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1.
Bull Exp Biol Med ; 167(2): 220-225, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31236878

RESUMO

Relationship between the residual effects of disorders in the cholinergic system and the activities of the cardiac, respiratory, and somatomotor systems of 1- and 16-day-old rats were studied. Experiments were carried out on intact conscious rats before and after drug injection (nicotinic cholinoreceptor blocker benzohexonium). In order to increase the level of cholinoreactive structure activation, acetylcholinesterase inhibition by eserine was carried out. Injection of benzohexonium caused rarefaction of HR, respiration rate, and a decrease of motor activity parameters in rats of both age groups. Injection of eserine after cholinolytic premedication led to further rarefaction of the respiration rate and HR. The reaction of the somatosensory system to changed level of cholinoreactive structure activation was age-specific. Motor activity increased in 1-day-old rats and was depressed significantly in 16-day-old ones.


Assuntos
Sistema Cardiovascular/efeitos dos fármacos , Compostos de Hexametônio/farmacologia , Córtex Motor/efeitos dos fármacos , Sistema Respiratório/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Atividade Motora/efeitos dos fármacos , Fisostigmina/farmacologia , Ratos , Ratos Wistar , Taxa Respiratória/efeitos dos fármacos
2.
Bull Exp Biol Med ; 166(1): 50-53, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30450520

RESUMO

The effects of intramuscular administration of neostigmine and physostigmine on Na+,K+-ATPase activity in various cerebral subdivisions were examined in rats. In CNS and peripheral tissues, both agents rapidly and significantly reduced activity of cholinesterases by 30-50%. The development of intoxication did not change the marker indices of stress reaction. In the cerebral cortex, physostigmine increased Na+,K+-ATPase activity, whereas neostigmine suppressed it. In addition, neostigmine decreased activity of this enzyme in the cerebellum. In contrast, both agents produced no effects on Na+,K+-ATPase activity in the striatum. The data corroborate the view on functional interaction between Na+,K+-ATPase and nicotinic cholinoreceptors in rat cerebral cortex.


Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Neostigmina/farmacologia , Fisostigmina/farmacologia , ATPase Trocadora de Sódio-Potássio/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Masculino , Ratos , Ratos Wistar
3.
Int J Pharm ; 553(1-2): 467-473, 2018 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-30389473

RESUMO

Pre-administration of physostigmine can prevent poisoning against nerve agent exposure by reversibly binding to cholinesterase. However, its cholinesterase protection-based prophylactic effect can be eliminated rapidly due to short biological half-life. Liposomes are useful for encapsulating hydrophilic drugs like physostigmine, and can be used for sustained release after parenteral injection. Thus, physostigmine liposomes were prepared by the pH-gradient condition-based remote-loading method for subcutaneous injection. In addition, polyethylene glycol (PEG)-lipid was applied to further extend the release of physostigmine and its prophylactic action. In vitro release of physostigmine, pharmacokinetics and duration of prophylactic effect were then evaluated. Physostigmine was dissolved in distilled water and used as a solution group for comparison. The prepared liposomes showed spherical shape and their particle size was around 130 µm. Addition of PEG-lipid in liposomes significantly increased the entrapment efficiency of physostigmine. Both control and PEG liposomes exhibited sustained release pattern compared to the solution. Moreover, the release of PEG liposomes was relatively slower than that of the control liposomes. Pharmacokinetic study in rats revealed that physostigmine liposomes exhibited lower maximum plasma concentration and longer half-life compared to the solution. Plasma cholinesterase inhibition ratio in the liposomal group decreased more gradually compared to the solution. Moreover, PEG liposomes showed higher plasma concentration of physostigmine and cholinesterase inhibition ratio compared to the control liposomes. These results suggest that PEG liposomes have potential to enhance the duration of cholinesterase-protecting effect of physostigmine.


Assuntos
Química Farmacêutica/métodos , Inibidores da Colinesterase/administração & dosagem , Lipídeos/química , Fisostigmina/administração & dosagem , Animais , Inibidores da Colinesterase/farmacocinética , Inibidores da Colinesterase/farmacologia , Preparações de Ação Retardada , Portadores de Fármacos/química , Meia-Vida , Concentração de Íons de Hidrogênio , Interações Hidrofóbicas e Hidrofílicas , Lipossomos , Masculino , Camundongos , Células NIH 3T3 , Agentes Neurotóxicos/envenenamento , Tamanho da Partícula , Fisostigmina/farmacocinética , Fisostigmina/farmacologia , Polietilenoglicóis/química , Ratos , Ratos Sprague-Dawley
4.
J Therm Biol ; 77: 86-95, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30196904

