improving performance (conditioned response, CR), in this work autoshaping lever-press vs. nose-poke response was compared; secondly, new set of animals were randomly assigned to SB-699551 plus forgetting or amnesia protocols. Results show that the nose-poke operandum reduced inter-individual variance, increased CR and produced a progressive CR until 48-h. After one week of no training/testing sessions (i.e., interruption of 216 h), the forgetting was observed; i.e., the CR% of control-saline group significantly decreased. In contrast, SB-699551 at 0.3 and 3.0 mg/kg prevents forgetting. Additionally, as previously reported the non-competitive NMDA receptor antagonist dizocilpine (0.2 mg/kg) or the non-selective cholinergic antagonist scopolamine (0.3 mg/kg) decreased CR in STM. SB-699551 (0.3 mg/kg) alone also produced amnesia-like effect. Co-administration of SB-699551-dizocilpine or SB-699551-scopolamine reversed the SB-699551 induced-amnesic effects in LTM (24-h). Nose-poke seems to be a reliable operandum. The anti-amnesic and anti-forgetting mechanisms of amnesic SB-699551-dose remain unclear. The present findings are consistent with the notion that low doses of 5-HT5A receptor antagonists might be useful for reversing memory deficits associated to forgetting and amnesia. Of course, further experiments are necessary.


Assuntos
Amnésia/metabolismo , Memória/fisiologia , Receptores de Serotonina/metabolismo , Antagonistas da Serotonina/uso terapêutico , Amnésia/induzido quimicamente , Amnésia/tratamento farmacológico , Análise de Variância , Animais , Compostos de Bifenilo/uso terapêutico , Antagonistas Colinérgicos/toxicidade , Condicionamento Clássico/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Modelos Animais de Doenças , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Comportamento Exploratório/efeitos dos fármacos , Extinção Psicológica/efeitos dos fármacos , Masculino , Memória/efeitos dos fármacos , Ratos , Ratos Wistar , Escopolamina/toxicidade
16.
Bull Exp Biol Med ; 166(1): 1-6, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30417305

RESUMO

We studied the participation of DNA-methylation processes in the mechanisms of memory storage and reconsolidation, amnesia induction, and in recovery of the conditioned food aversion memory in edible snails. It was found that daily injections of DNA methyltransferases inhibitor over 3 days combined with a reminder of a conditioned food stimulus did not affect memory storage. The administration of DNA methyltransferase inhibitors did not suppress induction of amnesia caused the NMDA receptor antagonist/reminder. Injections of DNA methyltransferase inhibitors combined with the reminder led to memory recovery in 3 days after amnesia induction. Thus, DNA methyltransferase inhibitors in the same doses did not affect storage and reconsolidation of memory, as well as the mechanisms of amnesia induction. At the same time, injections of inhibitors led to memory recovery, apparently, due to disruption of reactivation and amnesia development.


Assuntos
Metilases de Modificação do DNA/metabolismo , Memória/efeitos dos fármacos , Ftalimidas/farmacologia , Triptofano/análogos & derivados , Valina/análogos & derivados , Amnésia/tratamento farmacológico , Amnésia/enzimologia , Amnésia/prevenção & controle , Animais , Metilases de Modificação do DNA/antagonistas & inibidores , Ftalimidas/uso terapêutico , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Triptofano/farmacologia , Triptofano/uso terapêutico , Valina/farmacologia , Valina/uso terapêutico
17.
Biomed Pharmacother ; 108: 374-390, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30227331

RESUMO

Bergenia ciliata (Haw) Sternb. possess immunomodulatory, anti-inflammatory, antioxidant, anti-urolithiatic, wound healing, anti-malarial, anti-diabetic and anti-cancer properties. Moreover, the methanolic extracts of the rhizomes of the plant were found to demonstrate beneficial neuroprotective effects in the intracerebroventricular streptozotocin-induced model in rats. Thus, the present study was undertaken to further explore the neuroprotective potential of the aqueous (BA) and methanolic extracts (BM) of B. ciliata through various in-vitro and in-vivo studies. Both the extracts at all tested concentrations i.e. 50-50,000 ng/mL did not cause any significant reduction of cell viability of SH-SY5Y cells when tested for 48 h when assessed through MTT and resazurin metabolism- based cell viability assays. The pre-treatment with the extracts could confer significant (p < 0.001) and dose-dependent protective effects against NMDA induced injury in SH-SY5Y cells. BM [IC50: 5.7 and 5.19 µg/mL for acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) respectively] led to more potent inhibition of both the enzymes as compared to BA (IC50: 227.12 and 23.25 µg/mL for AChE and BuChE respectively). BM also proved to be a 1.85-fold better scavenger of the DPPH free radicals as compared to BA. Thus, BM was taken further for the evaluation of the beneficial effects of 14-day pre-treatment in rats in the scopolamine (2 mg/kg, i.p.) induced amnesia model at 125, 250 and 500 mg/kg, p.o. BM pre-treatment at 250 and 500 mg/kg could significantly ameliorate the cognitive impairment (p < 0.001), inhibit AChE (p < 0.001) and BuChE (p < 0.05) activity, restore GSH levels (p < 0.05) in serum and brain homogenates and recover the morphology of hippocampal neurons back to normal. Moreover, the BM administration at 500 mg/kg also showed beneficial effects through the significant (p < 0.05) reduction of Aß1-42, phosphorylated tau (p-tau) and GSK-3ß immunoreactivity in the brain homogenates of the intracerebroventricularly streptozotocin (ICV STZ) injected rats as observed from the results of the ELISA assays. The outcomes of the study unveiled that BM exerts its beneficial effects through prevention of NMDA induced excitotoxic cell death, dual cholinesterase inhibition, antioxidant activity coupled with the reduction of the immunoreactivity for the Aß1-42, p-tau and GSK-3ß indicating its potential to be screened further for various other models to determine the exact mechanism of action.


