RESUMEN
Introduction: Cognitive impairment associated with old age or various brain disorders may be very disabling for affected individuals, placing their carers and public health services under considerable stress. The standard-of-care drugs produce only transient improvement of cognitive impairment in older people, so the search for novel, safe and effective therapeutics that would help to reverse or delay cognitive impairment is warranted. Repurposing pharmacological therapies with well-established safety record for additional indications is a promising recent trend in drug development. Vertigoheel (VH-04), a multicomponent drug made of Ambra grisea, Anamirta cocculus L., Conium maculatum, and Petroleum rectificatum, has been successfully used for several decades in the treatment of vertigo. Here, we investigated effects of VH-04 on cognitive performance in standard behavioral tests assessing different types of memory and explored cellular and molecular underpinnings of VH-04's biological activity. Methods: In the majority of behavioral experiments, namely in the spontaneous and rewarded alternation tests, passive avoidance test, contextual/cued fear conditioning, and social transmission of food preference, we examined the ability of single and repeated intraperitoneal administrations of VH-04 to improve cognitive parameters of mice and rats disrupted by the application of the muscarinic antagonist scopolamine. In addition, we also assessed how VH-04 affected novel object recognition and influenced performance of aged animals in Morris water maze. Furthermore, we also studied the effects of VH-04 on primary hippocampal neurons in vitro and mRNA expression of synaptophysin in the hippocampus. Results: Administration of VH-04 positively influenced visual recognition memory in the novel object recognition test and alleviated the impairments in spatial working memory and olfactory memory caused by the muscarinic antagonist scopolamine in the spontaneous alternation and social transmission of food preference tests. In addition, VH-04 improved retention of the spatial orientation memory of old rats in the Morris water maze. In contrast, VH-04 did not have significant effects on scopolamine-induced impairments in tests of fear-aggravated memory or rewarded alternation. Experiments in vitro showed that VH-04 stimulated neurite growth and possibly reversed the age-dependent decrease in hippocampal synaptophysin mRNA expression, which implies that VH-04 may preserve synaptic integrity in the aging brain. Discussion: Our findings allow a cautious conclusion that in addition to its ability to alleviate manifestations of vertigo, VH-04 may be also used as a cognitive enhancer.
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The purpose of this study was to evaluate the efficacy of the radical scavenger IAC (bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl) decantionate) in alleviating behavioral deficits and reducing amyloid-ß (Aß) accumulation in an Alzheimer's disease (AD) transgenic Tg2576 mouse model. Daily treatment with IAC (3-30 mg/kg, i.p.) was started at the age of 6 months and continued until the mice were 13 months old. At the age of 9 months and again at 12 months, the mice were tested in open field and water maze tests. At the age of 13 months, the mice were sacrificed and the brains processed for immunohistochemistry. Mortality was significantly reduced in all IAC-treated groups. In addition, IAC treatment improved the water maze hidden platform training performance but had no effect on motor activity in the open field or water maze swim speed in transgenic mice. Lastly, IAC treatment (10 mg/kg) significantly reduced the cortical Aß plaque burden. In vitro, IAC is able to increase the number of neurites and neurite branches in cultured cortical primary neurons. In conclusion, IAC slowed down the development of the AD-like phenotype in Tg2576 mice and accelerated neurite growth in cultured neurons.
Asunto(s)
Enfermedad de Alzheimer/patología , Precursor de Proteína beta-Amiloide/genética , Cognición/fisiología , Aprendizaje por Laberinto/fisiología , Piperidinas/uso terapéutico , Placa Amiloide/tratamiento farmacológico , Placa Amiloide/genética , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animales , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Células Cultivadas , Cognición/efectos de los fármacos , Cricetinae , Modelos Animales de Enfermedad , Depuradores de Radicales Libres/farmacología , Depuradores de Radicales Libres/uso terapéutico , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Piperidinas/farmacología , Placa Amiloide/patología , Ratas , Ratas WistarRESUMEN
Experimental evidence suggests that reactive free radicals are generated during brain ischemia. We investigated the effect of a novel brain penetrant, low molecular weight, non-peptidyl carbon, oxygen- and nitrogen-centered radical scavenger, IAC, on infarct volume and sensory-motor performance in a rat transient middle cerebral artery occlusion model (tMCAO). Rats received 90 min tMCAO and treated with i.p. or i.v. injections of vehicle or IAC following tMCAO. Sensory-motor performance was evaluated by neuroscore tests (NS). Cerebral infarct volume was evaluated at 72 h after tMCAO. Rats treated with IAC i.p. (1 or 6 h after the onset of tMCAO) or i.v. (1 h after the onset of tMCAO) showed significant improvement in NS during the 3 or 21 day follow-up period when compared to vehicle treated rats. Cerebral infarct volumes were significantly decreased compared to vehicle in rats receiving IAC i.p. 1 h or 6 h after occlusion, approximately 30.5% decrease compared to vehicle, or i.v. 1 h after the onset of tMCAO, 48.6% decrease compared to vehicle. These results demonstrate that IAC has neuroprotective properties with a wide therapeutic window following tMCAO in rats. IAC could therefore be a candidate for the treatment of stroke.