RESUMO

There is evidence that central cholinergic stimulation increases heat dissipation in normotensive rats besides causing changes on the cardiovascular system via modulation of baroreceptors activity. However, the contribution of the central cholinergic system on thermoregulatory responses and its relationship with cardiovascular adjustments in spontaneously hypertensive rats (SHRs), an animal model of reduced baroreceptor sensitivity and thermoregulatory deficit, has not been completely clarified. Therefore, the aim of this study was to verify the involvement of the central cholinergic system in cardiovascular and thermoregulatory adjustments in SHRs. Male Wistar rats (n = 17) and SHRs (n = 17) were implanted with an intracerebroventricular cannula for injections of 2 µL of physostigmine (phy) or saline solution. Tail temperature (Ttail), internal body temperature (Tint), systolic arterial pressure (SAP), heart rate (HR) and metabolic rate were registered during 60 min while the animals remained at rest after randomly receiving the injections. The variability of the SAP and the HR was estimated by the fast Fourier transform. Phy treatment began a succession of cardiovascular and thermoregulatory responses that resulted in increased SAP, reduced HR and increased Ttail in both Wistar and SHRs groups. The magnitude of these effects seems to be more intense in SHRs, since the improvement of heat dissipation reflected in Tint. Taken together, these results provide evidence that hypertensive rats present greater cardiovascular and thermoregulatory responses than normotensive rats after central cholinergic stimulation.


Assuntos
Pressão Sanguínea/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Hipertensão/fisiopatologia , Fisostigmina/farmacologia , Animais , Hipertensão/tratamento farmacológico , Hipertensão/metabolismo , Masculino , Pressorreceptores/metabolismo , Ratos Endogâmicos SHR , Ratos Wistar
5.
J Neural Transm (Vienna) ; 125(10): 1487-1494, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30039507

RESUMO

Delirium is a common complication seen after surgery and anesthesia, in particular in older patients. Although the etiology of postoperative delirium is only incompletely understood, various lines of evidence suggest that proinflammatory signaling from the peripheral site of inflammation to central nervous system results in a decrease of cerebral acetylcholine (ACh) levels thereby inducing neuroinflammation. To corroborate this theory, we applied an animal model for characterization of the neuroinflammatory response after partial hepatectomy (HPx). In this model, the surgery-induced decrease in cerebral ACh levels can be prevented by intraoperative application of physostigmine. Thus, ACh-associated changes in the expression and secretion of inflammation-related compounds can be assessed by comparing the results obtained after surgery, in physostigmine-treated and untreated controls. This way we were able to show that the decrease of cerebral ACh triggers increased secretion of IL-1ß, IL-6, TNFα, MIP-2 (CCL3), RANTES, MCP1, IFNgamma, and IP-10. A gene array covering the expression of 370 inflammation-related genes indicated 13 candidates that are induced upon cerebral ACh decrease after HPx. Quantification of the changes in the expression of these candidates by the comparative CT method revealed a significant increase (> 1.5-fold) in the expression of IL-1ß, IL-6, TNFα, MIP2, RANTES, MCP1, TLR2, TLR4, HMGB1, TNFSF6, TNFSF12, IL1R1 and ILR6. Thus, our results suggest that peripheral surgery induces a reduction of cerebral ACh levels which trigger a complex neuroinflammatory response. From a clinical point of view, manipulating cerebral ACh levels by procholinergic drugs such as physostigmine could become an option to therapeutically target this kind of neuroinflammation.


Assuntos
Acetilcolina/metabolismo , Encéfalo/metabolismo , Inibidores da Colinesterase/uso terapêutico , Encefalite/etiologia , Complicações Intraoperatórias/etiologia , Fisostigmina/uso terapêutico , Complicações Pós-Operatórias/etiologia , Acetilcolina/líquido cefalorraquidiano , Animais , Encéfalo/efeitos dos fármacos , Quimiocinas/biossíntese , Quimiocinas/líquido cefalorraquidiano , Quimiocinas/genética , Inibidores da Colinesterase/farmacologia , Citocinas/biossíntese , Citocinas/líquido cefalorraquidiano , Citocinas/genética , Delírio/etiologia , Encefalite/genética , Encefalite/prevenção & controle , Perfilação da Expressão Gênica , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatectomia/efeitos adversos , Complicações Intraoperatórias/líquido cefalorraquidiano , Complicações Intraoperatórias/prevenção & controle , Masculino , Camundongos , Modelos Animais , Fisostigmina/farmacologia , Complicações Pós-Operatórias/líquido cefalorraquidiano , Complicações Pós-Operatórias/prevenção & controle , Ratos , Ratos Wistar
6.
Cell Transplant ; 27(4): 607-621, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29871513

RESUMO

OBJECTIVE: Although cerebral ischemia can activate endogenous reparative processes, such as proliferation of endogenous neural stem cells (NSCs) in the subventricular zone (SVZ) and subgranular zone (SGZ), the majority of these new cells die shortly after injury and do not appropriately differentiate into neurons, or migrate and functionally integrate into the brain. The purpose of this study was to examine a novel strategy for treatment of stroke after injury by optimizing the survival of ischemia-induced endogenous NSCs in the SVZ and SGZ. METHODS: Adult SVZ and SGZ NSCs were grown as neurospheres in culture and treated with a p53 inactivator, pifithrin-α (PFT-α), and an amyloid precursor protein (APP)-lowering drug, posiphen, and effects on neurosphere number, size and neuronal differentiation were evaluated. This combined sequential treatment approach was then evaluated in mice challenged with middle cerebral artery occlusion (MCAo). Locomotor behavior and cognition were evaluated at 4 weeks, and the number of new surviving neurons was quantified in nestin creERT2-YFP mice. RESULTS: PFT-α and posiphen enhanced the self-renewal, proliferation rate and neuronal differentiation of adult SVZ and SGZ NSCs in culture. Their sequential combination in mice challenged with MCAo-induced stroke mitigated locomotor and cognitive impairments and increased the survival of SVZ and SGZ NSCs cells. PFT-α and the combined posiphen+PFT-α treatment similarly improved locomotion behavior in stroke challenged mice. Notably, however, the combined treatment provided significantly more potent cognitive function enhancement in stroke mice, as compared with PFT-α single treatment. INTERPRETATION: Delayed combined sequential treatment with an inhibitor of p53 dependent apoptosis (PFT-α) and APP synthesis (posiphen) proved able to enhance stroke-induced endogenous neurogenesis and improve the functional recovery in stroke animals. Whereas the combined sequential treatment provided no further improvement in locomotor function, as compared with PFT-α alone treatment, suggesting a potential ceiling in the locomotion behavioral outcome in stroke animals, combined treatment more potently augmented cognitive function recovery after stroke.


