RESUMO

Investigating new drugs or formulations that target Alzheimer disease (AD) is critical for advancing therapeutic interventions. Therefore, this study aimed to assess the effectiveness of nanoencapsulated curcumin (NC Curc) in alleviating memory impairment, oxidative stress, and neuroinflammation in a validated AD model. Male Wistar rats were given bilateral intracerebroventricular injections of either saline or streptozotocin (STZ) (3 mg/3 µL/site) to establish the AD model (day 0). On day 22, daily oral administrations of curcumin (6 mg/kg), NC Curc (6 mg/kg), or a vehicle (unloaded NC) were initiated and continued for 14 days. NC Curc significantly reversed memory deficits in object recognition and inhibitory avoidance tests induced by STZ. Both formulations of curcumin attenuated elevated acetylcholinesterase activity caused by STZ. Importantly, NC Curc alone effectively mitigated STZ-induced oxidative stress. Additionally, NC Curc treatment normalized GFAP levels, suggesting a potential reduction in neuroinflammation in STZ-treated rats. Our findings indicate that NC Curc improves memory in an AD rat model, highlighting its enhanced therapeutic effects compared to unencapsulated curcumin. This research significantly contributes to understanding the therapeutic and neurorestorative potential of NC Curc in AD, particularly in reversing pathophysiological changes.

RESUMO

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been widely used due to its specific and reproducible neurotoxic effect on the nigrostriatal system, being considered a convenient model of dopaminergic neurodegeneration to study interventions therapeutics. The purple pitanga (Eugenia uniflora) is a polyphenol-rich fruit with antioxidant and antidepressant properties, among others. Therefore, this study investigated the effect of purple pitanga extract (PPE) on acute early oxidative stress induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats. Male Wistar rats were pre-treated orally with PPE (1000 mg/kg) or vehicle. After 24 h, MPTP (0.1 mg/10µL/nostril) or vehicle was administered bilaterally into the animal's nostrils, and 6 h later, the olfactory bulb (OB), striatum (ST), and substantia nigra (SN) were collected to evaluate the oxidative stress parameters. Our findings revealed that OB and SN were the most affected areas after 6 h of MPTP infusion; an early increase in reactive oxygen species (ROS) levels was observed, while pretreatment with a single dose of PPE prevented this increment. No differences in thiobarbituric acid reactive species (TBARS) and 3-nitrotyrosine (3-NT) formation were observed, although 4-hydroxy-2-nonenal (4-HNE) levels increased, which is the most toxic form of lipid peroxidation, in the MPTP group. The PPE pretreatment could prevent this increase by increasing the NPSH levels previously decreased by MPTP. Furthermore, PPE prevents the Na+/K + ATPase strongly inhibited by MPTP, showing the neuroprotective capacity of the PPE by inhibiting the MPTP-generated oxidation. Thus, we demonstrated for the first time the antioxidant and neuroprotective effects of PPE against the early MPTP neurotoxicity.

Assuntos

Eugenia , Fármacos Neuroprotetores , Ratos , Masculino , Animais , Camundongos , Antioxidantes/farmacologia , Antioxidantes/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Eugenia/metabolismo , Ratos Wistar , Estresse Oxidativo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Substância Negra/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Camundongos Endogâmicos C57BL , Modelos Animais de Doenças

RESUMO

Parkinson's disease is a multisystemic neurodegenerative disorder that includes motor and non-motor symptoms, and common symptoms include memory loss and learning difficulties. Thus, we investigated the neuroprotective potential of a hydroalcoholic extract of Brazilian purple cherry (Eugenia uniflora) (HAE-BC) on memory impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats and the involvement of hippocampal BDNF/TrkB/p75NTR pathway in its effects. Adult male Wistar rats were exposed to MPTP (1 mg/nostril) or vehicle. Twenty-four hours later, the HAE-BC treatments began at doses of 300 or 2000 mg/kg/day or vehicle for 14 days. From 7 days after the MPTP induction, the animals were subjected to behavioral tests to evaluate several cognitive paradigms. HAE-BC treatments, at both doses, blocked the MPTP-caused disruption in the social recognition memory, short- and long-term object recognition memories, and working memory. Furthermore, MPTP-induced motor deficit linked to striatal tyrosine hydroxylase levels decreased, which was blocked by HAE-BC. Our findings demonstrated that HAE-BC blocked the MPTP-induced increase in the hippocampal pro-BDNF, TrkB.t1, and p75NTR levels. The pro-BDNF/p75NTR interaction negatively regulates synaptic transmission and plasticity, and the neuroprotective effect of HAE-BC was related, at least partly, to the modulation of this hippocampal signaling pathway. Thus, our study reports the first evidence of the potential therapeutic of E. uniflora in a Parkinson's disease model in rodents.