Assuntos
Amnésia/tratamento farmacológico , Disfunção Cognitiva/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Extratos Vegetais/farmacologia , Acetilcolinesterase/metabolismo , Amnésia/induzido quimicamente , Amnésia/metabolismo , Animais , Antioxidantes/farmacologia , Encéfalo/efeitos dos fármacos , Butirilcolinesterase/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/metabolismo , Humanos , Masculino , N-Metilaspartato/farmacologia , Neurônios/efeitos dos fármacos , Ratos , Ratos Wistar , Escopolamina/farmacologia , Estreptozocina/farmacologia
18.
Phytomedicine ; 47: 113-120, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30166095

RESUMO

BACKGROUND: Matricaria chamomilla L. is a medicinal herb traditionally used as the anti-inflammatory, antimicrobial, antiviral, anxiolytic and antidepressant agent. Nevertheless, supporting evidence demonstrated its memory enhancing activity and antioxidant properties. PURPOSE: To investigate the effects of the hydroalcoholic extract of M. chamomilla L. on memory processes in a scopolamine-induced a rat model of amnesia and to reveal its underlying mechanism of action. METHODS: The hydroalcoholic extract (25 and 75 mg/kg) was intraperitoneally administered to rats once daily for 7 days, and scopolamine (0.7 mg/kg) was injected 30 min before the behavioral testing to induce memory impairment. The phytochemical composition of the extract was quantified by HPLC/DAD analysis. Y-maze and radial arm-maze tests were employed for memory assessing. Acetylcholinesterase activity was measured in the rat hippocampus. Superoxide dismutase, glutathione peroxidase, and catalase specific activities along with the total content of reduced glutathione and protein carbonyl and malondialdehyde levels were also measured in the rat hippocampus. qRT-PCR was used to quantify BDNF mRNA and IL1ß mRNA expression in the rat hippocampus. RESULTS: We first identified the chlorogenic acid, apigenin-7-glucoside, rutin, cynaroside, luteolin, apigenin and derivatives of apigenin-7-glucoside as the extract major components. Furthermore, we showed that the extract reversed the scopolamine-induced decreasing of the spontaneous alternation in the Y-maze test and the scopolamine-induced increasing of the working and reference memory errors in the radial arm maze test. Also, the scopolamine-induced alteration of the acetylcholinesterase activity and the oxidant-antioxidant balance in the rat hippocampus was recovered by the treatment with the extract. Finally, we demonstrated that the extract restored the scopolamine-decreased BDNF expression and increased IL1ß expression in the rat hippocampus. CONCLUSION: These findings suggest that the extract could be a potent neuropharmacological agent against amnesia via modulating cholinergic activity, neuroinflammation and promoting antioxidant action in the rat hippocampus.


Assuntos
Matricaria/química , Transtornos da Memória/tratamento farmacológico , Extratos Vegetais/farmacologia , Amnésia/tratamento farmacológico , Animais , Antioxidantes/farmacologia , Cognição/efeitos dos fármacos , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Transtornos da Memória/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Ratos , Escopolamina/efeitos adversos , Superóxido Dismutase/metabolismo
19.
Eur J Pharm Sci ; 123: 459-474, 2018 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-30077712