Assuntos
Benzotiazóis/uso terapêutico , Neurogênese , Fisostigmina/análogos & derivados , Recuperação de Função Fisiológica , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Tolueno/análogos & derivados , Animais , Atrofia , Benzotiazóis/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Autorrenovação Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Cognição/efeitos dos fármacos , Quimioterapia Combinada , Ventrículos Laterais/patologia , Ventrículos Laterais/fisiopatologia , Masculino , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/metabolismo , Atividade Motora/efeitos dos fármacos , Células-Tronco Neurais/efeitos dos fármacos , Células-Tronco Neurais/metabolismo , Neurogênese/efeitos dos fármacos , Fisostigmina/farmacologia , Fisostigmina/uso terapêutico , Recuperação de Função Fisiológica/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Tolueno/farmacologia , Tolueno/uso terapêutico
7.
J Neuroimmune Pharmacol ; 13(3): 383-395, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29790105

RESUMO

Tissue damage and pathogen invasion during surgical trauma have been identified as contributing factors leading to neuroinflammation in the hippocampus, which can be protected by stimulation of the cholinergic anti-inflammatory pathway using the acetylcholinesterase inhibitor physostigmine. Macroautophagy, an intracellular degradation pathway used to recycle and eliminate damaged proteins and organelles by lysosomal digestion, seems to be important for cell survival under stress conditions. This study aimed to examine the role of autophagy in physostigmine-mediated hippocampal cell protection in a rat model of surgery stress. In the presence or absence of physostigmine, adult Wistar rats underwent surgery in combination with lipopolysaccharide (LPS). Activated microglia, apoptosis-, autophagy-, and anti-inflammatory-related genes and -proteins in the hippocampus were determined by Real-Time PCR, Western blot and fluorescence microscopy after 1 h, 24 h and 3 d. Surgery combined with LPS-treatment led to microglia activation after 1 h and 24 h which was accompanied by apoptotic cell death after 24 h in the hippocampus. Furthermore, it led to a decreased expression of ATG-3 after 24 h and an increased expression of p62/ SQSTM1 after 1 h and 24 h. Administration of physostigmine significantly increased autophagy related markers and restored the autophagic flux after surgery stress, detected by increased degradation of p62/ SQSTM1 in the hippocampus after 1 h and 24 h. Furthermore, physostigmine reduced activated microglia and apoptosis relevant proteins and elevated the increased expression of TGF-beta1 and MFG-E8 after surgery stress. In conclusion, activation of autophagy may be essential in physostigmine-induced neuroprotection against surgery stress.


Assuntos
Autofagia/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Hipocampo/patologia , Lipopolissacarídeos/antagonistas & inibidores , Fármacos Neuroprotetores/farmacologia , Fisostigmina/farmacologia , Estresse Fisiológico , Animais , Apoptose/efeitos dos fármacos , Proteínas Relacionadas à Autofagia/biossíntese , Proteína Beclina-1/metabolismo , Inflamação/genética , Inflamação/patologia , Inflamação/psicologia , Lipopolissacarídeos/toxicidade , Ativação de Macrófagos/efeitos dos fármacos , Masculino , Microglia/efeitos dos fármacos , Proteínas Associadas aos Microtúbulos/metabolismo , Peptídeo Sintases/biossíntese , Período Pós-Operatório , Ratos , Ratos Wistar , Proteína Sequestossoma-1/biossíntese
8.
Bull Exp Biol Med ; 165(1): 44-47, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29796810

RESUMO

Parameters of cardiac activity after administration of the cholinesterase inhibitor physostigmine were analyzed in newborn rats and on day 16 of postnatal development. The type of cardiovascular response to acetylcholine excess in newborns and 16-day-old rats were similar, but they significantly differed by the magnitude, which suggests that that maturation of cholinergic structures involved in the regulation of cardiac activity is completed during the early postnatal ontogeny.