Assuntos

Eugenia , Fármacos Neuroprotetores , Doença de Parkinson , Ratos , Animais , Masculino , Camundongos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Doença de Parkinson/tratamento farmacológico , Ratos Wistar , Eugenia/metabolismo , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/prevenção & controle , Transtornos da Memória/metabolismo , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL

RESUMO

BACKGROUND: Curcumin (CUR) is a bioactive compound with several proven pharmacological properties. However, the major limitation for therapeutic use of CUR is its low bioavailability. In this sense, an alternative to this question is the use of polymeric nanocapsules (NC) as drug/nutraceutical delivery systems. Thus, the aim of current study was to assess the effect of CUR-loaded NC and their different coatings in chick embryo model, evaluating angiogenic, teratogenic and oxidative stress parameters. METHODS: The physicochemical characterization of unloaded and loaded NC with different coatings: (U-NC (P80), U-NC (PEG), U-NC (EUD), U-NC (CS), CUR-NC (P80), CUR-NC (PEG), CUR-NC (EUD) and CUR-NC (CS)) were performed. After 9 days of incubation, eggs were treated (10 mL/kg eggs; via injection) with NC (unloaded and loaded with CUR) and CUR-solution. In sequence, hen's egg test-chorioallantoic membrane (HET-CAM), angiogenic assay, external abnormalities, weight of embryos and oxidative stress markers (TBARS, NPSH, ROS and CAT) were analyzed. RESULTS: CUR-NC (P80, PEG, EUD and CS) treatments caused antiangiogenic and non-teratogenic effects in chick embryo model. Still, CUR-NC (P80), CUR-NC (PEG), CUR-NC (EUD) and CUR-NC (CS) did not alter markers of oxidative stress (TBARS, NPSH, CAT) studied. Only CUR-NC (EUD) caused increase in ROS levels. CONCLUSION: Wherefore, these findings of present study represent a advance in research of drug/nutraceutical delivery systems.

Assuntos

Curcumina/farmacologia , Nanocápsulas , Estresse Oxidativo/efeitos dos fármacos , Polímeros/química , Inibidores da Angiogênese/administração & dosagem , Inibidores da Angiogênese/farmacologia , Inibidores da Angiogênese/toxicidade , Animais , Embrião de Galinha , Galinhas , Membrana Corioalantoide/efeitos dos fármacos , Curcumina/administração & dosagem , Curcumina/toxicidade , Sistemas de Liberação de Medicamentos , Ovos , Espécies Reativas de Oxigênio/metabolismo

