RESUMEN
Nerve agents are highly toxic organophosphorus compounds that inhibit acetylcholinesterase resulting in rapid accumulation of the neurotransmitter acetylcholine (ACh) causing a cholinergic syndrome including respiratory failure. In the present study, respiratory responses and antimuscarinic treatment efficacy was evaluated ex vivo using rat precision-cut lung slices (PCLS) exposed to the nerve agent VX. The respiratory effects were evaluated either by adding exogenous ACh directly to the culture medium or by applying electric-field stimulation (EFS) to the PCLS to achieve a release of endogenous ACh from neurons in the lung tissue. The airway contraction induced by both methods was enhanced by VX and resulted in lingering airway recovery, in particular when airways were exposed to a high VX-dose. Both contractions induced by EFS and exogenously added ACh were significantly reduced by administration of the antimuscarinic drugs atropine or scopolamine. Two additions of atropine or scopolamine after maximal ACh-induced airway response was demonstrated effective to reverse the contraction. By adding consecutive doubled doses of antimuscarinics, high efficiency to reduce the cholinergic airway response was observed. However, the airways were not completely recovered by atropine or scopolamine, indicating that non-muscarinic mechanisms were involved in the smooth muscle contractions. In conclusion, it was demonstrated that antimuscarinic treatment reversed airway contraction induced by VX but supplemental pharmacological interventions are needed to fully recover the airways. Further studies should therefore clarify the mechanisms of physiological responses in lung tissue following nerve agent exposures to improve the medical management of poisoned individuals.
Asunto(s)
Atropina/farmacología , Fibras Colinérgicas/efectos de los fármacos , Inhibidores de la Colinesterasa/toxicidad , Pulmón/inervación , Antagonistas Muscarínicos/farmacología , Contracción Muscular/efectos de los fármacos , Músculo Liso/inervación , Compuestos Organotiofosforados/toxicidad , Escopolamina/farmacología , Acetilcolina/metabolismo , Acetilcolina/farmacología , Acetilcolinesterasa/metabolismo , Animales , Fibras Colinérgicas/enzimología , Relación Dosis-Respuesta a Droga , Estimulación Eléctrica , Femenino , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/metabolismo , Ratas Sprague-DawleyRESUMEN
We aimed to investigate the therapeutic effects of an Elaeagnus glabra f. oxyphylla (EGFO) ethanol extract in mice with scopolamine-induced memory dysfunction. Fifty male mice were randomly divided into a normal control group, a scopolamine-treated group, a scopolamine and EGFO extract-treated group, and a scopolamine and tacrine-treated group. EGFO (50 or 100 mg/kg/day) was received for 21 days. Step-through passive avoidance and Y-maze tests were performed to examine the effects of treatment on learning and memory impairments. Acetylcholine (Ach) levels and acetylcholinesterase (AchE) activity were measured via an enzyme-linked immunosorbent assay (ELISA). Levels of choline acetyltransferase (ChAT), nerve growth factor (NGF), cAMP response element-binding protein (CREB), and apoptosis-related protein expression were determined via Western blot analysis. EGFO pretreatment significantly attenuated scopolamine-induced memory impairments, relative to findings observed in the scopolamine-treated group. Levels of cholinergic factors in the brain tissues were markedly attenuated in the scopolamine-treated group. EGFO treatment also attenuated neural apoptosis in scopolamine-treated mice by decreasing the expression of apoptosis-related proteins such as Bax, Bcl2, cleaved caspase-3, and TUNEL staining. These results suggest that EGFO improves memory and cognition in a mouse model of memory impairment by restoring cholinergic and anti-apoptotic activity, possibly via activation of CREB/NGF signaling.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Fibras Colinérgicas/efectos de los fármacos , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Elaeagnaceae , Trastornos de la Memoria/prevención & control , Memoria/efectos de los fármacos , Factor de Crecimiento Nervioso/metabolismo , Preparaciones de Plantas/farmacología , Transmisión Sináptica/efectos de los fármacos , Acetilcolina/metabolismo , Acetilcolinesterasa/metabolismo , Animales , Apoptosis/efectos de los fármacos , Proteínas Reguladoras de la Apoptosis/metabolismo , Encéfalo/metabolismo , Encéfalo/fisiopatología , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/patología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Elaeagnaceae/química , Proteínas Ligadas a GPI/metabolismo , Masculino , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/metabolismo , Trastornos de la Memoria/psicología , Ratones Endogámicos ICR , Preparaciones de Plantas/aislamiento & purificación , EscopolaminaRESUMEN
The Chinese formula Bushen-Yizhi (BSYZ) has been reported to ameliorate cognitive dysfunction. However the mechanism is still unclear. In this study, we employ an aging model, SAMP8 mice, to explore whether BSYZ could protect dementia through SIRT1/endoplasmic reticulum (ER) stress pathway. Morris water maze and the fearing condition test results show that oral administration of BSYZ (1.46 g/kg/d, 2.92 g/kg/d and 5.84 g/kg/d) and donepezil (3 mg/kg/d) shorten the escape latency, increase the crossing times of the original position of the platform and the time spent in the target quadrant, and increase the freezing time. BSYZ decreases the activity of acetylcholinesterase (AChE), and increases the activity of choline acetyltransferase (ChAT) and the concentration of acetylcholine (Ach) in both hippocampus and cortex. In addition, western blot results (Bcl-2, Bax and Caspase-3) and TUNEL staining show that BSYZ prevents neuron from apoptosis, and elevates the expression of neurotrophic factors, including nerve growth factor (NGF), postsynapticdensity 95 (PSD95) and synaptophysin (SYN), in both hippocampus and cortex. BSYZ also increases the protein expression of SIRT1 and alleviates ER stress-associated proteins (PERK, IRE-1α, eIF-2α, BIP, PDI and CHOP). These results indicate that the neuroprotective mechanism of BSYZ might be related with SIRT1/ER stress pathway.