Assuntos
Inibidores da Colinesterase/farmacologia , Frequência Cardíaca/efeitos dos fármacos , Fisostigmina/farmacologia , Animais , Animais Recém-Nascidos , Eletrocardiografia , Ratos , Ratos Wistar
9.
J Emerg Med ; 54(6): e113-e115, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29681419

RESUMO

BACKGROUND: Sublingual atropine, dosed at 0.4-0.8 mg, is used by dentists as an antisialogogue to facilitate and increase the speed of procedures. Concentrated ophthalmic atropine drops (10 mg/mL) are commonly used off-label for this purpose. These highly concentrated drops may result in medication errors, atropine toxicity, and the antimuscarinic toxidrome. We report a case of a man who suffered acute delirium and dysarthria (from dry mouth) after an iatrogenic overdose from a dental procedure. His symptoms were initially interpreted as a stroke, but they completely resolved with physostigmine. CASE REPORT: A 57-year-old man presented with acute dysarthria and delirium after a dental procedure; 4 hours earlier he was fitted for a temporary replacement of some premolar/molar teeth. He received sublingual atropine to assist in gingival drying for molding of his prosthesis, but a calculation error resulted in the administration of approximately 113 mg. A stroke evaluation was initially planned; however, 2.5 mg of intravenous physostigmine completely reversed his symptoms. His symptoms reoccurred and were successfully treated twice more with physostigmine; the patient was observed overnight with no additional symptoms and safely discharged the next morning. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Ophthalmic atropine drops are highly concentrated and may cause an overdose after ingestion of small amounts. This novel case highlights the importance of considering antimuscarinic poisoning in cases of acute delirium or dysarthria after dental procedures and stands as a reminder to inquire about the use of atropine drops in such cases. Timely recognition of the antimuscarinic toxidrome and appropriate use of physostigmine may prevent unnecessary testing while providing an effective therapy. This case also highlights the need for observation after resolution of delirium treated with physostigmine.


Assuntos
Atropina/efeitos adversos , Atropina/toxicidade , Disartria/tratamento farmacológico , Fisostigmina/farmacologia , Administração Sublingual , Antídotos/uso terapêutico , Assistência Odontológica/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Menores/efeitos adversos , Procedimentos Cirúrgicos Menores/métodos , Antagonistas Muscarínicos/uso terapêutico , Fisostigmina/farmacocinética , Fisostigmina/uso terapêutico , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/tratamento farmacológico
10.
Respir Physiol Neurobiol ; 257: 93-99, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-29369803

RESUMO

A cholinergic system has been described in the nucleus tractus solitarii (NTS). However, no information is available on the role played by acetylcholine (ACh) in the modulation of the cough reflex within the caudal NTS that has an important function in cough regulation. We addressed this issue making use of bilateral microinjections (30-50 nl) of 10 mM ACh combined with 5 mM physostigmine as well as of 10 mM mecamylamine or 10 mM scopolamine into the caudal NTS of pentobarbital sodium-anesthetized, spontaneously breathing rabbits. Microinjections of ACh/physostigmine caused depressant effects on the cough reflex induced by mechanical and chemical stimulation of the tracheobronchial tree. They also elicited transient increases in respiratory frequency and decreases in abdominal activity. These effects were prevented by scopolamine, but not by mecamylamine. The results show for the first time that ACh exerts an inhibitory modulation of the cough reflex through muscarinic receptors within the caudal NTS. They also may provide hints for novel antitussive approaches.


Assuntos
Acetilcolina/farmacologia , Antitussígenos/farmacologia , Agonistas Colinérgicos/farmacologia , Tosse/tratamento farmacológico , Reflexo/efeitos dos fármacos , Núcleo Solitário/efeitos dos fármacos , Acetilcolina/metabolismo , Animais , Tosse/metabolismo , Masculino , Mecamilamina/farmacologia , Microinjeções , Fisostigmina/farmacologia , Coelhos , Receptores Colinérgicos/metabolismo , Reflexo/fisiologia , Escopolamina/farmacologia , Núcleo Solitário/metabolismo
11.
Psychopharmacology (Berl) ; 235(1): 291-299, 2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29119218

RESUMO

RATIONALE: Sleep-dependent memory consolidation depends on the concerted reactivation of memories in the hippocampo-neocortical system. The communication of reactivated information from the hippocampus to the neocortex is assumed to be enabled by low levels of acetylcholine, particularly during slow-wave sleep (SWS). Recent studies suggest that the reactivation of memories does not only occur spontaneously but can also be externally triggered by re-presenting learning-associated cues during sleep. OBJECTIVES: Here we investigated whether the beneficial effect of cued memory reactivation during sleep depends on similar mechanisms as spontaneous reactivation, and specifically on low cholinergic tone. METHODS: In two experimental nights, healthy volunteers learned a visuo-spatial memory task in the presence of an odor before going to sleep for 40 min. In one night, subjects were presented with the odor again during SWS, whereas in the other night they received an odorless vehicle. In half of the subjects, the availability of acetylcholine during sleep was increased by administering the acetylcholine-esterase inhibitor physostigmine. RESULTS: Contrary to our hypothesis, increased cholinergic tone during sleep did not abolish the beneficial effect of odor cueing: memory performance was better after odor cueing compared to odorless vehicle, independent of physostigmine or placebo administration. CONCLUSIONS: This finding challenges the assumption that odor-cued and spontaneous memory reactivation rely on the same neuropharmacological mechanisms.


