RESUMEN
MLC901 (NurAiDII) is used as a treatment for stroke patients. It has been shown that MLC901 improves motor and cognitive recovery in ischemic and traumatic brain-injured rodents. The present study seeks to delineate cognitive effects induced by MLC901 in normal, noninjured mice. To this end, the behaviors of vehicle- and MLC901-treated C57BL/6 mice in hippocampus-dependent (passive avoidance, Morris water maze) and hippocampus-independent (novel object recognition) cognitive tasks are compared. The potential influence of the compound on the anxiety level and nycthemeral rhythm of mice is also assessed. In addition, the long-term effects of MLC901 on hippocampal neurogenesis are measured. The results clearly demonstrate that MLC901 promotes extinction in passive avoidance and reversal learning in the Morris water maze and improves the performance of mice in novel object recognition. In parallel, this study shows the long-term proneurogenesis effects of MLC901 that result in the increase in the number of mature neurons in the hippocampus. If these observations can be extended to humans, then MLC901 could represent a promising therapeutic strategy.
Asunto(s)
Cognición/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Hipocampo/efectos de los fármacos , Medicina Tradicional China/métodos , Neurogénesis/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Inmunohistoquímica , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND AND PURPOSE: We have described a novel antidepressant peptide, spadin, that acts by blocking the TWIK-related-potassium channel, type 1 (TREK-1). Here, we examined possible mechanisms of action of spadin at both molecular and cellular levels. EXPERIMENTAL APPROACHES: Effects of spadin were measured in primary cultures of neurons or tissues from mice injected i.v. with spadin. Western blots, qPCR, histochemical and electrophysiological techniques were used. KEY RESULTS: In vitro, spadin increased neuronal membrane potential and activated both the MAPK and PI3K signalling pathways, in a time- and concentration-dependent manner. The latter pathway was involved in the protective effect of spadin against staurosporine-induced apoptosis. Also, spadin enhanced both mRNA expression and protein of two markers of synaptogenesis, the post-synaptic density protein of 95 kDalton (PSD-95) and synapsin. We confirmed these effects on synaptogenesis by the observation that spadin treatment significantly increased the proportion of mature spines in cortical neurons. Finally, in vivo injections of spadin led to a rapid increase in both mRNA expression and protein level of brain-derived neurotrophic factor (BDNF) in the hippocampus, confirming the antidepressant action of the peptide. We argue for a new role of spadin in synaptogenesis as both PSD-95 and synapsin mRNA expression and protein levels were further enhanced in the hippocampus, following treatment in vivo with the peptide. CONCLUSIONS AND IMPLICATIONS: These findings provide new mechanisms of action for the rapidly acting antidepressant peptide spadin by stimulating expression of BDNF and synaptic proteins, both in vitro and in vivo.
Asunto(s)
Antidepresivos/farmacología , Neuronas/efectos de los fármacos , Péptidos/farmacología , Sinapsis/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Homólogo 4 de la Proteína Discs Large , Relación Dosis-Respuesta a Droga , Guanilato-Quinasas/metabolismo , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Masculino , Potenciales de la Membrana/efectos de los fármacos , Proteínas de la Membrana/metabolismo , Ratones , Neuronas/citología , Neuronas/fisiología , Cultivo Primario de Células , Transducción de Señal/efectos de los fármacos , Estaurosporina/toxicidad , Sinapsinas/metabolismoRESUMEN
Depression is a disease that is particularly frequent, affecting up to 20% of the population in Western countries. The origins of this pathology involve multiple genes as well as environmental and developmental factors leading to a disorder that remains difficult to treat. Several therapies for depression have been developed and these mainly target monoamine neurotransmitters. However, these treatments are not only associated with numerous adverse effects, but they are also ineffective for more than one-third of patients. Therefore, the need to develop new concepts to treat depression is crucial. Recently, studies using knockout mouse models have provided evidence for a crucial role of two members of the two-pore domain potassium channel (K2P ) family, tandem P-domain weak inward rectifying K(+) (TWIK)-related K(+) channel 1 (TREK-1) and TWIK-related acid-sensitive K(+) channel 3 (TASK-3) in the pathophysiology of depression. It is believed that TREK-1 and TASK-3 antagonists could lead to the development of new antidepressants. Herein, we describe the discovery of spadin, a natural peptide released from the maturation of the neurotensin receptor-3 (also known as sortilin), which specifically blocks the activity of the TREK-1 channel and displays particular antidepressant properties, with a rapid onset of action and the absence of adverse effects. The development of such molecules may open a new era in the field of psychiatry.
