RESUMO

Alzheimer's disease (AD) and depression are inflammatory pathologies, leading to increased inflammatory response and neurotoxicity. Therefore, this study aimed to evaluate the effect of the treatment with fluoxetine and/or galantamine and/or donepezil on the levels of proinflammatory and anti-inflammatory cytokines in a mixed animal model of depression and dementia. Adult male Wistar rats underwent chronic mild stress (CMS) protocol for 40 days and were subjected to stereotaxic surgery for intra-hippocampal administration of amyloid-beta (Aꞵ) peptide or artificial cerebrospinal fluid (ACSF) to mimic the dementia animal model. On the 42nd day, animals were treated with water, galantamine, donepezil, and/or fluoxetine, orally for 17 days. On the 57th and 58th days, the Splash and Y-maze tests for behavior analysis were performed. The frontal cortex and hippocampus were used to analyze the tumor necrosis factor alfa (TNF-α), interleukin 1 beta (IL-1ꞵ), IL-6, and IL-10 levels. The results of this study show that animals subjected to CMS and administration of Aꞵ had anhedonia, cognitive impairment, increased TNF-α and IL-1ꞵ levels in the frontal cortex, and reduced IL-10 levels in the hippocampus. All treatment groups were able to reverse the cognitive impairment. Only donepezil did not decrease the TNF-α levels in the hippocampus. Fluoxetine + galantamine and fluoxetine + donepezil reversed the anhedonia. Fluoxetine reversed the anhedonia and IL-1ꞵ levels in the frontal cortex. In addition, fluoxetine + donepezil reversed the reduction of IL-10 levels in the hippocampus. The results indicate a pathophysiological interaction between AD and depression, and the association of medications in the future may be a possible therapeutic strategy to reduce inflammation, especially the fluoxetine-associated treatments.

Assuntos

Demência , Depressão , Modelos Animais de Doenças , Donepezila , Fluoxetina , Galantamina , Hipocampo , Ratos Wistar , Animais , Masculino , Fluoxetina/farmacologia , Fluoxetina/uso terapêutico , Donepezila/farmacologia , Donepezila/uso terapêutico , Ratos , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Demência/tratamento farmacológico , Depressão/tratamento farmacológico , Galantamina/farmacologia , Galantamina/uso terapêutico , Citocinas/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Estresse Psicológico/complicações , Peptídeos beta-Amiloides/metabolismo , Anedonia/efeitos dos fármacos

RESUMO

This study aimed to evaluate the in silico and in vitro inhibitory effect of the combined use of galantamine (GAL) and donepezil (DON) against acetylcholinesterase and butyrylcholinesterase (BuChE) enzymes. In silico and in vitro cholinesterase analysis were carried out for GAL and DON alone and combined. Molecular modeling studies were carried out (docking analysis, molecular dynamics simulation, and quantum theory of atoms in molecules). Cholinesterase's inhibitory activities by modified Ellman's method and the drug combination effect using the Chou-Talalay method were assayed. GAL/DON combination showed the co-occupancy of the ligands in both enzymes through in silico studies. Regarding in vitro BuChE inhibition analyses, three of five combinations showed an interaction between GAL and DON at the threshold of additive affect (0.9 < CI < 1.1), with a tendency toward a synergistic effect for higher concentrations. This is the first report showing the efficacy of the GAL/DON combinations inhibiting BuChE, showing the importance of analyzing the behavior of different ligands when co-occupancy into the active site is possible. These combinations might be a possible therapy to improved efficacy, reduced doses, minor side effects, and high levels of the neurotransmitter in the synaptic space for Alzheimer's disease.

Assuntos

Doença de Alzheimer , Galantamina , Humanos , Galantamina/farmacologia , Butirilcolinesterase/metabolismo , Donepezila/farmacologia , Inibidores da Colinesterase/farmacologia , Acetilcolinesterase/metabolismo , Relação Estrutura-Atividade , Doença de Alzheimer/tratamento farmacológico , Simulação de Acoplamento Molecular

RESUMO

BACKGROUND: Two classes of medications are used to treat Alzheimer's disease (AD); donepezil, galantamine, and rivastigmine are acetylcholinesterase inhibitors, and memantine is a non-competitive antagonist of the N-methyl-D-aspartate receptor. Although these are typically taken orally, there are transdermal therapeutic systems (TTSs) commercially available for rivastigmine and donepezil. The transdermal route has been preferable for guardians/caregivers due to ease of use, reduced side effects, and improved adherence to therapy. OBJECTIVE: The study aimed to obtain knowledge of the properties of these drugs and to search for patents relating to the TTS for AD using the Espacenet platform. METHODS: The search terms were "rivastigmine AND transdermal AND skin delivery AND Alzheimer's", changing the drugs "memantine", "donepezil", and "galantamine", between January 2015 and January 2022. Title and abstract were used to choose patents. RESULTS: TTSs present some limit factors in terms of absorption due to skin physiology and the size of the molecules with established limits of percutaneous penetration (molecular mass of 500 g/mol and log P of 5). We found 1, 4, 4, and 2 patents for galantamine, rivastigmine, donepezil, and memantine, respectively. Galantamine TTS seems to be more challenging due to the molecular mass of 287.35 g/mol and logP of 1.8. The permeator of absorption is necessary. Memantine, rivastigmine, and donepezil present logP of 3.28, 2.3, and 4.27 and molecular weights of 179.30, 250.34, and 415.96 g/mol, respectively. CONCLUSION: TTSs are primarily effective for delivering small molecules. The use of absorption enhancers and irritation mitigators can be necessary to enhance the performance. The development of these technologies is essential for the convenience of patients and caregivers.