Asunto(s)
Disfunción Cognitiva/metabolismo , Medicamentos Herbarios Chinos/farmacología , Estrés del Retículo Endoplásmico/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Sirtuina 1/metabolismo , Animales , Apoptosis/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Neuronas Colinérgicas/efectos de los fármacos , Neuronas Colinérgicas/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Aprendizaje/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Reconocimiento en Psicología/efectos de los fármacosRESUMEN
This study explored the curative effect and underlying mechanisms of a traditional Chinese medicine compound prescription, Bushen-Yizhi formula (BSYZ), in ibotenic acid (IBO)-induced rats. Morris water maze and novel object recognition tests showed that BSYZ significantly improved spatial and object memory. Brain immunohistochemistry staining showed that BSYZ significantly up-regulated expression of choline acetyltransferase (ChAT) and nerve growth factor (NGF) in the hippocampus and cortex. The protein tyrosine kinase high-affinity receptor TrkA was slightly increased in the hippocampus and cortex, and significantly enhanced in the nucleus basalis of Meynert (NBM) after BSYZ intervention. The immunoreactivity of the p75 low-affinity receptor in BSYZ-treated rats was significantly strengthened in the cortex. Similar expression trends of nerve growth factor (NGF), TrkA, and p75 mRNA were observed in the hippocampus and cortex. Additionally, BSYZ reversed IBO-induced disorders of acetylcholine (ACh) levels, ChAT, and cholinesterase (ChE) in the cortex, which was consistent with the changes in mRNA levels of ChAT and acetylcholinesterase (AChE). Expression of ChAT and AChE proteins and mRNA in the hippocampus was up-regulated, whereas the apoptosis-relative protein cleaved caspase-3 was decreased after administration of BSYZ. Moreover, changes in cell death were confirmed by histological morphology. Thus, the results indicated that the BSYZ formula could ameliorate memory impairments in IBO-induced rats, and it exerted its therapeutic action probably by modulating cholinergic pathways, NGF signaling, and anti-apoptosis. Overall, it is suggested that the BSYZ formula might be a potential therapeutic approach for the treatment of Alzheimer's disease (AD) and other cholinergic impairment-related diseases.
Asunto(s)
Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Fibras Colinérgicas/efectos de los fármacos , Trastornos del Conocimiento/tratamiento farmacológico , Cognición/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Ácido Iboténico , Nootrópicos/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/fisiopatología , Fibras Colinérgicas/metabolismo , Colinesterasas/metabolismo , Trastornos del Conocimiento/inducido químicamente , Trastornos del Conocimiento/metabolismo , Trastornos del Conocimiento/fisiopatología , Trastornos del Conocimiento/psicología , Modelos Animales de Enfermedad , Aprendizaje por Laberinto/efectos de los fármacos , Factor de Crecimiento Nervioso/metabolismo , Proteínas del Tejido Nervioso , Ratas Sprague-Dawley , Receptor trkA/metabolismo , Receptores de Factores de Crecimiento , Receptores de Factor de Crecimiento Nervioso/metabolismo , Reconocimiento en Psicología/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Factores de TiempoRESUMEN
Hexachlorophene (HCP) is known to induce myelin vacuolation corresponding to intramyelinic edema of nerve fibers in the central and peripheral nervous system in animals. This study investigated the effect of maternal exposure to HCP on hippocampal neurogenesis in rat offspring using pregnant rats supplemented with 0 (controls), 100, or 300 ppm HCP in the diet from gestational day 6 to day 21 after delivery. On postnatal day (PND) 21, the numbers of T box brain 2(+) progenitor cells and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling(+) apoptotic cells in the hippocampal subgranular zone (SGZ) decreased in female offspring at 300 ppm, which was accompanied by myelin vacuolation and punctate tubulin beta-3 chain staining of nerve fibers in the hippocampal fimbria. In addition, transcript levels of the cholinergic receptor, nicotinic beta 2 (Chrnb2) and B-cell CLL/lymphoma 2 (Bcl2) decreased in the dentate gyrus. HCP-exposure did not alter the numbers of SGZ proliferating cells and reelin- or calcium-binding protein-expressing γ-aminobutyric acid (GABA)-ergic interneuron subpopulations in the dentate hilus on PND 21 and PND 77. Although some myelin vacuolation remained, all other changes observed in HCP-exposed offspring on PND 21 disappeared on PND 77. These results suggest that maternal HCP exposure reversibly decreases type-2b intermediate-stage progenitor cells via the mitochondrial apoptotic pathway in offspring hippocampal neurogenesis at 300 ppm HCP. Neurogenesis may be affected by dysfunction of cholinergic inputs into granule cell lineages and/or GABAergic interneurons as indicated by decreased transcript levels of Chrnb2 and numbers of Chrnb2(+) interneurons caused by myelin vacuolation in the septal-hippocampal pathway.