Asunto(s)
Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Péptidos/farmacología , Bloqueadores de los Canales de Potasio/farmacología , Canales de Potasio de Dominio Poro en Tándem/antagonistas & inhibidores , Animales , Antidepresivos/uso terapéutico , Depresión/fisiopatología , Humanos , Péptidos/efectos adversos , Péptidos/uso terapéutico , Bloqueadores de los Canales de Potasio/efectos adversos , Bloqueadores de los Canales de Potasio/uso terapéutico , Canales de Potasio de Dominio Poro en Tándem/metabolismoRESUMEN
BACKGROUND: Treatments for stroke and other brain injuries are limited. NeuroAiD has been shown to be beneficial in clinical studies. We reviewed the pharmacological effects of NeuroAiD on the normal and ischemic brain and neurons. METHODS: In vivo and in vitro experiments using mouse model of stroke (focal ischemia), rat model of cardiac arrest (global ischemia) and cortical neurons in culture were reviewed and summarized. RESULTS: NeuroAiD improved survival, attenuated infarct size, improved functional recovery in the model of focal ischemia, and protected neurons against glutamate-induced injury. Furthermore, it enhanced cognitive recovery by reducing hippocampal CA1 cell degeneration, DNA fragmentation, Bax expression and ma-londialdehyde release in the model of global ischemia. Activation of the Akt survival pathway and opening of KATP channels may contribute to the neuroprotective properties of NeuroAiD. NeuroAiD increased BDNF expression and induced proliferation of cells which differentiate and mature into neurons. It enhanced rosette formation of human embryonic stem cells. NeuroAiD-treated embryonic cortical neurons developed into neurons with longer neurites, denser outgrowths and networks, and more synaptic release sites. CONCLUSIONS: NeuroAiD demonstrated both neuroprotective and neuroregenerative properties in rodent models of focal and global ischemia and in cortical cell cultures. These properties would be important for developing a treatment strategy in reducing the long-term disability of stroke, cardiac arrest and other brain injuries.
Asunto(s)
Lesiones Encefálicas/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Regeneración Nerviosa/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Accidente Cerebrovascular/tratamiento farmacológico , Animales , Encéfalo/patología , Química Encefálica/efectos de los fármacos , Isquemia Encefálica/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Humanos , Ratones , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , RatasRESUMEN
Despite several decades of research, current antidepressant (AD) treatments remain of a limited efficacy justifying the need to find new drugs. These drugs have to be more efficacious, more rapid and display lesser side effects. Using rodent models, we recently identified spadin as a new antidepressant molecule that acts more quickly than classical ADs, working within 4 days to get same effects obtained with other ADs after 21 days. Spadin blocks TREK-1 K(2P) potassium channels that are considered as new targets for ADs. Deletion of the TREK-1 channel is known to increase sensitivity to pain, seizures and ischemia. Thus blocking these channels could result in deleterious side effects. In this study we showed that spadin did not interfere with other TREK-1 controlled functions such as pain, epilepsy and ischemia. We also demonstrated that spadin was unable to inhibit currents generated by TREK-2, TRAAK, TASK and TRESK four other K2P channels. More importantly, spadin did not induce cardiac dysfunctions, did not block I(Kr) and I(Ks) and did not modify the systolic pressure or cardiac pulses. After a three week treatment spadin remained an efficacious AD and did not modify the infarct size in brain following focal ischemia. Finally, we showed that kainate induced seizures and glycemia were not modified by spadin treatments. These data, together with those previously published reinforce the idea that spadin represents a good candidate for a new generation of ADs. This article is part of a Special Issue entitled 'Anxiety and Depression'.
Asunto(s)
Antidepresivos/uso terapéutico , Depresión/tratamiento farmacológico , Péptidos/uso terapéutico , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Animales , Fenómenos Biofísicos/efectos de los fármacos , Fenómenos Biofísicos/genética , Glucemia/efectos de los fármacos , Infarto Encefálico , Antígenos CD8/genética , Línea Celular Transformada , Chlorocebus aethiops , Convulsivantes/toxicidad , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ingestión de Líquidos/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Estimulación Eléctrica , Proteínas Fluorescentes Verdes/genética , Suspensión Trasera , Humanos , Infarto de la Arteria Cerebral Media/complicaciones , Ácido Kaínico/toxicidad , Potenciales de la Membrana/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Dolor/genética , Dolor/fisiopatología , Dimensión del Dolor , Técnicas de Placa-Clamp , Pentilenotetrazol/toxicidad , Canales de Potasio/genética , Canales de Potasio/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Natación/psicología , TransfecciónRESUMEN
Global ischemia leads to damage in the hippocampal CA1 region and is associated with behavioral deficits. NeuroAid (MLC601 and MLC901), a Traditional Chinese Medicine is used in China for patients after stroke. We have investigated here the effects of MLC901 on brain injury and deficits after global ischemia in the rat. Global ischemia induced by four-vessel occlusion resulted in degeneration of CA1 neurons. MLC901 (0.074 mg/ml) prevented both necrosis and apoptosis of neurons up to 3 h after ischemia. These positive MLC901 effects were associated with a decrease in Bax expression and in levels of the lipid peroxidation product malondialdehyde. Using the PI3-kinase inhibitor LY294002 we also demonstrated the critical role of the Akt pathway in MLC901-mediated neuroprotection. MLC901 enhanced neurogenesis. Furthermore, MLC901 improved functional recovery of rats after global ischemia as assessed by the Morris water maze. In this test MLC901 reduced the increase in escape latency and in swim distance induced by ischemia. MLC901 also improved post-ischemic grip strength. If observations made with rats can be extended to humans, then MLC901 will represent a novel therapeutic strategy after cardiac arrest with a clinically interesting time window of protection.