RESUMO

Women older than 60 have a higher risk of dementia, aging-related cognitive decline, and Alzheimer's Disease (AD) than the rest of the population. The main reason is hormonal senescence after menopause, a period characterized by a decline in estrogen levels. Since the effectiveness of drugs currently approved for the treatment of AD is limited, it is necessary to seek the development of new therapeutic strategies. Vitamin D deficiency is prevalent in AD patients and individuals with dementia in general. The supplementation of this vitamin in dementia patients might be an interesting approach for increasing the effectiveness of pre-existing medications for dementia treatment. Thus, the present study aims to investigate the effect of vitamin D treatment associated with memantine and donepezil in female mice submitted to ovariectomy (OVX) for five months and subjected to a dementia animal model induced by intracerebroventricular injection of aggregated amyloid ßeta (Aß1-42). For this purpose, Balb/c mice were divided into five experimental groups, which received 17 days of combined therapy with vitamin D, donepezil, and memantine. Then, animals were subjected to behavioral tests. OVX groups exhibited reduced levels of estradiol (E2) in serum, which was not altered by the combined therapy. Higher levels of vitamin D3 were found in the OVX animals submitted to the triple-association treatment. Mice exposed to both OVX and the dementia animal model presented impairment in short and long-term spatial and habituation memories. Also, female mice exposed to Aß and OVX exhibited a reduction in brain-derived neurotrophic factor (BDNF) and interleukin-4 (IL-4) levels, and an increase in tumor necrose factor-α (TNFα) levels in the hippocampus. Besides, increased levels of IL-1ß in the hippocampus and cerebral cortex were observed, as well as a significant increase in immunoreactivity for glial fibrillary acidic protein (GFAP), an astrocytes marker, in the hippocampus. Notably, triple-association treatment reversed the effects of the exposition of mice to Aß and OVX in the long-term spatial and habituation memories impairment, as well as reversed changes in TNFα, IL-1ß, IL-4, and GFAP immunoreactivity levels in the hippocampus of treated animals. Our results indicate that the therapeutic association of vitamin D, memantine, and donepezil has beneficial effects on memory performance and attenuated the neuroinflammatory response in female mice subjected to OVX associated with a dementia animal model.

Assuntos

Doença de Alzheimer , Fármacos Neuroprotetores , Camundongos , Feminino , Animais , Memantina/farmacologia , Memantina/uso terapêutico , Donepezila/metabolismo , Donepezila/farmacologia , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Vitamina D/farmacologia , Interleucina-4/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Vitaminas , Hipocampo/metabolismo , Peptídeos beta-Amiloides/metabolismo

RESUMO

Abstract Donepezil-HCl is a member of the acetylcholinesterase inhibitors that is indicated for the symptomatic treatment of Alzheimer's disease (AD) and has many side effects. In this study, to reduce the side effects of Donepezil-HCl and increase the penetration of the drug through the blood-brain barrier, we aimed to design a solid lipid nanoparticle (SLN) formulation. The effects of the different formulation parameters, such as homogenization speed, sonication time, lipid and drug concentration, surfactant type and concentration, and volume of the aqueous phase, were assessed for optimization. The particle size and PDI increased with increasing lipid concentration but decreased with increasing amounts of surfactant (Tween 80) and co-surfactant (lecithin). When the homogenization rate and sonication time increased, the particle size decreased and the encapsulation efficiency increased. The optimized formulation exhibited particle size, PDI, encapsulation efficiency, and zeta potential of 87.2±0.11 nm; 0.22±0.02; 93.84±0.01 %; -17.0±0.12 mV respectively. The in vitro release investigation revealed that approximately 70% of Donepezil-HCl was cumulatively released after 24 hours. TEM analysis proved that spherical and smooth particles were obtained and formulations had no toxic effect on cells. The final optimized formulation could be a candidate for Donepezil-HCl application in Alzheimer's treatment with reduced side effects and doses for patients

Assuntos

Padrões de Referência , Pesquisa/instrumentação , Nanopartículas/análise , Donepezila/efeitos adversos , Técnicas In Vitro/métodos , Preparações Farmacêuticas/administração & dosagem , Doença de Alzheimer/patologia