Asunto(s)
Fibras Colinérgicas/efectos de los fármacos , Hexaclorofeno/toxicidad , Hipocampo/efectos de los fármacos , Exposición Materna/efectos adversos , Vaina de Mielina/metabolismo , Células-Madre Neurales/efectos de los fármacos , Neurogénesis/efectos de los fármacos , Efectos Tardíos de la Exposición Prenatal , Vacuolas/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Apoptosis/efectos de los fármacos , Linaje de la Célula , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/patología , Femenino , Neuronas GABAérgicas/efectos de los fármacos , Neuronas GABAérgicas/metabolismo , Neuronas GABAérgicas/patología , Regulación del Desarrollo de la Expresión Génica/efectos de los fármacos , Edad Gestacional , Hipocampo/metabolismo , Hipocampo/patología , Interneuronas/efectos de los fármacos , Interneuronas/metabolismo , Interneuronas/patología , Células-Madre Neurales/metabolismo , Células-Madre Neurales/patología , Fenotipo , Embarazo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , ARN Mensajero/metabolismo , Ratas , Receptores Nicotínicos/efectos de los fármacos , Receptores Nicotínicos/genética , Receptores Nicotínicos/metabolismo , Proteína Reelina , Tubulina (Proteína)/metabolismo , Vacuolas/metabolismo , Vacuolas/patologíaRESUMEN
In our previous research, Cordyceps militaris (CM) had a hypoglycemic effect in normal rats. In this study we wanted to elucidate whether CM also had an effect on diabetic rats. Twelve rats with streptozotocin-induced diabetes were separated randomly into 2 groups. First, aqueous extracts of CM 10 mg/kg (CM group) or saline (control group) was fed to the rats; then the plasma glucose levels were assayed. Second, the signaling proteins IRS-1 and GLUT-4 collected from the muscle were detected. Finally, another 2 groups of rats were injected with atropine 0.1 mg/kg intraperitoneally just before the CM/saline feeding, and the assays mentioned above were repeated. Blood glucose decreased 7.2% in the CM group but only 1.5% in the control group (P < 0.05). The IRS-1 signal was 2.9-fold higher than actin in the CM group but only 0.8-fold higher in the control group (P < 0.005). In GLUT-4 signal, the difference was 1.7- vs. 0.6-fold, respectively, compared with actin (P < 0.05). However, atropine injection made CM-induced hypoglycemia or elevation of IRS-1 and GLUT-4 not significant. In conclusion, CM had a hypoglycemic effect in diabetic rats and atropine blocked it. Therefore, the cholinergic activation also was considered to be involved in the hypoglycemic effect of CM in rats with streptozotocin-induced diabetes.
Asunto(s)
Glucemia/efectos de los fármacos , Colinérgicos/farmacología , Fibras Colinérgicas/efectos de los fármacos , Cordyceps/química , Diabetes Mellitus Experimental/tratamiento farmacológico , Hipoglucemiantes/farmacología , Animales , Atropina/antagonistas & inhibidores , Fraccionamiento Químico , Colinérgicos/química , Hipoglucemiantes/química , Masculino , Distribución Aleatoria , Ratas , Ratas Wistar , AguaRESUMEN
Previous studies have shown that Cordyceps militaris (CM) has a hypoglycemic effect, but the actual mechanism remains unclear. This study explored the hypoglycemic mechanism of aqueous extracts of CM in normal Wistar rats. First, the optimal dose of CM for lowering plasma glucose and insulin secretion was tested. Further, atropine and hemicholinium-3 (HC-3) were injected and a western blot was used to investigate insulin signaling. It was found that 10 mg/kg CM extracts had a stronger hypoglycemic effect than a higher dose (100 mg/kg); therefore, a dose of 10 mg/kg was used in subsequent experiments. In normal rats, CM extracts decreased plasma glucose by 21.0% and induced additional insulin secretion by 54.5% after 30 min. When atropine or HC-3 was injected, CM induced a hypoglycemic effect, but the enhancement of insulin secretion was blocked. By western blotting, significant increases in the insulin receptor substrate 1 (IRS-1) and glucose transporter 4 (GLUT-4) were observed after CM feeding. However, the elevation of these signaling proteins was abolished by atropine or HC-3. Taken together, these findings indicate that CM can lower plasma glucose via the stimulation of insulin secretion and cholinergic activation involved in the hypoglycemic mechanism of normal Wistar rats.
Asunto(s)
Glucemia/efectos de los fármacos , Colinérgicos/farmacología , Cordyceps/química , Hipoglucemiantes/farmacología , Insulina/metabolismo , Animales , Atropina/administración & dosificación , Atropina/farmacología , Glucemia/metabolismo , Western Blotting , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Modelos Animales de Enfermedad , Transportador de Glucosa de Tipo 4/metabolismo , Hemicolinio 3/administración & dosificación , Hemicolinio 3/farmacología , Proteínas Sustrato del Receptor de Insulina/metabolismo , Secreción de Insulina , Masculino , Ratas , Ratas WistarRESUMEN
OBJECTIVES: Postoperative ileus is major cause of postoperative complication and prolonged hospitalization. Jatrorrhizine, which is a protoberberine alkaloid isolated from the medicinal plants Berberis aristata and Coptis chinensis, has been found to increase contractility of gastric antral and ileum smooth muscles of rat gastrointestinal tract. We have investigated whether jatrorrhizine could offset gastrointestinal transit in rat with postoperative ileus. METHODS: Postoperative ileus was induced by laparotomy with intestinal manipulation under anaesthesia. Gastrointestinal transit was evaluated by measurement of gastric emptying, geometric centre and the migration of Evans blue. KEY FINDINGS: Postoperative ileus significantly delayed gastric emptying and intestinal transit. Jatrorrhizine dose-dependently (0.1, 0.3 and 1 mg/kg) offset delayed gastric emptying and intestinal transit (geometric centre and the migration of Evans blue) in postoperative ileus. Pretreatment of animals with atropine inhibited the action of jatrorrhizine on gastric emptying and intestinal transit, but pretreatment of animals with SB204070 did not influence the effect of jatrorrhizine on gastric emptying and intestinal transit in postoperative ileus. CONCLUSIONS: Jatrorrhizine offset postoperative ileus-induced delayed gastric emptying and intestinal transit in rats, an action mediated via the cholinergic pathway, but not involving activation of 5-HT(4) receptors.