Assuntos
Aprendizagem por Associação , Inibidores da Colinesterase/farmacologia , Consolidação da Memória , Memória/fisiologia , Odorantes , Estimulação Física/métodos , Fisostigmina/farmacologia , Sono de Ondas Lentas/fisiologia , Adulto , Análise de Variância , Aprendizagem por Associação/efeitos dos fármacos , Aprendizagem por Associação/fisiologia , Sinais (Psicologia) , Hipocampo/efeitos dos fármacos , Humanos , Masculino , Consolidação da Memória/efeitos dos fármacos , Consolidação da Memória/fisiologia , Adulto Jovem
12.
Biomed Pharmacother ; 97: 895-904, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29136766

RESUMO

Boldine, a bioactive compound, has been reported to be neuroprotective, but its effect on learning and memory has not been explored. So, the present study was aimed to study the effect of boldine on the learning and memory of the Swiss albino male young and aged mice. Boldine (1.5, 3 and 6mg/kg, po) and physostigmine salicylate (0.1mg/kg, ip) were administered to separate groups of mice for 7 successive days. Morris water maze was utilized as a behavioural model to study the effect of drugs on learning and memory of mice. Boldine and physostigmine significantly improved learning and memory of young as well as aged mice, as indicated by decrease in escape latency time during training session and increase in time spent in target quadrant during retrieval session. No significant effect on locomotor activities of mice was observed due to drug treatments. Memory-enhancing activity of boldine (3mg/kg) was found to be comparable to physostigmine. Boldine significantly reversed scopolamine-, sodium nitrite- and aging-induced amnesia in mice. Moreover, boldine attenuated oxidative stress, as shown by a significant decrease in brain malondialdehyde as well as brain nitrite levels and a significant increase in brain GSH level of young as well as aged mice. Brain acetylcholinesterase activity was also significantly inhibited by boldine in young as well as aged mice. In conclusion boldine administered for 7 successive days exhibited significant improvement of learning and memory of young and aged mice possibly through inhibition of brain acetylcholinesterase activity and alleviation of brain oxidative stress.


Assuntos
Aporfinas/farmacologia , Aprendizagem em Labirinto/efeitos dos fármacos , Memória/efeitos dos fármacos , Nootrópicos/farmacologia , Acetilcolinesterase/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Fatores Etários , Amnésia/tratamento farmacológico , Animais , Aporfinas/administração & dosagem , Comportamento Animal , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Glutationa/metabolismo , Masculino , Malondialdeído/metabolismo , Camundongos , Nitritos/metabolismo , Nootrópicos/administração & dosagem , Estresse Oxidativo/efeitos dos fármacos , Fisostigmina/análogos & derivados , Fisostigmina/farmacologia
13.
Brain Res Bull ; 137: 23-34, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29122691

RESUMO

Central cholinergic systems regulate the hypothalamic-pituitary-adrenal (HPA) axis differentially in males and females (sexual diergism). We previously investigated the role of muscarinic receptors in this regulation by administering physostigmine (PHYSO), an acetylcholinesterase inhibitor, to male and female rats pretreated with scopolamine (SCOP), a nonselective muscarinic antagonist. SCOP pretreatment enhanced adrenocorticotropic hormone (ACTH) and corticosterone (CORT) responses in both sexes, but males had greater ACTH responses while females had greater CORT responses. In the present study, we further explored the role of muscarinic receptor subtypes in HPA axis regulation by administering PHYSO to male and female rats following SCOP or various doses of either the M1 or the M2 selective muscarinic receptor antagonists, pirenzepine (PIREN) or methoctramine (METHO). Blood was sampled before and at multiple times after PHYSO. ACTH and CORT were determined by highly specific immunoassays. M1 antagonism by PIREN prior to PHYSO resulted in sustained, dose-dependent increases in ACTH and CORT: ACTH responses were similar in both sexes, and CORT responses were greater in females. M2 antagonism by METHO prior to PHYSO resulted in overall decreases in ACTH and CORT: ACTH and CORT responses were higher in females but lower in both sexes than the hormone responses following PIREN or SCOP pretreatment. Area under the curve analyses supported these findings. These results suggest that specific muscarinic receptor subtypes differentially influence the HPA axis in a sexually diergic manner.


Assuntos
Inibidores da Colinesterase/farmacologia , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Fisostigmina/farmacologia , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Caracteres Sexuais , Hormônio Adrenocorticotrópico/sangue , Animais , Corticosterona/sangue , Diaminas/farmacologia , Relação Dose-Resposta a Droga , Feminino , Sistema Hipotálamo-Hipofisário/metabolismo , Masculino , Pirenzepina/farmacologia , Sistema Hipófise-Suprarrenal/metabolismo , Ratos Sprague-Dawley , Escopolamina/farmacologia
14.
Br J Pharmacol ; 175(11): 1903-1914, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-28264149