RESUMO

Alzheimer's disease is characterized by a progressive deterioration of neurons resulting in a steady loss of cognitive functions and memory. Many treatments encounter the challenge of overcoming the blood-brain barrier, thus the intranasal route is a non-invasive effective alternative that enhances the drug delivery in the target organ-the brain-and reduces the side effects associated with systemic administration. This study aimed at developing intranasal gels of donepezil as an approach to Alzheimer's disease. Three different gels were elaborated and characterized in terms of pH, morphology, gelation temperature, rheology, and swelling. An in vitro release study and an ex vivo permeation in porcine nasal mucosa were conducted on Franz diffusion cells. The tolerability of the formulations was determined by the cytotoxicity in human nasal cells RPMI 2650. Results showed that pluronic gels exhibit the higher release rate and enhanced permeation compared to chitosan gel. Moreover, the combination of Pluronic F-127 and Transcutol® P exerted a synergic effect on the permeation of donepezil through the nasal mucosa. The resulting gels showed suitable tolerance in the RPMI 2650 cell line and physicochemical characteristics for intranasal delivery, and thus gel formulations administered by nasal mucosa could be an alternative strategy to improve the bioavailability of donepezil.

RESUMO

The spontaneous object recognition (SOR) task is one of the most widely used behavioral protocols to assess visual memory in animals. However, only recently was it shown that nonhuman primates also perform well on this task. Here we further characterized this new monkey recognition memory test by assessing the performance of adult marmosets after an acute systemic administration of two putative amnesic agents: the competitive muscarinic acetylcholine receptor antagonist scopolamine (SCP; 0.05 mg/kg) and the noncompetitive N-methyl-d-aspartate glutamate receptor antagonist MK-801 (0.015 mg/kg). We also determined whether the acetylcholinesterase inhibitor donepezil (DNP; 0.50 mg/kg), a clinically-used cognitive enhancer, reverses memory deficits caused by either drug. The subjects had an initial 10 min sample trial where two identical neutral objects could be explored. After a 6 h retention interval, recognition was based on an exploratory preference for a new rather than familiar object during a 10 min test trial. Both SCP and MK-801 impaired the marmosets' performance on the SOR task, as both objects were explored equivalently. Co-administration of 0.50 mg/kg of DNP reversed the SCP- but not the MK-801-induced memory deficit. These results indicate that cholinergic and glutamatergic pathways mediate object recognition memory in the monkey SOR task.

Assuntos

Maleato de Dizocilpina/farmacologia , Teste de Campo Aberto/efeitos dos fármacos , Reconhecimento Psicológico/efeitos dos fármacos , Escopolamina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Callithrix/metabolismo , Donepezila/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Feminino , Haplorrinos/metabolismo , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Antagonistas Muscarínicos/farmacologia , Nootrópicos/farmacologia , Receptores Muscarínicos/metabolismo

RESUMO

SUMMARY OBJECTIVE: To observe the effects of Dengzhan Shengmai capsule combined with donepezil hydrochloride on cognitive function, daily living ability, and safety in patients with Alzheimer's disease. METHODS: A total of 294 patients with Alzheimer's disease were randomly divided into a treatment group and a control group, 147 cases each group. The control group was given oral donepezil hydrochloride 5 mg once a day, and the treatment group was given oral Dengzhan Shengmai capsule 0.36 g three times a day, based on the control group. RESULTS: At 3 and 6 months of treatment, the ADAS-cog score of the treatment group was 48.69±6.23 and 44.24±5.53; for the control group, 45.48±5.94 and 41.57±5.10. The difference between the two groups is statistically significant (p<0.05). At 3 and 6 months of treatment, the NO level in the treatment group was (46.28±6.68) umol/l, (43.55±7.92) umol/l, and the control group was (42.95±7.92) umol/l, (38.89±5.93) umol/l. The differences between both groups were statistically significant (p<0.05). At 3 and 6 months of treatment, ET levels in the treatment group were (156.08±17.39) ng/l, (144.91±17.60) ng/l, and the control group was (150.48±22.94) ng/l, (135.04±10.08) ng/l. Correlation analysis showed that ADAS-cog score was negatively correlated with NO and ET (p<0.001). CONCLUSIONS: Dengzhan Shengmai capsule combined with donepezil hydrochloride can improve cognitive function and the living capacity of patients with Alzheimer's disease, reduce the production of neurotoxic substances NO and ET, and provide higher safety.