Asunto(s)
Berberina/análogos & derivados , Fibras Colinérgicas/efectos de los fármacos , Tránsito Gastrointestinal/efectos de los fármacos , Ileus/tratamiento farmacológico , Complicaciones Posoperatorias/tratamiento farmacológico , Animales , Atropina/uso terapéutico , Berberina/uso terapéutico , Relación Dosis-Respuesta a Droga , Interacciones Farmacológicas , Azul de Evans , Vaciamiento Gástrico/efectos de los fármacos , Vaciamiento Gástrico/fisiología , Tránsito Gastrointestinal/fisiología , Laparotomía/efectos adversos , Masculino , Agonistas Muscarínicos/uso terapéutico , Extractos Vegetales/uso terapéutico , Plantas Medicinales , Ratas , Ratas Wistar , Receptores de Serotonina 5-HT4/metabolismo , Antagonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Factores de TiempoRESUMEN
Acetylcholine (ACh) influences a vast array of phenomena in cortical systems. It alters many ionic conductances and neuronal firing behavior, often by regulating membrane potential oscillations in populations of cells. Synaptic inhibition has crucial roles in many forms of oscillation, and cholinergic mechanisms regulate both oscillations and synaptic inhibition. In vitro investigations using bath-application of cholinergic receptor agonists, or bulk tissue electrical stimulation to release endogenous ACh, have led to insights into cholinergic function, but questions remain because of the relative lack of selectivity of these forms of stimulation. To investigate the effects of selective release of ACh on interneurons and oscillations, we used an optogenetic approach in which the light-sensitive non-selective cation channel, Channelrhodopsin2 (ChR2), was virally delivered to cholinergic projection neurons in the medial septum/diagonal band of Broca (MS/DBB) of adult mice expressing Cre-recombinase under the control of the choline-acetyltransferase (ChAT) promoter. Acute hippocampal slices obtained from these animals weeks later revealed ChR2 expression in cholinergic axons. Brief trains of blue light pulses delivered to untreated slices initiated bursts of ACh-evoked, inhibitory post-synaptic currents (L-IPSCs) in CA1 pyramidal cells that lasted for 10's of seconds after the light stimulation ceased. L-IPSC occurred more reliably in slices treated with eserine and a very low concentration of 4-AP, which were therefore used in most experiments. The rhythmic, L-IPSCs were driven primarily by muscarinic ACh receptors (mAChRs), and could be suppressed by endocannabinoid release from pyramidal cells. Finally, low-frequency oscillations (LFOs) of local field potentials (LFPs) were significantly cross-correlated with the L-IPSCs, and reversal of the LFPs near s. pyramidale confirmed that the LFPs were driven by perisomatic inhibition. This optogenetic approach may be a useful complementary technique in future investigations of endogenous ACh effects.
Asunto(s)
Acetilcolina/metabolismo , Hipocampo/fisiología , Potenciales Postsinápticos Inhibidores/genética , Potenciales Postsinápticos Inhibidores/efectos de la radiación , Luz , Periodicidad , Animales , Región CA1 Hipocampal/efectos de los fármacos , Región CA1 Hipocampal/metabolismo , Región CA1 Hipocampal/fisiología , Región CA1 Hipocampal/efectos de la radiación , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Fibras Colinérgicas/efectos de la radiación , Antagonistas de Receptores de GABA-A/farmacología , Vectores Genéticos/genética , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Hipocampo/efectos de la radiación , Técnicas In Vitro , Potenciales Postsinápticos Inhibidores/efectos de los fármacos , Ratones , Antagonistas Muscarínicos/farmacología , Células Piramidales/efectos de los fármacos , Células Piramidales/metabolismo , Células Piramidales/fisiología , Células Piramidales/efectos de la radiación , Receptor Cannabinoide CB1/metabolismo , Rodopsina/genéticaRESUMEN
The aim of this study is to explore the mechanisms by which electroacupuncture (EA) enhances the hypoglycemic effect of exogenous insulin in a streptozotocin- (STZ-) diabetic rats. Animals in the EA group were anesthetized and subjected to the insulin challenge test (ICT) and EA for 60 minutes. In the control group, rats were subjected to the same treatment with the exception of EA stimulation. Blood samples were drawn to measure changes in plasma glucose, free fatty acids (FFA), and insulin levels. Western blot was used to assay proteins involved in insulin signaling. Furthermore, atropine, hemicholinium-3 (HC-3), and Eserine were used to explore the relationship between EA and cholinergic nerve activation during ICT. EA augmented the blood glucose-lowering effects of EA by activating the cholinergic nerves in STZ rats that had been exposed to exogenous insulin. This phenomenon may be related to enhancement of insulin signaling rather than to changes in FFA concentration.