RESUMO

BACKGROUND AND PURPOSE: Clinical studies have identified links between cholinergic signalling and depression in human subjects. Increased cholinergic signalling in hippocampus also increases behaviours related to anxiety and depression in mice, which can be reversed by ACh receptor antagonists. EXPERIMENTAL APPROACH: As the α7 subunit of the nicotinic ACh receptor (nAChR) is highly expressed in hippocampus, we determined whether blocking α7 nAChRs could reverse the effects of increased ACh signalling in anxiety- and depression-related behaviours in mice. KEY RESULTS: Administration of the α7 nAChR agonist GTS-21 had no effect in tail suspension or forced swim tests. Conversely, the α7 nAChR antagonist methyllycaconitine (MLA) induced significant antidepressant-like effects in male mice in these paradigms, consistent with previous studies, but this was not observed in female mice. MLA also decreased physostigmine-induced c-fos immunoreactivity (a marker of neuronal activity) in hippocampus. Local knockdown of α7 nAChRs in hippocampus had no effect on its own but decreased a subset of depression-like phenotypes induced by physostigmine in male mice. Few effects of α7 nAChR knockdown were observed in depression-like behaviors in female mice, possibly due to a limited response to physostigmine. There was no significant effect of hippocampal α7 nAChR knockdown on anxiety-like phenotypes in male mice. However, a modest increase in anxiety-like behavior was observed in female mice infused with a scrambled control vector in response to physostigmine administration, that was not seen after a7 nAChR knockdown in the hippocampus. CONCLUSIONS AND IMPLICATIONS: These results suggest that ACh signalling through α7 nAChRs in the hippocampus contributes to regulation of a subset of depression-like behaviours when ACh is increased, as can occur under stressful conditions. These studies also provide evidence for sex differences that may be relevant for treatments of mood disorders based on cholinergic signalling. LINKED ARTICLES: This article is part of a themed section on Nicotinic Acetylcholine Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.11/issuetoc.


Assuntos
Comportamento Animal/efeitos dos fármacos , Depressão/tratamento farmacológico , Hipocampo/efeitos dos fármacos , Fisostigmina/farmacologia , Receptor Nicotínico de Acetilcolina alfa7/metabolismo , Animais , Depressão/metabolismo , Depressão/cirurgia , Feminino , Hipocampo/metabolismo , Hipocampo/cirurgia , Masculino , Camundongos , Camundongos Endogâmicos C57BL
15.
Arch Toxicol ; 92(3): 1161-1176, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29167930

RESUMO

The asexual freshwater planarian Dugesia japonica has emerged as a medium-throughput alternative animal model for neurotoxicology. We have previously shown that D. japonica are sensitive to organophosphorus pesticides (OPs) and characterized the in vitro inhibition profile of planarian cholinesterase (DjChE) activity using irreversible and reversible inhibitors. We found that DjChE has intermediate features of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Here, we identify two candidate genes (Djche1 and Djche2) responsible for DjChE activity. Sequence alignment and structural homology modeling with representative vertebrate AChE and BChE sequences confirmed our structural predictions, and show that both DjChE enzymes have intermediate sized catalytic gorges and disrupted peripheral binding sites. Djche1 and Djche2 were both expressed in the planarian nervous system, as anticipated from previous activity staining, but with distinct expression profiles. To dissect how DjChE inhibition affects planarian behavior, we acutely inhibited DjChE activity by exposing animals to either an OP (diazinon) or carbamate (physostigmine) at 1 µM for 4 days. Both inhibitors delayed the reaction of planarians to heat stress. Simultaneous knockdown of both Djche genes by RNAi similarly resulted in a delayed heat stress response. Furthermore, chemical inhibition of DjChE activity increased the worms' ability to adhere to a substrate. However, increased substrate adhesion was not observed in Djche1/Djche2 (RNAi) animals or in inhibitor-treated day 11 regenerates, suggesting this phenotype may be modulated by other mechanisms besides ChE inhibition. Together, our study characterizes DjChE expression and function, providing the basis for future studies in this system to dissect alternative mechanisms of OP toxicity.


Assuntos
Colinesterases/genética , Colinesterases/metabolismo , Resposta ao Choque Térmico/fisiologia , Planárias/fisiologia , Animais , Inibidores da Colinesterase/farmacologia , Colinesterases/química , Diazinon/farmacologia , Evolução Molecular , Regulação Enzimológica da Expressão Gênica , Técnicas de Silenciamento de Genes , Resposta ao Choque Térmico/efeitos dos fármacos , Sistema Nervoso/enzimologia , Fisostigmina/farmacologia , Planárias/efeitos dos fármacos , Conformação Proteica
16.
Brain Res ; 1677: 118-128, 2017 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-28963051