Assuntos

Humanos , Medicamentos de Ervas Chinesas/efeitos adversos , Doença de Alzheimer/tratamento farmacológico , Método Duplo-Cego , Inibidores da Colinesterase , Cognição , Donepezila

RESUMO

A new series of ten multifunctional Cinnamoyl-N-acylhydrazone-donepezil hybrids was synthesized and evaluated as multifunctional ligands against neurodegenerative diseases. The molecular hybridization approach was based on the combination of 1-benzyl-4-piperidine fragment from the anti-Alzheimer AChE inhibitor donepezil (1) and the cinnamoyl subunit from curcumin (2), a natural product with remarkable antioxidant, neuroprotective and anti-inflammatory properties, using a N-acylhydrazone fragment as a spacer subunit. Compounds 4a and 4d showed moderate inhibitory activity towards AChE with IC50 values of 13.04 and 9.1 µM, respectively. In addition, compound 4a and 4d showed a similar predicted binding mode to that observed for donepezil in the molecular docking studies. On the other hand, compounds 4a and 4c exhibited significant radical scavenging activity, showing the best effects on the DPPH test and also exhibited a significant protective neuronal cell viability exposed to t-BuOOH and against 6-OHDA insult to prevent the oxidative stress in Parkinson's disease. Similarly, compound 4c was capable to prevent the ROS formation, with indirect antioxidant activity increasing intracellular GSH levels and the ability to counteract the neurotoxicity induced by both OAß1-42 and 3-NP. In addition, ADMET in silico prediction indicated that both compounds 4a and 4c did not show relevant toxic effects. Due to their above-mentioned biological properties, compounds 4a and 4c could be explored as lead compounds in search of more effective and low toxic small molecules with multiple neuroprotective effects for neurodegenerative diseases.

Assuntos

Cinamatos/farmacologia , Donepezila/farmacologia , Hidrazonas/farmacologia , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Acetilcolinesterase/metabolismo , Butirilcolinesterase/metabolismo , Linhagem Celular Tumoral , Inibidores da Colinesterase/síntese química , Inibidores da Colinesterase/metabolismo , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/farmacologia , Cinamatos/síntese química , Cinamatos/metabolismo , Cinamatos/farmacocinética , Donepezila/síntese química , Donepezila/metabolismo , Donepezila/farmacocinética , Sequestradores de Radicais Livres/síntese química , Sequestradores de Radicais Livres/metabolismo , Sequestradores de Radicais Livres/farmacocinética , Sequestradores de Radicais Livres/farmacologia , Humanos , Hidrazonas/síntese química , Hidrazonas/metabolismo , Hidrazonas/farmacocinética , Ligantes , Simulação de Acoplamento Molecular , Estrutura Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Fármacos Neuroprotetores/farmacocinética , Ligação Proteica , Relação Estrutura-Atividade

RESUMO

Obesity is characterized by chronic inflammation of low grade. The cholinergic anti-inflammatory pathway favors the reduction of the inflammatory response. In this work the effect of stimulation of the cholinergic anti-inflammatory pathway on SHIRPA behavioral test and mitochondrial respiratory chain activity in obese mice was evaluated. The animals were paired in four groups: saline + control diet; donepezil + control diet; saline + high-fat diet and donepezil + high-fat diet. 5 mg/kg/day orally of donepezil or saline were given 7 days before the beginning of the diet until completing 11 weeks of the experiment. Food intake and body weight were measured. At the end of the experiment the animals were submitted to the SHIRPA behavioral test, soon after they were killed by decapitation, the open abdominal cavity and the mesenteric fat were removed. The hypothalamus, hippocampus, prefrontal cortex, and striatum were removed for evaluation of the mitochondrial respiratory chain. It can be observed that donepezil prevented weight gain and food consumption, as well as a tendency to prevent the accumulation of mesenteric fat in obese animals. There was no behavioral change in obese animals, nor did the influence of donepezil on these parameters. On the other hand, donepezil did not prevent inhibition of complex I activity, prevented the inhibition of complex II, and showed a tendency to prevent IV complex activity inhibited in obesity. With these results it can be concluded that the activation of the cholinergic anti-inflammatory pathway is promising for the alterations found in obesity.

Assuntos

Fármacos Antiobesidade/uso terapêutico , Encéfalo/metabolismo , Donepezila/uso terapêutico , Metabolismo Energético/efeitos dos fármacos , Obesidade/prevenção & controle , Animais , Peso Corporal/efeitos dos fármacos , Dieta Hiperlipídica , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Complexo I de Transporte de Elétrons/metabolismo , Complexo II de Transporte de Elétrons/antagonistas & inibidores , Complexo II de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/antagonistas & inibidores , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Masculino , Camundongos , Obesidade/metabolismo

RESUMO

Donepezil hydrochloride is one of the most prescribed anti-Alzheimer's drugs, despite being available for more than two decades, chromatographic methods for the quantification of the drug in biorelevant media that mimics pH physiological conditions in vivo (pH 1.2, 4.5, and 6.8) are not available in the literature. These media are used in the dissolution test, an important tool, for registration and quality control of medicines. Considering the need for methods with this purpose, this work aimed to develop and validate a sustainable UPLC-UV method for quantification of donepezil hydrochloride in tablets, specifically on assay and dissolution profile, with reduced environmental impacts. The proposed method has a run time of 2 min and requires for each run, only 0.8 mL of solvents, providing excellent green analysis. The method proved to be selective, linear, precise, accurate, robust in the range of 2-14 µg/mL. Three products (reference, similar, and generic) were analyzed and showed very rapid dissolution. The average content varied from 100.2 ± 0.6% to 109.5 ± 2.1%. Using dissolution efficiency (DE), the drug release profiles were compared in different biorelevant media.