Asunto(s)
Glucemia/metabolismo , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/fisiología , Diabetes Mellitus Experimental/metabolismo , Electroacupuntura , Hipoglucemiantes/farmacología , Insulina/farmacología , Animales , Atropina/farmacología , Colinérgicos/farmacología , Diabetes Mellitus Experimental/inducido químicamente , Modelos Animales de Enfermedad , Ácidos Grasos no Esterificados/sangre , Hemicolinio 3/farmacología , Insulina/sangre , Masculino , Fisostigmina/farmacología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Estreptozocina/efectos adversosRESUMEN
This study was aimed to investigate the protective effect of Liu Wei Dihuang (LWDH) against D-galactose (D-gal)-induced brain injury in rats and the existence of sex-dependent differences in LWDH protection. Sixty-four rats evenly composed of males and females were randomly assigned into 4 groups (n = 8): normal saline (NS) + NS (N + N), NS + LWDH (N + L), D-gal + NS (D + N) and D-gal + LWDH (D + L) groups. Rats in D + N and D + L groups received daily injection of D-gal (100 mg/kg, s.c.) for six weeks to establish the aging model, while rats in N + N and N + L groups were injected with the same volume of NS. From the third week, rats in N + L and D + L groups were orally administered with a decoction of LWDH for subsequent six weeks. Rats in N + N and D + N groups were orally administered just with the same volume of NS simultaneously. Morris water maze test was employed to evaluate the ability of learning and memory of the rats in all the groups. Acetylcholine (ACh) content, activities of choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) in visual cortex were assayed. Hematoxylin and eosin (HE) staining were used to observe the morphologic injury in hippocampus and visual cortex, and immunohistochemistry was performed to evaluate ChAT and AChE expression levels in the visual cortex. The results showed that the rats in D + N groups exhibited a longer escape latency to platform, lower swimming speed, less percent of target quadrant search time and platform crossings, compared with N + N groups, suggesting the establishment of aging model, while LWDH improved these indexes in D-gal-treated rats. Compared with D + N groups, LWDH increased ACh content and ChAT activity, and decreased AChE activity in visual cortex. Remarkable loss of neurons was found in hippocampus and visual cortex of aging rats, and the injury was significantly attenuated by LWDH. Immunohistochemistry showed D-gal-induced decreases of ChAT and AChE expressions were restored by LWDH. Furthermore, under the neural protection of LWDH, the improvement on platform crossings in male aging rats was better than that in female ones, while in ChAT expression and neuron density in visual cortex, female aging rats obtained more amelioration. These results suggest LWDH can markedly reverse the D-gal-induced cognitive impairments and neuronal damage in both hippocampus and visual cortex, which are achieved at least partly through restoring cholinergic system in central nervous system. Moreover, there is some sex difference in protective effects of LWDH against D-gal-induced impairment.
Asunto(s)
Encéfalo/metabolismo , Fibras Colinérgicas/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Galactosa/toxicidad , Fármacos Neuroprotectores/farmacología , Animales , Encéfalo/patología , Fibras Colinérgicas/patología , Trastornos del Conocimiento/prevención & control , Femenino , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Neuronas/patología , Distribución Aleatoria , Ratas , Ratas Sprague-Dawley , Corteza Visual/metabolismo , Corteza Visual/patologíaRESUMEN
We studied the long-term effects of a postnatal choline supplementation (from birth till weaning) in the truncated MeCP2-308 mouse model of Rett syndrome. Adult male mutant hemizygous (hz) mice showed a reduction of locomotor activity compared to wild type (wt) littermates. Early choline treatment restored wt-like locomotor activity levels in hz mice. Reduced striatal choline acetyl transferase (ChAT) activity and decreased levels of cortical mRNA NGF were found in hz mice. Choline supplementation increased striatal ChAT activity and also enhanced NGF and BDNF expression in cortical and hippocampal regions. As a whole, postnatal choline supplementation attenuates some of the behavioural and neurobiological abnormalities of the Mecp2-308 phenotype.
Asunto(s)
Colina/uso terapéutico , Fibras Colinérgicas/efectos de los fármacos , Suplementos Dietéticos , Síndrome de Rett/dietoterapia , Síndrome de Rett/psicología , Animales , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Colina/administración & dosificación , Colina/farmacología , Colina O-Acetiltransferasa/metabolismo , Fibras Colinérgicas/fisiología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Proteína 2 de Unión a Metil-CpG/genética , Ratones , Ratones Mutantes , Actividad Motora/efectos de los fármacos , Factor de Crecimiento Nervioso/metabolismo , Síndrome de Rett/metabolismo , Síndrome de Rett/fisiopatología , Escopolamina/farmacologíaRESUMEN
BACKGROUND: The main symptom of postoperative ileus (POI) is an intestinal motility disorder in which monocytes/macrophages and neutrophils play crucial roles. Prokinetic 5-hydroxytryptamine 4 receptor (5-HT4R) agonists and dopamine receptor antagonists are potential therapeutic agents for directly ameliorating the motility disorder associated with POI. AIM: To determine the effects of the 5-HT4R agonists mosapride citrate (MOS) and CJ-033466 on intestinal smooth muscle contractility relative to immune reactions after POI. METHODS: Intestinal manipulation (IM) was applied to the rat distal ileum. Both MOS (0.3 and 1 mg/kg, s.c.) and CJ-033466 (1 mg/kg, s.c.) were administered to the animals before and after IM. At 24 h after IM, isolated intestinal smooth muscle contractile activity in vitro, gastrointestinal transit in vivo, inflammatory mediator expression and leucocyte infiltration were measured. RESULTS: After IM, ileal circular muscle contractility in vitro and gastrointestinal transit in vivo were reduced and the number of macrophages and neutrophils increased in the inflamed muscle layer, resulting in the induction of inflammatory mediators such as interleukin 1 ß (IL-1ß), IL-6, tumour necrosis factor α (TNFα), monocyte chemoattractant protein 1 (MCP-1) and inducible nitric oxide synthase (iNOS). Both MOS and CJ-033466 significantly attenuated not only the intestinal motility dysfunction but also the leucocyte infiltration and inflammatory mediator expression after IM. The autonomic ganglionic blocker hexamethonium (1 mg/kg, i.p.) and the α7-nicotinic acetylcholine receptor (α7nAChR) antagonist methyl lycaconitine citrate (0.087 mg/kg, i.p.) blocked MOS-mediated ameliorative actions. Immunohistochemically, α7nAChR is expressed by monocytes/macrophages but not by neutrophils in the inflamed intestine. CONCLUSION: Stimulating the 5-HT4R accelerates acetyl choline (ACh) release from cholinergic myenteric neurons, which subsequently activates α7nAChR on activated monocytes/macrophages to inhibit their inflammatory reactions in the muscle layer. In addition to their gastroprokinetic action, 5-HT4R agonists might serve as novel therapeutic agents for POI characterised by anti-inflammatory potency.