RESUMO

Stroke commonly leads to adult disability and death worldwide. Its major symptoms are spastic hemiplegia and discordant motion, consequent to neuronal cell death induced by brain vessel occlusion. Acetylcholinesterase (AChE) is upregulated and allied with inflammation and apoptosis after stroke. Recent studies suggest that AChE inhibition ameliorates ischemia-reperfusion injury and has neuroprotective properties. (-)-Phenserine, a reversible AChE inhibitor, has a broad range of actions independent of its AChE properties, including neuroprotective ones. However, its protective effects and detailed mechanism of action in the rat middle cerebral artery occlusion model (MCAO) remain to be elucidated. This study investigated the therapeutic effects of (-)-phenserine for stroke in the rat focal cerebral ischemia model and oxygen-glucose deprivation/reperfusion (OGD/RP) damage model in SH-SY5Y neuronal cultures. (-)-Phenserine mitigated OGD/PR-induced SH-SY5Y cell death, providing an inverted U-shaped dose-response relationship between concentration and survival. In MCAO challenged rats, (-)-phenserine reduced infarction volume, cell death and improved body asymmetry, a behavioral measure of stoke impact. In both cellular and animal studies, (-)-phenserine elevated brain-derived neurotrophic factor (BDNF) and B-cell lymphoma 2 (Bcl-2) levels, and decreased activated-caspase 3, amyloid precursor protein (APP) and glial fibrillary acidic protein (GFAP) expression, potentially mediated through the ERK-1/2 signaling pathway. These actions mitigated neuronal apoptosis in the stroke penumbra, and decreased matrix metallopeptidase-9 (MMP-9) expression. In synopsis, (-)-phenserine significantly reduced neuronal damage induced by ischemia/reperfusion injury in a rat model of MCAO and cellular model of OGD/RP, demonstrating that its anti-apoptotic/neuroprotective/neurotrophic cholinergic and non-cholinergic properties warrant further evaluation in conditions of brain injury.


Assuntos
Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fisostigmina/análogos & derivados , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Apoptose/fisiologia , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/fisiologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/fisiologia , Inibidores da Colinesterase/farmacologia , Relação Dose-Resposta a Droga , Glucose/deficiência , Humanos , Masculino , Neurônios/metabolismo , Neurônios/patologia , Fisostigmina/farmacologia , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/metabolismo , Acidente Vascular Cerebral/patologia
17.
Prog Neuropsychopharmacol Biol Psychiatry ; 79(Pt B): 128-135, 2017 10 03.
Artigo em Inglês | MEDLINE | ID: mdl-28571775

RESUMO

AIM: Despite different theories regarding sleep physiological function, an overall census indicates that sleep is useful for neural plasticity which eventually strengthens cognition and brain performance. Different studies show that sleep deprivation (SD) leads to impaired learning and hippocampus dependent memory. According to some studies, cholinergic system plays an important role in sleep (particularly REM sleep), learning, memory, and its retrieval. So this study has been designed to investigate the effect of CA1 Cholinergic Muscarinic Receptors on memory acquisition deficit induced by total sleep deprivation (TSD) and REM sleep deprivation (RSD). METHOD: A modified water box (locomotor activity may be provide a limiting factor in this method of SD) or multiple platforms were used for induction of TSD or RSD, respectively. Inhibitory passive avoidance apparatus has been used to determine the effects of SD and its changes by physostigmine (as cholinesterase inhibitor) or scopolamine (muscarinic receptor antagonist) on memory formation. Because locomotor activity and pain perception induce critical roles in passive avoidance memory formation, we also measured these factors by open field and hot-plate instruments, respectively. RESULTS: The results showed that TSD and RSD for 24 hours impaired memory formation but they did not alter locomotor activity. TSD also induced analgesia effect, but RSD did not alter it. Intra-CA1 injection of physostigmine (0.0001µg/rat) and scopolamine (0.01µg/rat) did not alter memory acquisition in the sham-TSD or sham-RSD, by themselves. Moreover, intra-CA1 injection of sub-threshold dose of physostigmine (0.0001µg/rat) and scopolamine (0.01µg/rat) could restore the memory acquisition deficit induced by RSD, while scopolamine could restore TSD-induced amnesia. Both drugs reversed analgesia induced by TSD. None of previous interventions altered locomotor activity. CONCLUSION: According to this study, CA1 cholinergic muscarinic receptors play an important role in amnesia induced by both TSD and RSD. However further studies are needed for showing cellular and molecular mechanisms of surprising result of similar pharmacological effects using compounds with opposite profiles.


Assuntos
Região CA1 Hipocampal/metabolismo , Transtornos da Memória/metabolismo , Memória/fisiologia , Receptores Muscarínicos/metabolismo , Privação do Sono/psicologia , Sono REM , Animais , Região CA1 Hipocampal/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Masculino , Memória/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/etiologia , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Antagonistas Muscarínicos/farmacologia , Nootrópicos/farmacologia , Fisostigmina/farmacologia , Ratos Wistar , Escopolamina/farmacologia , Privação do Sono/complicações , Privação do Sono/metabolismo , Sono REM/fisiologia
18.
Mol Pharmacol ; 92(3): 318-326, 2017 09.
Artigo em Inglês | MEDLINE | ID: mdl-28630263

RESUMO

Physostigmine can potentiate and inhibit neuronal nicotinic receptors, in addition to inhibiting the activity of acetylcholinesterase. We found that receptors containing three copies of the α2 subunit are inhibited by low concentrations of physostigmine in contrast to receptors containing three copies of the α4 subunit that are potentiated. We exploited this observation to determine the regions required for the actions of physostigmine. Chimeric constructs of the α2 and α4 subunits located two regions in the extracellular amino-terminal domain of the subunit: the E loop (a loop of the transmitter-binding domain) and a region closer to the amino-terminus that collectively could completely determine the different effects of physostigmine. Point mutations then identified a single residue, α2(I92) versus α4(R92), that, when combined with transfer of the E loop, could convert the inhibition seen with α2 subunits to potentiation and the potentiation seen with α4 subunits to inhibition. In addition, other point mutations could affect the extent of potentiation or inhibition, indicating that a more extensive set of interactions in the amino-terminal domain plays some role in the actions of physostigmine.