RESUMO

Vasicine (VAS) is a potential natural cholinesterase inhibitor for treatment of Alzheimer's disease. Due to one chiral centre (C-3) presenting in molecule, VAS has two enantiomers, d-vasicine (d-VAS) and l-vasicine (l-VAS). The study was undertaken to investigate the stereoselective glucuronidation metabolism, pharmacokinetics, anti-amnesic effect and acute toxicity of VAS enantiomers. In results, the glucuronidation metabolic rate of l-VAS was faster than d-VAS in human liver microsomes and isoenzymes tests, and it was proved that the UDP-glucuronosyltransferase (UGT) 1A9 and UGT2B15 were the major metabolic enzymes for glucuronidation of l-VAS, while only UGT1A9 for d-VAS, which take responsibility of the significantly less metabolic affinity of d-VAS than l-VAS in HLM and rhUGT1A9. The plasma exposure of d-VAS in rats was 1.3-fold and 1.6-fold higher than that of l-VAS after intravenous and oral administration of d-VAS and l-VAS, respectively. And the plasma exposure of the major glucuronidation metabolite d-VASG was one of tenth of l-VASG or more less, no matter by intravenous or oral administration. Both d-VAS and l-VAS were exhibited promising acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activities, and the BChE inhibitory activity of d-VAS with IC50 of 0.03 ±â€¯0.001 µM was significantly stronger than that of l-VAS with IC50 of 0.98 ±â€¯0.19 µM. The molecular docking results indicated that d-VAS and l-VAS could bind to the catalytic active site (CAS position) either of human AChE and BChE, and the BChE combing ability of d-VAS (the score of GBI/WAS dG -7.398) was stronger than that of l-VAS (the score of GBI/WAS dG -7.135). Both d-VAS and l-VAS could improving the learning and memory on scopolamine-induced memory deficits in mice. The content of acetylcholine (ACh) after oral administration d-VAS increased more than that of l-VAS in mice cortex, through inhibiting cholinesterase (ChE) and increasing choline acetyltransferase (ChAT). In addition, the LD50 value of d-VAS (282.51 mg·kg-1) was slight lower than l-VAS (319.75 mg·kg-1). These results indicated that VAS enantiomers displayed significantly stereoselective metabolic, pharmacokinetics, anti-amnesic effect and toxic properties in vitro and in vivo. The d-VAS might be the dominant configuration for treating Alzheimer's disease.


Assuntos
Alcaloides/farmacocinética , Amnésia/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/farmacocinética , Glucuronídeos/metabolismo , Memória/efeitos dos fármacos , Quinazolinas/farmacocinética , Acetilcolinesterase/metabolismo , Administração Intravenosa , Administração Oral , Alcaloides/administração & dosagem , Alcaloides/química , Alcaloides/toxicidade , Amnésia/induzido quimicamente , Amnésia/psicologia , Animais , Butirilcolinesterase/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/química , Inibidores da Colinesterase/toxicidade , Modelos Animais de Doenças , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Glucuronosiltransferase/metabolismo , Cobaias , Humanos , Isomerismo , Masculino , Taxa de Depuração Metabólica , Desintoxicação Metabólica Fase II , Camundongos Endogâmicos C57BL , Microssomos Hepáticos/enzimologia , Simulação de Acoplamento Molecular , Quinazolinas/administração & dosagem , Quinazolinas/química , Quinazolinas/toxicidade , Coelhos , Ratos Sprague-Dawley , Escopolamina , Relação Estrutura-Atividade
20.
Biomed Pharmacother ; 105: 1344-1352, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30021372

RESUMO

Centella asiatica (CA) has been used by Ayurvedic medical practitioners in India for almost 3000 years. The neuropharmacological properties of CA and its constituents have been studied extensively. Anti-oxidant, free radical scavenging and cholinergic modulatory activities are the reported mechanisms of action for its efficacy in memory disorders. Its medicinal values are mainly attributed to the presence of several triterpenes, namely asiatic acid, madecassic acid, asiaticoside, and madecassoside. The present study was aimed to investigate the role of these triterpenes content in CA extract on the antioxidant, cholinesterase modulation and anti-amnesic properties. The fractions of CA extract enriched for (CAE-EF) and depleted/freed of (CAE-FF) triterpenes contents were compared with methanolic extract (CAE). Both in vitro and in vivo methods for evaluation of antioxidant and anticholinergic activities were used. In vitro, free radical scavenging assays (ABTS, DPPH, NO, NORAC, and ORAC) and cholinesterase (AChE and BuChE) inhibition assays were used. For evaluation of anti-amnesic effect, scopolamine induced amnesia in rats, as the acute model of memory loss was used. Following behavioural assessments (MWM, PA, EPM), biomarkers of oxidative stress (reduced GSH, MDA and SOD activity) and cholinesterase (AChE and BuChE) status were also estimated in cerebral cortex and hippocampus of rat brain. The methanolic extract (CAE) was found to perform best among all three fractions for in vitro free radical scavenging, cholinesterase inhibition, improvement of scopolamine-induced amnesia and also in vivo antioxidant effect and cholinesterase inhibitory activities. Interestingly triterpenes free fraction (CAE-FF) showed better antioxidant activity than triterpenes enriched fraction (CAE-EF) along with comparable anti-amnesic effect. This indicates that triterpenes are not solely responsible for antioxidant activity, cholinesterase inhibitory and anti-amnesic effect of CA.


Assuntos
Amnésia/tratamento farmacológico , Antioxidantes/farmacologia , Centella/química , Antagonistas Colinérgicos/farmacologia , Inibidores da Colinesterase/farmacologia , Triterpenos/farmacologia , Amnésia/metabolismo , Animais , Colinesterases/metabolismo , Masculino , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Metanol/química , Oxidantes/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Ratos , Ratos Wistar , Escopolamina/farmacologia
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