Asunto(s)
Ileus/prevención & control , Complicaciones Posoperatorias/prevención & control , Receptores Nicotínicos/fisiología , Receptores de Serotonina 5-HT4/fisiología , Agonistas del Receptor de Serotonina 5-HT4/uso terapéutico , Aminopiridinas/uso terapéutico , Animales , Benzamidas/uso terapéutico , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/fisiología , Modelos Animales de Enfermedad , Evaluación Preclínica de Medicamentos/métodos , Tránsito Gastrointestinal/efectos de los fármacos , Íleon/efectos de los fármacos , Ileus/metabolismo , Ileus/fisiopatología , Imidazoles/uso terapéutico , Mediadores de Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Morfolinas/uso terapéutico , Contracción Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Plexo Mientérico/efectos de los fármacos , Plexo Mientérico/fisiología , Infiltración Neutrófila/efectos de los fármacos , Complicaciones Posoperatorias/metabolismo , Complicaciones Posoperatorias/fisiopatología , Ratas , Ratas Sprague-Dawley , Receptores Nicotínicos/metabolismo , Técnicas de Cultivo de Tejidos , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
This study was performed to determine whether spinal cholinergic systems mediate the relieving effects of electroacupuncture (EA) on cold and warm allodynia in a rat model of neuropathic pain. For neuropathic surgery, the right superior caudal trunk was resected at the level between the S1 and S2 spinal nerves innervating the tail. Two weeks after the injury, the intrathecal (i.t.) catheter was implanted. Five days after the catheterization, the rats were injected with atropine (non-selective muscarinic antagonist, 30 microg), mecamylamine (non-selective nicotinic antagonist, 50 microg), pirenzepine (M(1) muscarinic antagonist, 10 microg), methoctramine (M(2) antagonist, 10 microg) or 4-diphenylacetoxy-N-methylpiperidine methiodide (4-DAMP) (M(3) antagonist, 10 microg). Ten minutes after the injection, EA was applied to the ST36 acupoint for 30 min. The cold and warm allodynia were assessed by the tail immersion test [i.e., immersing the tail in cold (4 degrees C) or warm (40 degrees C) water and measuring the latency of an abrupt tail movement] before and after the treatments. The i.t. atropine, but not mecamylamine, blocked the relieving effects of EA on cold and warm allodynia. Furthermore, i.t. pirenzepine attenuated the antiallodynic effects of EA, whereas methoctramine and 4-DAMP did not. These results suggest that spinal muscarinic receptors, especially M(1) subtype, mediate the EA-induced antiallodynia in neuropathic rats.
Asunto(s)
Fibras Colinérgicas/fisiología , Electroacupuntura , Neuralgia/fisiopatología , Neuralgia/terapia , Nervios Espinales/fisiopatología , Animales , Atropina/farmacología , Colinérgicos/farmacología , Fibras Colinérgicas/efectos de los fármacos , Frío , Diaminas/farmacología , Modelos Animales de Enfermedad , Calor , Hiperestesia/fisiopatología , Hiperestesia/terapia , Masculino , Mecamilamina/farmacología , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Piperidinas/farmacología , Pirenzepina/farmacología , Ratas , Ratas Sprague-Dawley , Receptor Muscarínico M1/efectos de los fármacos , Receptor Muscarínico M1/fisiología , Nervios Espinales/efectos de los fármacosRESUMEN
BACKGROUND: Alzheimer's disease (AD), the most common form of degenerative dementia, represents a tremendous unmet medical need. Although AD had already been described about 100 years ago and despite enormous research efforts, at present only few symptomatic treatment options exist for the more than 25 million patients worldwide. This situation might change as many targets for therapeutic intervention have been identified based on the in-depth study of the pathology of the disease in model systems and humans, and of its underlying genetics. OBJECTIVE/METHODS: These targets are highlighted in the context of contemporary drug discovery for the identification of new therapies. RESULTS/CONCLUSIONS: 'Translation' of recent discoveries into disease-modifying therapies has not yet been accomplished. The future will show whether the current drug discovery and development 'pipelines' of pharmaceutical companies yield efficacious new medicines for AD.