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Ésteres/uso terapéutico , Ataque Isquémico Transitorio/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Piperidinas/uso terapéutico , Análisis de Varianza , Animales , Conducta Animal , Infarto Cerebral/etiología , Infarto Cerebral/prevención & control , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ataque Isquémico Transitorio/complicaciones , Masculino , Desempeño Psicomotor/efectos de los fármacos , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
Diazepam binding inhibitor (DBI) and its processing products are endogenous modulators of GABAA and linked to various brain disorders ranging from anxiety and drug dependence to epilepsy. To investigate the physiological role of endogenously expressed DBI in the brain we created a transgenic mouse line overexpressing DBI gene. Transgenic mice had a 37x increased protein expression and immunohistochemistry showed excessive glial expression in the infragranular region of the dentate gyrus. Transgenic animals had significantly larger lateral ventricles and decreased plasticity of excitatory synapses without affecting either inhibitory or excitatory synaptic transmission. In behavioral tests transgenic animals had no differences in motor and exploratory activity, yet impaired hippocampus-dependent learning and memory. Overexpression did not cause anxiety or proconflict behavior, nor influenced kainic acid or pentylenetetrazole induced seizure activity. Our transgenic mouse line demonstrates that endogenously overexpressed DBI impairs hippocampus-dependent learning without anxiety or proconflict behavior.
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Inhibidor de la Unión a Diazepam/metabolismo , Hipocampo/fisiopatología , Hidrocefalia/etiología , Discapacidades para el Aprendizaje/genética , Potenciación a Largo Plazo/genética , Transmisión Sináptica/genética , Animales , Reacción de Prevención/fisiología , Conducta Animal , Femenino , Hidrocefalia/genética , Hidrocefalia/patología , Discapacidades para el Aprendizaje/patología , Imagen por Resonancia Magnética , Masculino , Ratones , Ratones Transgénicos , Fosfopiruvato Hidratasa/metabolismo , Tiempo de Reacción/genéticaRESUMEN
beta-Amyloid (Abeta) polypeptide plays a critical role in the pathogenesis of Alzheimer's disease (AD), which is characterized by progressive decline of cognitive functions, formation of Abeta deposits and neurofibrillary tangles, and loss of neurons. Increased genetic production or direct intracerebral administration of Abeta in animal models results in Abeta deposition, gliosis, and impaired cognitive functions. Whether aging renders the brain prone to Abeta and whether inflammation is required for Abeta-induced learning deficits is unclear. We show that intraventricular infusion of Abeta1-42 results in learning deficits in 9-month-old but not 2.5-month-old mice. Deficits that become detectable 12 weeks after the infusion are associated with a slight reduction in Cu,Zn superoxide dismutase activity but do not correlate with Abeta deposition and are not associated with gliosis. In rats, Abeta infusion induced learning deficits that were detectable 6 months after the infusion. Approximately 20% of the Abeta immunoreactivity in rats was associated with astrocytes. NMR spectrum analysis of the animals cerebrospinal fluid revealed a strong reduction trend in several metabolites in Abeta-infused rats, including lactate and myo-inositol, supporting the idea of dysfunctional astrocytes. Even a subtle increase in brain Abeta1-42 concentration may disrupt normal metabolism of astrocytes, resulting in altered neuronal functions and age-related development of learning deficits independent of Abeta deposition and inflammation.