Assuntos

Donepezila , Liberação Controlada de Fármacos , Controle de Qualidade , Solubilidade , Comprimidos/química

RESUMO

BACKGROUND: A potent acetylcholinesterase inhibitor, donepezil is a cognitive enhancer clinically used to treat neurodegenerative diseases. However, its complete pharmacological profile beyond cognition remains unclear. The zebrafish (Danio rerio) is rapidly becoming a powerful novel model organism in neuroscience and central nervous system drug screening. AIM: Here, we characterize the effects of 24-h donepezil administration on anxiety-like behavioral and endocrine responses in adult zebrafish. METHODS: We evaluated zebrafish anxiety-like behaviors in the novel tank, the light-dark and the shoaling tests, paralleled by assessing brain acetylcholinesterase activity and whole-body cortisol levels. RESULTS: Overall, donepezil dose-dependently decreased zebrafish locomotor activity in the novel tank test and reduced time in light in the light-dark test, likely representing hypolocomotion and anxiety-like behaviors. Donepezil predictably decreased brain acetylcholinesterase activity, also increasing whole-body cortisol levels, thus further linking acetylcholinesterase inhibition to anxiety-like behavioral and endocrine responses. CONCLUSION: Collectively, these findings suggest negative modulation of zebrafish affective behavior by donepezil, support the key role of cholinergic mechanisms in behavioral regulation in zebrafish, and reinforce the growing utility of zebrafish models for studying complex behavioral processess and their neuroendocrine and neurochemical regulation.

Assuntos

Ansiedade/tratamento farmacológico , Ansiedade/metabolismo , Comportamento Animal/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Hidrocortisona/metabolismo , Locomoção/efeitos dos fármacos , Animais , Inibidores da Colinesterase/administração & dosagem , Modelos Animais de Doenças , Donepezila/administração & dosagem , Feminino , Masculino , Peixe-Zebra

RESUMO

AIMS: Autonomic dysfunction in arterial hypertension affects cardiorespiratory control and gastric motility and has been characterized by increased sympathetic and reduced parasympathetic activity. In the present work we investigated the effects of anticholinesterase drugs [donepezil (DON) or pyridostigmine (PYR)] on cardiovascular, autonomic, and gastric parameters in L-NAME-induced hypertensive rats. MATERIALS AND METHODS: Daily oral gavage of L-NAME (70 mg/kg/day) was performed over 14 days in male Wistar rats (180-220 g), whereas daily oral gavage of DON or PYR (1.6 and 22 mg/kg/day, respectively) started 2 days after the L-NAME treatment initiation and lasted 12 days. The development of hypertension was verified by tail plethysmography technique. After the end of treatments, the animals were subjected to experimental protocols (6-12 animals per group; total number of animals used: 78). KEY FINDINGS: L-NAME hypertensive animals had no alterations in heart rate (HR) and intrinsic HR, but showed reduction in baroreflex sensitivity, parasympathetic tone, and gastric motility; and the sympathetic tone, chemoreflex sensitivity, and the LF (low frequency) band of systolic arterial pressure (SAP) variability were increased. DON or PYR attenuated the increase in mean arterial pressure (MAP) induced by L-NAME. Both anticholinesterase drugs were effective in preventing the decrease in baroreflex sensitivity, parasympathetic tone and gastric motility, and also prevented the increases in peripheral chemoreflex response and cardiac sympathetic tone. SIGNIFICANCE: Acetylcholinesterase inhibition with DON or PYR is a promising pharmacological approach to increase parasympathetic function, thus preventing the hypertension-induced alterations in the cardiovascular, gastrointestinal and autonomic systems.