RESUMO

Alzheimer's disease (AD) is a progressive brain disorder and complex mechanisms are involved in the physiopathology of AD. However, there is data suggesting that inflammation plays a role in its development and progression. Indeed, some non-steroidal anti-inflammatory drugs, such as meloxicam, which act by inhibiting cyclooxygenase-2 (COX-2) have been used as neuroprotective agents in different neurodegenerative disease models. The purpose of this study was to investigate the effects of co-nanoencapsulated curcumin and meloxicam in lipid core nanocapsules (LCN) on cognitive impairment induced by amyloid-beta peptide injection in mice. LCN were prepared by the nanoprecipitation method. Male Swiss mice received a single intracerebroventricular injection of amyloid-beta peptide aggregates (fragment 25-35, 3 nmol/3 µL) or vehicle and were subsequently treated with curcumin-loaded LCN (10 mg/kg) or meloxicam-loaded LCN (5 mg/kg) or meloxicam + curcumin-co-loaded LCN (5 and 10 mg/kg, respectively). Treatments were given on alternate days for 12 days (i.e., six doses, once every 48 hours, by intragastric gavage). Our data showed that amyloid-beta peptide infusion caused long-term memory deficits in the inhibitory avoidance and object recognition tests in mice. In the inhibitory avoidance test, both meloxicam and curcumin formulations (oil or co-loaded LCN) improved amyloid-beta-induced memory impairment in mice. However, only meloxicam and curcumin-co-loaded LCN attenuated non-aversive memory impairment in the object recognition test. Moreover, the beneficial effects of meloxicam and curcumin-co-loaded LCN could be explained by the anti-inflammatory properties of these drugs through cortical COX-2 downregulation. Our study suggests that the neuroprotective potential of meloxicam and curcumin co-nanoencapsulation is associated with cortical COX-2 modulation. This study was approved by the Committee on Care and Use of Experimental Animal Resources, the Federal University of Pampa, Brazil (approval No. 02-2015) on April 16, 2015.

RESUMO

BACKGROUND: Organophosphorus pesticides exert their toxic effects mainly by the inhibition of acetylcholinesterase (AChE), which is related to emotional disorders, such as depression. Atropine-oximes therapy is commonly used; however, the efficacy of oximes in the reactivation of AChE has been inconsistent. The objective of this study was to investigate the possible neuroprotective effect of (3Z)-5-Chloro-3-(hydroxyimino)indolin-2-one (Cℓ-HIN), a compound that combines the isatin and oxime functional groups, in rats exposed to malathion. The effect of Cℓ-HIN on the AChE activity and the BDNF-Trkß pathway in the prefrontal cortex of malathion-exposed rats were tested. METHODS: Wistar male rats were co-treated with Cℓ-HIN [50 mg/kg (p.o.) (3 mL/kg)] and/or malathion [250 mg/kg (i.p.) (5 mL/kg)] and performed behavioral tests twelve hours after these exposures. RESULTS: The Cℓ-HIN reversed the increased immobility time in the forced swimming test and the decreased grooming time in the splash test induced by malathion, but any significant difference was observed in locomotion analysis. These results demonstrate the antidepressant-like effect of Cℓ-HIN. The cortical AChE activity was reactivated by Cℓ-HIN in rats exposed to malathion. Malathion induced an increase in Trkß and a decrease in BDNF levels in the prefrontal cortex of rats, which were avoided by Cℓ-HIN. CONCLUSION: These findings support the hypothesis that Cℓ-HIN is an AChE reactivator with antidepressant-like properties, which is related to the improvement of BDNF-Trkß signaling after acute exposure to malathion in rats. Thus, the results allow suggesting the potential use of Cℓ-HIN as an oxime-based therapy against the neurotoxic effects of malathion.

Assuntos

Acetilcolinesterase/metabolismo , Antidepressivos/farmacologia , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Indóis/farmacologia , Malation/toxicidade , Oxindóis/farmacologia , Receptor trkB/metabolismo , Transdução de Sinais , Animais , Antidepressivos/administração & dosagem , Antidepressivos/química , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Indóis/administração & dosagem , Indóis/química , Indóis/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oxindóis/administração & dosagem , Oxindóis/química , Oxindóis/uso terapêutico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos

RESUMO

The inhibition of acetylcholinesterase (AChE) is a common outcome caused by organophosphorus (OPs) intoxication. Although inconsistent, the standard treatment consists of a muscarinic receptor antagonist (atropine) and AChE-reactivating molecules such as oximes. This study proposes to test unpublished compounds which contain the moieties of isatin and/or oxime have protective effects against the toxicity induced by malathion in two animal models: Artemia salina and Rattus norvegicus (Wistar rats). The lethality was assessed in A salina, and the calculated LD50 to (3Z)-5-chloro-3-(hydroxyimino) indolin-2-one oxime (Cℓ-HIN) and 2-(5-chloro-2-oxoindolin-3-ylidene)-hydrazinecarbothioamide (Cℓ-OXHS) was higher than 1000 µM while to 3-(phenylhydrazono) butan-2-one oxime (PHBO) was 38 µM. Our screening showed that Cℓ-HIN seems to be the most promising molecule, with low toxicity to A salina, protection against mortality (with or without atropine) and AChE inhibition induced by malathion. Similarly, the oral administration of 300 mg/kg of Cℓ-HIN induced low or no toxicity in rats. The plasma butyrylcholinesterase (BChE) and cortical AChE activities were reactivated by Cℓ-HIN (50 mg/kg, p.o.) in rats exposed to malathion (250 mg/kg, i.p). No difference was observed in paraoxonase-1 (PON-1) activity among groups treated. In conclusion, Cℓ-HIN restored the cholinesterase activities inhibited by malathion in A salina and rats with low toxicity in both. Thus, the data provide evidence that Cℓ-HIN, a compound that combines isatin and oxime functional groups, is safe and has important properties to reactivate the cholinesterases inhibited by malathion. In addition, we demonstrate the importance of a preliminary assessment in an alternative model in order to reduce the use of mammalians in drug discovery.

Assuntos

Inibidores da Colinesterase/toxicidade , Isatina/farmacologia , Malation/toxicidade , Oximas/farmacologia , Animais , Artemia , Reativadores da Colinesterase/administração & dosagem , Reativadores da Colinesterase/química , Reativadores da Colinesterase/farmacologia , Modelos Animais de Doenças , Descoberta de Drogas/métodos , Feminino , Inseticidas/toxicidade , Isatina/administração & dosagem , Isatina/química , Dose Letal Mediana , Masculino , Oximas/administração & dosagem , Oximas/química , Ratos , Ratos Wistar

RESUMO

The unloaded polymeric nanocapsules (NCs) present incredible characteristics as drug carriers. However, the toxicity caused by NCs with different coatings is still a challenge for contemporary toxicology. Allied to this, preclinical studies are performed in males, disregarding possible gender-dependent toxicity. Thus, the aim of present study was to evaluate the influence of different NCs coatings on toxicological and behavioral parameters in female rats. The physicochemical characterization of NCs with different surface coatings: NC1 (Polysorbate 80), NC2 (PEG), NC3 (Eudragit®RS 100) and NC4 (Chitosan) were performed. Female rats were treated with saline, NC1, NC2, NC3 or NC4 daily for 14 days, p.o. After 24 h of last treatment, animals were submitted to behavioral tests. Only after behavioral tests, female rats were euthanized, organs were removed and weighted. After, histopathological, biochemical and oxidative stress analysis were performed. All NCs-coatings did not cause alterations in behavioral tests. For markers of hepatic, renal damage and lipid profile, the different coatings showed a low toxicity. NCs did not alter weight of organs and histopathological analysis. Also, all NCs-coatings did not modify redox balance in organs studied, only NC2 induced a increase of FRAP levels in intestine. This study demonstrated that the different NCs-coatings did not cause behavioral changes and showed a low toxicity in female rats.

Assuntos

Comportamento Animal/efeitos dos fármacos , Portadores de Fármacos/química , Nanocápsulas , Polímeros/química , Animais , Portadores de Fármacos/toxicidade , Feminino , Polímeros/toxicidade , Ratos , Ratos Wistar