Assuntos
Antagonistas Nicotínicos/farmacologia , Fisostigmina/farmacologia , Receptores Nicotínicos/química , Animais , Humanos , Camundongos , Domínios Proteicos , Subunidades Proteicas , Receptores Nicotínicos/efeitos dos fármacos , Relação Estrutura-Atividade , Xenopus laevis
19.
Chem Biol Interact ; 272: 37-46, 2017 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-28499986

RESUMO

Alzheimer's disease (AD) is a neurodegenerative disorder pathologically characterized by severe neuronal and glial structural changes and progressive cognitive decline. N-acetylcysteine (NAC) is a well-known pharmacological agent with pro-neurogenic properties and neuroprotective effects. In this study, we evaluated NAC protective effects on cognitive impairment and associated pathological markers in a streptozotocin (STZ)-induced sporadic dementia of AD type mice model. Animals were divided into six groups: I) Sham, II) NAC, III) physostigmine (PHY), IV) STZ, V) NAC + STZ and VI) PHY + NAC. NAC (5 mg/kg) and PHY (0.25 mg/kg) were administrated orally for 30 consecutive days and STZ (2.5 mg/kg) intracerebroventricularly at the first and third days. Novel object recognition (NOR, days 26-27) and Morris water maze (MWM, days 26-30) tasks were assessed to evaluate learning and memory. On the thirty-first day animals were euthanized and brains collected for biochemical analysis. Interestingly, our results showed that STZ treatment induced cognitive impairment in mice in the NOR and MWM tasks. Both NAC and PHY treatments prevented from this impairment. The increase in AChE activity and decrease in pTrkB and MnSOD levels caused by STZ in the cerebral cortex and hippocampus, were prevented by the NAC and PHY treatments. The decrease in SYN, MAP2 and GFAP expressions were also prevented by NAC and PHY treatments. In conclusion, NAC treatment prevented the cognitive impairment induced by STZ, normalizing the AChE activity and rescuing the synaptic plasticity loss. Our results suggest that NAC is a promising therapeutic strategy for the treatment of AD.


Assuntos
Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Disfunção Cognitiva/induzido quimicamente , Disfunção Cognitiva/tratamento farmacológico , Plasticidade Neuronal/efeitos dos fármacos , Acetilcolinesterase/metabolismo , Animais , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Imuno-Histoquímica , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Atividade Motora/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo/efeitos dos fármacos , Fisostigmina/farmacologia , Receptor trkB/metabolismo , Estreptozocina/toxicidade , Superóxido Dismutase/metabolismo
20.
Respir Physiol Neurobiol ; 242: 102-107, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28445778

RESUMO

Vagal innervations have a great role in the respiratory function and are the main route of signal transmission from respiratory neural centers into the trachea and others conducting airways. We have investigated the role of central mechanisms related to vagal neural pathways and the cholinergic outflow in tracheobronchial smooth muscle tone and lung mechanics parameters. Parameters of lung mechanics such as lung resistance (RL), dynamic compliance (Cdyn) and pressure in bypassed tracheal segment (Ptseg) were measured before and after vagotomy and asphyxia test. Before vagotomy (BV), the control measurements were obtained and physostigmine was administered systemically, in increasing dose 10, 40 and 100µg/kg body weight (bw) with 15min interval between doses. After vagotomy (AV), administration of physostigmine with the same doses as BV has been done and the asphyxia challenge was conducted as per study protocol. The values of Ptseg and RL after physostigmine administration, BV vs. AV, respectively, at maximal dose of 100µg/kg bw were 32.5±3.3cm H2O, and 10.6±1.5cm H2O (p<0.0001); 0.16±0.04cm H2O/mL/s, and 0.067±0.006cm H2O/mL/s AV (P<0.05). The Cydn values were affected after physostigmine administration only at the lowest dose of 10µg/kg bw, and BV was 0.75±0.05mL/cm H2O vs. 0.53±0.04mL/cm H2O AV (P<0.004). Cholinergic outflow produced increases in tracheal tone, lung resistance and a decrease in dynamic compliance before, but not after vagotomy. Our results show the high impact of central neuronal mechanism in parameters of lung mechanics and respiration. This study indicates that vagal nerves have a crucial role, in the transmission of impulses initiated from central nervous system, in regulating the respiration by contraction or relaxation of airway smooth muscle tone.


Assuntos
Inibidores da Colinesterase/farmacologia , Pulmão/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Fisostigmina/farmacologia , Traqueia/efeitos dos fármacos , Nervo Vago/fisiologia , Resistência das Vias Respiratórias/efeitos dos fármacos , Resistência das Vias Respiratórias/fisiologia , Animais , Colinesterases/metabolismo , Relação Dose-Resposta a Droga , Furões , Pulmão/enzimologia , Masculino , Modelos Animais , Tono Muscular/efeitos dos fármacos , Tono Muscular/fisiologia , Músculo Liso/enzimologia , Fármacos Neuromusculares/farmacologia , Fármacos do Sistema Respiratório/farmacologia , Traqueia/enzimologia , Vagotomia
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