Assuntos

Acetilcolinesterase/metabolismo , Inibidores da Colinesterase/farmacologia , Hipertensão/prevenção & controle , NG-Nitroarginina Metil Éster/efeitos adversos , Substâncias Protetoras/farmacologia , Brometo de Piridostigmina/farmacologia , Animais , Pressão Arterial/efeitos dos fármacos , Sistema Nervoso Autônomo/efeitos dos fármacos , Barorreflexo/efeitos dos fármacos , Sistema Cardiovascular/efeitos dos fármacos , Inibidores da Colinesterase/metabolismo , Modelos Animais de Doenças , Donepezila/metabolismo , Donepezila/farmacologia , Frequência Cardíaca , Hipertensão/metabolismo , Masculino , Substâncias Protetoras/metabolismo , Brometo de Piridostigmina/metabolismo , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos , Volume Sistólico

RESUMO

Intracerebroventricular streptozotocin injection (icv STZ) is a well established sporadic Alzheimer's disease (AD) model in rodents. AD is characterized by neuronal degeneration accompanied by central oxidative stress. Studies also indicate peripheral oxidative damage in AD, but if the icv STZ model of sporadic AD mimics this feature is an open question. This study aimed to investigate if icv STZ administration induces peripheral oxidative stress and the antioxidant action of Ebselen, compared to the reference drug (donepezil), in this sporadic AD model. Male adult Swiss mice received icv STZ (days 1 and 3). Mice received Ebselen (10 mg/kg, i.p) or Donepezil (5 mg/kg, i.p) for 14 days. Mice were killed and the kidney and liver were excised to determine parameters of oxidative stress and toxicity markers. The mice icv STZ-injected showed peripheral oxidative stress. Ebselen reversed renal lipid peroxidation in the icv STZ administered mice by modulating NPSH levels, SOD and CAT activities, whereas Donepezil, modulated only NPSH levels. Ebselen and Donepezil counteracted hepatic lipid peroxidation in STZ-injected mice by modulating NPSH levels and CAT activity. The δ-ALA-D activity was inhibited in the kidney, but not in the liver, whereas the icv STZ-injected mice had an increase in the GST activity in both tissues. Ebselen reversed the increase in the hepatic GST activity of the STZ-injected mice. Donepezil increased renal GST activity in the control mice. In conclusion, this study demonstrates that the icv STZ administration induced peripheral oxidative stress. Ebselen, similar to Donepezil, was effective against peripheral oxidative stress in a mouse model of sporadic AD.

Assuntos

Doença de Alzheimer/metabolismo , Antioxidantes/farmacologia , Azóis/farmacologia , Compostos Organosselênicos/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Animais , Antioxidantes/química , Azóis/química , Biomarcadores , Catálise , Modelos Animais de Doenças , Cromatografia Gasosa-Espectrometria de Massas , Glutationa Transferase/metabolismo , Isoindóis , Rim/efeitos dos fármacos , Rim/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Metabolômica/métodos , Camundongos , Compostos Organosselênicos/química , Oxirredução/efeitos dos fármacos , Estreptozocina/efeitos adversos

RESUMO

Histamine H3 receptors (H3R) have attracted interest of research groups as drug target to several CNS disorders. Data suggests that H3R antagonists exert neuroprotective, cognitive enhancement and antidepressant effects in rodents. The LINS01 compounds were reported as selective H3R antagonists, but their effects on memory, anxiety-like behaviour and spontaneous locomotor activity were not evaluated to date. Therefore, this study employed the plus-maze discriminative avoidance task (PM-DAT) to assess concomitantly the effects of LINS01 compounds on short- and long-term memory, anxiety-like behaviour and spontaneous locomotor activity. Thirty-eight adult male Wistar rats were divided into five groups (n = 7-8 per group) according to the treatment. The animals were treated with donepezil (1 mg/kg) and clobenpropit (3 mg/kg) (reference compounds), and with two LINS01 compounds at doses of 5 mg/kg (LINS01003 and LINS01004), and then submitted to the PM-DAT protocol. Saline (vehicle) was used as control group. The behavioural data showed that anxiety-like behaviour, spontaneous locomotor activity and memory effects (short- and long-term) were not affected by the treatment with LINS01004 or clobenpropit. Conversely, treatment with LINS01003 and donepezil impaired the maintenance of discriminative avoidance long-term memory, a hippocampal-dependent memory. Donepezil-treated rats also showed decreased spontaneous locomotor activity and anxiolytic-like effects. In summary, considering that hippocampal damage and memory impairment are associated with Alzheimer's disease (AD), this work brought important findings regarding the contribution of the histamine system to the effects of LINS01 compounds on memory, anxiety and motility, and suggests that H3R antagonism had no effects on anxiety-like behaviour and do not impair discriminative avoidance memory. Furthermore, the findings herein raise new questions about donepezil's function in an "impaired" system such as AD, since it prevented the long-term memory formation in healthy rats.