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder classically characterized by cognitive functions impairment. However, its symptomatology is complex and the depression is one of the most frequent behavioral changes in AD. AD pathology includes neuroinflammation and oxidative stress resulting in the Aß protein accumulation. Curcumin is a natural phenolic compound that shows antioxidant and anti-inflammatory properties. Nevertheless, therapeutic use of curcumin is limited due to its low bioavailability and biodistribution. In this context, the use of curcumin-loaded nanocapsules (NLC C) emerges to overcome its limitations. Thus, the present study investigated the effects of NLC C on the depressant-like behavior and oxidative stress induced by an animal model of AD. For this, Swiss male mice were divided into five groups. The Aß, Aß + NLC C and Aß + Curcumin groups received Aß25-35 aggregate (3 nmol/3 µL, i.c.v.). Control and NLC C groups received only vehicle. The NLC C were administered via gavage at a dose of 10 mg/kg in alternate days for 12 days. Our results demonstrated that Aß infusion induced a depressantant-like behavior observed in the tail suspension and forced swimming tests, which was reversed by NLC C treatment. No change was observed in mice locomotion. Furthermore, NLC C reduced the Aß-generated oxidative stress in the prefrontal cortex, evidenced by the increase in the reactive species levels, superoxide dismutase and catalase activities. Importantly, NLC C were more effective than the free curcumin. Thus, we demonstrated the antidepressant-like and antioxidant effects of NLC C in a mouse model of AD, suggesting its therapeutic potential for this disorder.

Assuntos

Doença de Alzheimer/tratamento farmacológico , Antidepressivos/farmacologia , Antioxidantes/farmacologia , Curcumina/farmacologia , Depressão/tratamento farmacológico , Estresse Oxidativo/efeitos dos fármacos , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/patologia , Peptídeos beta-Amiloides/farmacologia , Animais , Escala de Avaliação Comportamental , Catalase/metabolismo , Curcumina/uso terapêutico , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Inflamação , Masculino , Camundongos , Nanocápsulas , Fragmentos de Peptídeos/metabolismo , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Superóxido Dismutase/metabolismo

RESUMO

The experimental design aiming at evaluating the performance of drugs nanoencapsulated involves inclusion of a formulation without drug (unloaded). This formulation has sometimes presented per se effect. In this sense, we sought to evaluate the toxicity of unloaded polymeric nanocapsules (NCs) with different surfaces (cationic and anionic) in male Wistar rats in male Wistar rats. The physicochemical characterization of NCs with different surfaces: polysorbate 80 (P80), polyethylene glycol (PEG), eudragit ®RS 100 (EUD) and chitosan (CS) was performed. Rats were treated with unloaded NCs (P80, PEG, EUD and CS surfaces) daily for 14 days per oral route. 24 h of last treatment, animals were euthanized and organs were removed and weighted. After, biochemical determinations were performed. In general, NCs-surfaces did not cause alterations in body weight, weight of organs and histopathological analysis. PEG-surface NCs did not generate hepatotoxicity. In investigation of lipid profile, the surface with P80 changed TC and HDL-C levels. Besides that, all NCs did not alter oxidative stress markers in organs studied (TBARS and Reactive Species) and CS-surface presented antioxidant activity in kidney. This study demonstrated that NCs-surfaces depending on their physicochemical characteristics had low or no toxicity.

Assuntos

Nanocápsulas/toxicidade , Polímeros/toxicidade , Testes de Toxicidade , Alanina Transaminase/metabolismo , Animais , Ânions , Antioxidantes/metabolismo , Aspartato Aminotransferases/metabolismo , Peso Corporal/efeitos dos fármacos , Cátions , Colesterol/metabolismo , Creatinina/metabolismo , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Comportamento Alimentar/efeitos dos fármacos , Ferro/metabolismo , Masculino , Nanocápsulas/química , Tamanho do Órgão/efeitos dos fármacos , Oxirredução , Ratos Wistar , Espécies Reativas de Oxigênio/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Ureia/metabolismo

RESUMO

Neurotrophic factors comprise essential secreted proteins that have several functions in neural and non-neural tissues, mediating the development, survival and maintenance of peripheral and central nervous system. Therefore, neurotrophic factor issue has been extensively investigated into the context of neurodegenerative diseases. Alzheimer's disease and Parkinson's disease show changes in the regulation of specific neurotrophic factors and their receptors, which appear to be critical for neuronal degeneration. Indeed, neurotrophic factors prevent cell death in degenerative processes and can enhance the growth and function of affected neurons in these disorders. Based on recent reports, this review discusses the main findings related to the neurotrophic factor support - mainly brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor - in the survival, proliferation and maturation of affected neurons in Alzheimer's disease and Parkinson's disease as well as their putative application as new therapeutic approach for these diseases management.