Asunto(s)
Enfermedad de Alzheimer/tratamiento farmacológico , Sistemas de Liberación de Medicamentos , Nootrópicos/uso terapéutico , Anciano , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Péptidos beta-Amiloides/efectos de los fármacos , Péptidos beta-Amiloides/inmunología , Animales , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Fibras Colinérgicas/efectos de los fármacos , Ensayos Clínicos como Asunto , Descubrimiento de Drogas , Evaluación Preclínica de Medicamentos , Humanos , Inmunización Pasiva , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Mutación , Proteínas del Tejido Nervioso/agonistas , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Proteínas del Tejido Nervioso/genética , Ovillos Neurofibrilares/efectos de los fármacos , Nootrópicos/farmacología , Placa Amiloide/efectos de los fármacos , VacunaciónRESUMEN
In this study, we have assessed the impact of vitamin E and exercise on acquisition and retention of spatial memory for a given task in aging rats, using a T-maze. Acetylcholine esterase (AChE) and cholineacetyl transferase (ChAT) activities and acetylcholine (ACh) were measured in the cerebral cortex (CC) of male Wistar rats of 4- (adult), 12- (middle-aged) and 18-months (old) of age. Animals were categorized into sedentary [(SEC (N)], sedentary supplemented [SEC (+E)], swim trained [SWT (N)] and swim trained supplemented [SWT (+E)]. In the old, ChAT activity increased in the SEC (+E). AChE activity was highest in the adults, irrespective of training or supplementation. By contrast, ACh concentration remained unaltered with age, exercise and supplementation. Middle-aged and old rats were benefited in terms of a better acquisition and retention in the case of those that were trained and supplemented with Vitamin E. Adults showed better retention in all the groups after 7 and 15 days, while in the middle-aged, training was beneficial after 15 days. We observed decreased AChE activity when old rats were trained with the supplement. Our results also suggest that this regimen may be analogous to the AChE inhibitors that are widely advocated to derive positive benefits in up-regulating the possible reduction in ACh and in turn age-associated memory deficits.
Asunto(s)
Acetilcolina/metabolismo , Envejecimiento/metabolismo , Antioxidantes/farmacología , Corteza Cerebral/efectos de los fármacos , Fibras Colinérgicas/efectos de los fármacos , Nootrópicos/farmacología , Esfuerzo Físico , Vitamina E/farmacología , Acetilcolinesterasa/metabolismo , Factores de Edad , Animales , Corteza Cerebral/metabolismo , Colina O-Acetiltransferasa/metabolismo , Fibras Colinérgicas/metabolismo , Aprendizaje/efectos de los fármacos , Masculino , Recuerdo Mental/efectos de los fármacos , Nootrópicos/sangre , Ratas , Ratas Wistar , Natación , Vitamina E/sangreRESUMEN
This study tested the hypothesis that septal cholinergic lesions impair acquisition of a delayed matching to position (DMP) T-maze task in male rats by affecting learning strategy. Rats received either the selective cholinergic immunotoxin, 192 IgG-saporin (SAP) or artificial cerebrospinal fluid directly into the medial septum. Two weeks later, animals were trained to acquire the DMP task. SAP-treated rats took significantly longer to acquire the task than corresponding controls. Both SAP-treated and control rats adopted a persistent turn and utilized a response strategy during early periods of training. By the time rats reached criterion the persistent turn was no longer evident, and all rats had shifted to an allocentric strategy, i.e., were relying on extramaze cues to a significant degree. During the acquisition period, SAP-treated rats spent significantly more days showing a persistent turn and using a response strategy than corresponding controls. The added time spent using a response strategy accounted entirely for the added days required to reach criterion among the SAP-treated rats. This suggests that the principal mechanism by which septal cholinergic lesions impair DMP acquisition in male rats is by increasing the predisposition to use a response vs. a place strategy, thereby affecting the ability to switch from one strategy to another.
Asunto(s)
Fibras Colinérgicas/fisiología , Trastornos del Conocimiento/fisiopatología , Aprendizaje por Laberinto/fisiología , Análisis de Varianza , Animales , Anticuerpos Monoclonales/toxicidad , Aprendizaje por Asociación/efectos de los fármacos , Aprendizaje por Asociación/fisiología , Conducta Animal/efectos de los fármacos , Conducta Animal/fisiología , Colina O-Acetiltransferasa/metabolismo , Fibras Colinérgicas/efectos de los fármacos , Trastornos del Conocimiento/inducido químicamente , Señales (Psicología) , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Inmunotoxinas/toxicidad , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Memoria a Corto Plazo/efectos de los fármacos , Memoria a Corto Plazo/fisiología , Neuronas/citología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Ratas , Ratas Sprague-Dawley , Proteínas Inactivadoras de Ribosomas Tipo 1/toxicidad , Saporinas , Tabique del Cerebro/citología , Tabique del Cerebro/efectos de los fármacos , Tabique del Cerebro/fisiología , Percepción Espacial/efectos de los fármacos , Percepción Espacial/fisiología , Conducta Espacial/efectos de los fármacos , Conducta Espacial/fisiología , Factores de TiempoRESUMEN
The effect of Daikenchuto, a traditional herbal medicine, on gastrointestinal hypoperistalsis in postoperative ileus (POI) was investigated. POI was induced by laparotomy with manipulation of the gastrointestine under anesthesia, and gastrointestinal transit was calculated by migration of Evans blue. Daikenchuto (270 - 2,700 mg/kg, p.o.) dose-dependently improved the delayed gastrointestinal transit in POI. This effect of Daikenchuto was partially inhibited by SB204070 (1 mg/kg, s.c.), a 5-hydroxytriptamine(4) (5-HT(4))-receptor antagonist and completely abolished by atropine (1 mg/kg, s.c.), a muscarine-receptor antagonist. Among the constituents of Daikenchuto, the medical herb zanthoxylum fruit (60 mg/kg, p.o.) and maltose syrup (2,400 mg/kg, p.o.) significantly ameliorated the delayed gastrointestinal transit, but ginseng and processed ginger did not affect the gastrointestinal transit in the rat POI. The improvement induced by zanthoxylum fruit was also inhibited by atropine or SB204070. In addition, the high osmotic pressure of the maltose syrup (2400 mg/10 mL per kg) was related to the improvement of delayed gastrointestinal transit. These results demonstrated that Daikenchuto ameliorates postoperative hypoperistalsis via cholinergic nerves and 5-HT(4) receptors and that osmotic pressure also may be involved in this action. Moreover, zanthoxylum fruit and maltose syrup were crucial medical herbs contributing to the ability of Daikenchuto.