Assuntos

Ansiedade/induzido quimicamente , Comportamento Animal/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos H3/farmacologia , Locomoção/efeitos dos fármacos , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Animais , Benzofuranos/farmacologia , Donepezila/farmacologia , Imidazóis/farmacologia , Masculino , Piperazinas/farmacologia , Ratos , Ratos Wistar , Tioureia/análogos & derivados , Tioureia/farmacologia

RESUMO

Oral fast-dispersible film was prepared by utlizing donepezil hydrochloride (drug) and various cellulose derivatives such as hydroxypropyl methyl cellulose (hypermellose) (HPMC), microcrystalline cellulose (MCC) and nanocrystalline cellulose (NCC) to treat Alzheimer's disease. NCC was synthesized by ultra-sonication method using MCC and this was converted to thinfilm formulation (NCC-F) using solvent casting technique. The interaction between the polymer and the drug was investigated by spectral analysis such as UV, FTIR, and 1H- NMR. FTIR confirmed that the compatibility of drug and polymer in ODF formulation. NCC-F has shown an average surface roughness of 77.04 nm from AFM and the average particle size of 300 nm from SEM analysis. Nano sized particle of NCC-F leads faster in vitro dissolution rate (94.53%) when compared with MCC-F and F3 formulation. Animal model (in vivo) studies of NCC-F formulation has reached peak plasma concentration (Cmax) up to 19.018 ng/mL in the span of (tmax) 4 h with greater relative bioavailability of 143.1%. These results suggested that high surface roughness with nanosized NCC-F formulation attained extended drug availability up to (t1/2) 70 h.

Assuntos

Animais , Masculino , Feminino , Ratos , Técnicas In Vitro/métodos , Dissolução/classificação , Donepezila/agonistas , Sonicação/métodos , Preparações Farmacêuticas/análise , Celulose , Espectroscopia de Infravermelho com Transformada de Fourier/métodos , Modelos Animais , Doença de Alzheimer/patologia

RESUMO

Donepezil is used to treat symptomatically the Alzheimer's disease (AD). This drug is a specific inhibitor of the enzyme acetylcholinesterase (AChE), whose main physiological function is to hydrolyze the neurotransmitter acetylcholine. The main objective of this work was to study the effect of donepezil on human erythrocytes as AChE is present in its membrane. For this purpose, human erythrocytes and molecular model of its membrane built-up of dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) were used. The latter correspond to classes of phospholipids present in the outer and inner monolayers of the human erythrocyte membrane, respectively. Our experimental evidences obtained from X-ray diffraction and differential scanning calorimetry (DSC) analysis indicated that donepezil was capable of interacting with both phospholipids. Fluorescence spectroscopy results showed a moderate increase in the fluidity of the hydrophobic tails of DMPC and isolated unsealed human erythrocyte membranes (IUM). On the other hand, results by scanning electron microscopy (SEM) and optical defocusing microscopy (DM) showed that the drug changed the normal biconcave shape of the erythrocytes inducing the formation of stomatocytes (cup-shaped cells). This effect was explained by the incorporation of donepezil molecules into the erythrocyte membrane and interactions with AChE.

Assuntos

Acetilcolinesterase/efeitos dos fármacos , Doença de Alzheimer/tratamento farmacológico , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Eritrócitos/efeitos dos fármacos , Nootrópicos/farmacologia , Inibidores da Colinesterase/uso terapêutico , Dimiristoilfosfatidilcolina/metabolismo , Donepezila/uso terapêutico , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/metabolismo , Humanos , Nootrópicos/uso terapêutico , Fosfatidiletanolaminas/metabolismo

RESUMO

BACKGROUND: Acetylcholinesterase inhibition prevents autonomic imbalance, reduces inflammation, and attenuates the development of hypertension. Considering that vascular dysfunction is a crucial feature of arterial hypertension, we investigated the effects of chronic administration of acetylcholinesterase inhibitors-pyridostigmine or donepezil-on vascular reactivity of spontaneously hypertensive rats (SHR). METHODS: Endothelium-dependent relaxant responses to acetylcholine (ACh) and contractile responses induced by electric field stimulation (EFS) and alpha-adrenergic agonist were studied in mesenteric resistance arteries from SHR and Wistar Kyoto rats. SHR were treated for 16 weeks with vehicle, pyridostigmine (1.5 mg/kg/day) or donepezil (1.4 mg/kg/day). RESULTS: Pyridostigmine and donepezil decreased the vasoconstrictor responses to EFS, which were increased in vehicle-treated SHR. Acetylcholinesterase inhibition increased the modulatory effects of nitric oxide (NO) on SHR vascular reactivity, that is, N(ω)-nitro-(L)-arginine methyl ester (L-NAME) increased EFS-induced contractions and reduced ACh-induced relaxation, with more significant effects in pyridostigmine- and donepezil-treated SHR. The acetylcholinesterase inhibitors also decreased vascular reactive oxygen species levels. CONCLUSIONS: This study demonstrates for the first time that long-term administration of acetylcholinesterase inhibitors, pyridostigmine or donepezil, attenuates vascular reactivity dysfunction in SHR by decreasing reactive oxygen species generation and increasing NO bioavailability; possibly via increased endothelial NO synthase activity, and inhibition of NADPH oxidase activity.