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Envejecimiento/fisiología , Péptidos beta-Amiloides/administración & dosificación , Péptidos beta-Amiloides/farmacología , Discapacidades para el Aprendizaje/inducido químicamente , Aprendizaje por Laberinto/efectos de los fármacos , Fragmentos de Péptidos/administración & dosificación , Fragmentos de Péptidos/farmacología , Animales , Encéfalo/citología , Encéfalo/enzimología , Encéfalo/patología , Inflamación/metabolismo , Infusiones Intravenosas , Discapacidades para el Aprendizaje/metabolismo , Espectroscopía de Resonancia Magnética , Masculino , Ratones , Ratones Endogámicos C57BL , Ratas , Ratas Endogámicas SHRRESUMEN
Post-stroke seizures occur in 5-20% of patients. Modeling of stroke-induced seizures in animals provides a useful tool for investigating the molecular basis of epileptogenesis and for developing therapies for stroke patients at increased risk for epileptogenesis. The questions addressed in the study were: (1) Do rats develop spontaneous seizures after transient occlusion of the middle cerebral artery (MCAO)? (2) Is epileptogenesis associated with impaired hippocampus-dependent spatial learning and memory? (3) Are the functional abnormalities linked to axonal plasticity in the dentate gyrus? (4) Does the sensorimotor impairment induced by MCAO predict the risk of epileptogenesis? Adult male Sprague-Dawley rats were subjected to MCAO for 120 min. Development of spontaneous seizures was monitored by 1 week of continuous video-electroencephalographic (EEG) recordings at 3, 7, and 12 months after MCAO. Spontaneous seizures were not detected during 1-year follow-up in ischemic rats. Animals were, however, impaired in the spatial memory task (P<0.001), which was not associated with altered hippocampal LTP or abnormal mossy fiber sprouting (Timm staining). Animals also had a long-lasting sensorimotor deficit (P<0.05). The present study indicates that MCAO causes long-lasting sensorimotor and spatial memory impairment, but does not induce epileptogenesis or spontaneous seizures.
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Isquemia Encefálica/complicaciones , Epilepsia/etiología , Trastornos de la Memoria/etiología , Arteria Cerebral Media/fisiología , Trastornos del Movimiento/etiología , Trastornos Somatosensoriales/etiología , Animales , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Electrodos Implantados , Electroencefalografía , Hipocampo/patología , Hipocampo/fisiopatología , Discapacidades para el Aprendizaje/etiología , Discapacidades para el Aprendizaje/fisiopatología , Potenciación a Largo Plazo/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Trastornos de la Memoria/psicología , Fibras Musgosas del Hipocampo/patología , Trastornos del Movimiento/psicología , Plasticidad Neuronal/fisiología , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Trastornos Somatosensoriales/psicologíaRESUMEN
Estrogen is implicated in hippocampus-dependent spatial learning as well as structural organization and electrophysiological properties of the rat hippocampus but little is known about its mechanisms of action in mice. In this study, we investigated pharmacologically whether estrogen interacts with the hippocampal N-methyl-D-aspartate (NMDA) receptors in ovariectomized mice as postulated for rats. Female C57BL/6J mice were ovariectomized at 5 months, and 2 weeks before testing at 12 months, half of them received subcutaneous estrogen pellets containing 0.18 mg of 17 beta-estradiol. The competitive NMDA-antagonist, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), was administered at 5.0 and 10.0 microM to block induction of long-term potentiation (LTP) in the hippocampal slice and intraperitoneally at 0.5, 2.0, and 5.0 mg/kg to impair spatial learning in the water maze. Estrogen treatment shifted the dose-response curve to CPP in both experiments. First, 10 microM CPP blocked the initiation of LTP in all mice, but 5 microM only in ovariectomized non-estrogen-treated mice. Second, final level of acquisition and probe trial performance in the water maze were less affected by high doses of CPP in the estrogen-treated ovariectomized mice than in non-treated group. In control tests for motor side effects, estrogen treatment did not reduce the tendency of CPP to decrease locomotor activity in the open field and impair balance on a rotating rod, and estrogen by itself decreased swimming speed as did CPP, but these effects did not interact. Our findings support the notion that estrogen treatment increases the number of active NMDA-receptors in the mouse hippocampus.