Asunto(s)
Tránsito Gastrointestinal/efectos de los fármacos , Ileus/tratamiento farmacológico , Extractos Vegetales/farmacología , Complicaciones Posoperatorias/tratamiento farmacológico , Animales , Fibras Colinérgicas/efectos de los fármacos , Fibras Colinérgicas/metabolismo , Relación Dosis-Respuesta a Droga , Azul de Evans , Zingiber officinale/química , Laparotomía/efectos adversos , Masculino , Maltosa/química , Maltosa/farmacología , Medicina Tradicional de Asia Oriental , Presión Osmótica , Panax/química , Peristaltismo/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/química , Ratas , Ratas Sprague-Dawley , Receptores de Serotonina 5-HT4/efectos de los fármacos , Receptores de Serotonina 5-HT4/metabolismo , Zanthoxylum/química , ZingiberaceaeRESUMEN
We previously demonstrated that the Kampo formula chotosan (CTS) ameliorated spatial cognitive impairment via central cholinergic systems in a chronic cerebral hypoperfusion (P2VO) mouse model. In this study, the object discrimination tasks were used to determine if the ameliorative effects of CTS on P2VO-induced cognitive deficits are a characteristic pharmacological profile of this formula, with the aim of clarifying the mechanisms by which CTS enhances central cholinergic function in P2VO mice. The cholinesterase inhibitor tacrine (THA) and Kampo formula saikokeishito (SKT) were used as controls. P2VO impaired object discrimination performance in the object recognition, location, and context tests. Daily administration of CTS (750 mg/kg, p.o.) and THA (2.5 mg/kg, i.p.) improved the object discrimination deficits, whereas SKT (750 mg/kg, p.o.) did not. In ex vivo assays, tacrine but not CTS or SKT inhibited cortical cholinesterase activity. P2VO reduced the mRNA expression of m(3) and m(5) muscarinic receptors and choline acetyltransferase but not that of other muscarinic receptor subtypes in the cerebral cortex. Daily administration of CTS and THA but not SKT reversed these expression changes. These results suggest that CTS and THA improve P2VO-induced cognitive impairment by normalizing the deficit of central cholinergic systems and that the beneficial effect on P2VO-induced cognitive deficits is a distinctive pharmacological characteristic of CTS.
Asunto(s)
Fibras Colinérgicas/efectos de los fármacos , Trastornos del Conocimiento/prevención & control , Medicamentos Herbarios Chinos/farmacología , Reconocimiento en Psicología/efectos de los fármacos , Acetilcolinesterasa/genética , Actinas/genética , Animales , Antiinflamatorios no Esteroideos/farmacología , Antiinflamatorios no Esteroideos/uso terapéutico , Isquemia Encefálica/complicaciones , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Circulación Cerebrovascular/efectos de los fármacos , Colina O-Acetiltransferasa/genética , Fibras Colinérgicas/patología , Inhibidores de la Colinesterasa/farmacología , Enfermedad Crónica , Trastornos del Conocimiento/etiología , Discriminación en Psicología/efectos de los fármacos , Conducta Exploratoria/efectos de los fármacos , Masculino , Medicina Kampo , Ratones , Ratones Endogámicos ICR , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores Muscarínicos/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Tacrina/farmacologíaRESUMEN
AIM: To explore the mechanism of the exciting effects of electro-acupuncture (EA) at Sibai on the gastric myoelectric activities. METHODS: A total of 32 rats were randomly divided into four groups. Through intraperitoneal injection with atropine (the anti-cholinergic agent by blockade of muscarinic receptors), hexamethonium (automatic nerve ganglion-blocking agent) and reserpine (anti-adrenergic agent by depleting the adrenergic nerve terminal of its norepinephrine store), effects of EA at Sibai on the gastric myoelectric activities of the denervated rats were observed. RESULTS: After intraperitoneal injection of atropine and hexamethonium, the average amplitude and ratio of period to time in the phase of high activity of gastric myoelectric slow wave, and the average numbers of the peaks of gastric myoelectric fast wave were significantly decreased (P<0.01, P<0.05, P<0.01), while after intraperitoneal injection of reserpine, the aforementioned three parameters were increased (P<0.01, P<0.05, P<0.01). EA at Sibai point partially relieved the inhibitory effect of atropine and hexamethonium on the gastric myoelectric activities in the rats (P<0.05 or P>0.05). CONCLUSION: Cholinergic and adrenergic nervous systems and autonomic nerve ganglion participate in the peripheral passage of the controlling effects of EA at Foot Yangming Channel on gastrointestinal tract.