ABSTRACT
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'.
Subject(s)
Antidepressive Agents/therapeutic use , Depression/drug therapy , Peptides/therapeutic use , Potassium Channels, Tandem Pore Domain/metabolism , Animals , Biophysical Phenomena/drug effects , Biophysical Phenomena/genetics , Blood Glucose/drug effects , Brain Infarction , CD8 Antigens/genetics , Cell Line, Transformed , Chlorocebus aethiops , Convulsants/toxicity , Disease Models, Animal , Dose-Response Relationship, Drug , Drinking/drug effects , Eating/drug effects , Electric Stimulation , Green Fluorescent Proteins/genetics , Hindlimb Suspension , Humans , Infarction, Middle Cerebral Artery/complications , Kainic Acid/toxicity , Membrane Potentials/drug effects , Mice , Mice, Inbred C57BL , Pain/genetics , Pain/physiopathology , Pain Measurement , Patch-Clamp Techniques , Pentylenetetrazole/toxicity , Potassium Channels/genetics , Potassium Channels/metabolism , Potassium Channels, Tandem Pore Domain/genetics , Seizures/chemically induced , Seizures/drug therapy , Swimming/psychology , TransfectionABSTRACT
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.