Assuntos

Anti-Hipertensivos/farmacologia , Inibidores da Colinesterase/farmacologia , Donepezila/farmacologia , Hemodinâmica/efeitos dos fármacos , Hipertensão/prevenção & controle , Artérias Mesentéricas/efeitos dos fármacos , Brometo de Piridostigmina/farmacologia , Acetilcolinesterase/metabolismo , Animais , Pressão Arterial/efeitos dos fármacos , Modelos Animais de Doenças , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Hipertensão/enzimologia , Hipertensão/fisiopatologia , Artérias Mesentéricas/enzimologia , Artérias Mesentéricas/fisiopatologia , NADPH Oxidases/metabolismo , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos Endogâmicos SHR , Ratos Endogâmicos WKY , Espécies Reativas de Oxigênio/metabolismo , Resistência Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos

RESUMO

Donepezil is one of the main compounds used in the therapy of Alzheimer's disease. Oral administration of this drug presents many drawbacks, resulting in treatment non-adherence among patients. Thus, the development of transdermal formulations for donepezil delivery is important. The aim of this study was to prepare and to evaluate nanostructured lipid carrier-based gels (NLC gel) able to improve the skin delivery of donepezil free base (DPB). The components of nanostructured lipid carriers (NLCs) were selected after evaluating their enhancing effects using in vitro DPB skin delivery assays. DPB-loaded NLC were prepared by a microemulsion technique, by employing stearic acid as a solid lipid, oleic acid as a liquid lipid, lecithin as a surfactant, and sodium taurodeoxycholate as a co-surfactant. The DPB-NLC dispersions were characterized morphologically using atomic force microscopy and physicochemically using dynamic light scattering and surface charge measurements. These data along, with the encapsulation studies, indicated that uniformly nano-sized particles with high drug encapsulation were fabricated. In vitro skin permeation assays were performed, and the results indicated that drug skin permeation from DPB-NLC gel was increased, not only by the enhancing effect of their components, but the lipid nanocarriers also presented an additional enhancing effect to increase drug flux across the skin. Therefore, DPB-NLC gel is an interesting formulation for the enhanced treatment of Alzheimer's disease.

Assuntos

Donepezila/química , Sistemas de Liberação de Medicamentos , Lipídeos/química , Nanoestruturas/química , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Géis/química , Tamanho da Partícula , Absorção Cutânea , Propriedades de Superfície

RESUMO

We previously examined cerebral blood flow (CBF) with single-photon emission computed tomography (SPECT) in Alzheimer's disease (AD) with reference to drug treatment (donepezil) and psychosocial intervention. OBJECTIVE: The aim is to provide "brain-based" evidence for psychosocial interventions using SPECT. METHODS: The participants were 27 consecutive outpatients with AD who received the drug and psychosocial intervention, and SPECT three times (baseline, pre-/post-intervention) at 6 month-intervals. The significance level of changes in CBF (Z score) and the extent of significantly changed areas, calculated with the eZIS system, were used as monitoring parameters. The participants were classified into three groups: improve (post-intervention CBF increased), worsening (progressive decline), and no change. RESULTS: Six, 8, and 13 patients were classified as improve, worsening, and no change, respectively. All subjects in the improve group showed improvement in cognitive test scores for the MMSE and/or the CGI scores associated with the brain area with a CBF increase (right parietal lobe), suggesting appropriate psychosocial intervention (visuospatial intervention). CONCLUSION: These results suggest that monitoring of CBF with the eZIS system may be clinically applicable for monitoring of drug treatment and psychosocial intervention in AD patients.

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Nós examinamos previamente o fluxo sanguíneo cerebral (FSC) com tomografia computadorizada de emissão de fóton único (SPECT) na doença de Alzheimer (DA) com referência ao tratamento medicamentoso (donepezila) e intervenção psicossocial. OBJETIVO: Fornecer evidências "baseadas no cérebro" para intervenções psicossociais usando o SPECT. MÉTODOS: Os participantes foram 27 pacientes ambulatoriais consecutivos com DA que receberam a droga e intervenção psicossocial, e SPECT por três vezes (basal, pré/pós-intervenção) em intervalos de seis meses. O nível de significância das mudanças no FSC (escore Z) e a extensão das áreas significativamente alteradas calculadas com o sistema eZIS foram utilizados como parâmetros de monitoramento. Os participantes foram classificados em três grupos: melhora (FSC pós-intervenção aumentada), piora (declínio progressivo) e nenhuma mudança. RESULTADOS: Seis, oito e 13 pacientes foram classificados como melhora, piora e sem alteração, respectivamente. Todos no grupo melhora mostraram aumento dos escores no MEEM e/ou nos escores do CGI associados à área do cérebro com aumento do FSC (lobo parietal direito), sugerindo intervenção psicossocial apropriada (intervenção visoespacial). CONCLUSÃO: Estes resultados sugerem que o monitoramento do FSC com o sistema eZIS pode ser clinicamente aplicável para o monitoramento do tratamento medicamentoso e intervenção psicossocial em pacientes com DA.