Stroke is the third most common cause of death in the developed world and is also the leading cause of serious long-term adult disability; many survivors never recover sufficient function to live independently. Although rapid intervention to restore blood flow to the affected area can improve outcomes, the brain has limited capacity for repair and there is currently no treatment that helps recovery. The zone immediately surrounding the damaged area is critically important for recovery since motor and sensory neurons in this region can make new connections and compensate for those killed by the stroke.
Immediately after a stroke, tonic inhibition in the affected area increases to reduce excitability and limit the extent of the damage, but this increased tonic inhibition also has the effect of reducing plasticity in surrounding areas. Researchers at UCLA and the University of Otago have now shown that the increased tonic inhibition can persist for weeks and eventually hinder recovery. In experimentally induced stroke in mice, tonic neural inhibition was found to be increased in the area surrounding the stroke damage and shown to be mediated by extrasynaptic GABAA receptors. After a stroke in the motor cortex, six weeks treatment with L-655,708, a subtype-selective inverse agonist of the α5-subunit-containing extrasynaptic GABAA receptor, restored tonic inhibition to pre-stroke levels and led to a sustained improvement of motor function. In keeping with a protective role of tonic inhibition immediately after a stroke, the treatment was only effective if delayed until three days after the stroke; initiating treatment too early increased the damage caused by the stroke.
The results suggest that reduction of tonic inhibition by reducing extrasynaptic GABAA receptor function could be beneficial in promoting recovery after stroke and possibly other brain traumas. A treatment that is effective following delayed administration would offer a significant advantage over existing interventions which must be carried out within a few hours of the stroke occurring.
Stroke continues to be a major health issue and is a significant cause of death and disability. The recent introduction of clot-dissolving therapies has had a significant impact on survival, although the narrow window of opportunity for successful treatment remains a challenge. For those surviving stroke, the period immediately following is critical for recovery of physical and cognitive abilities. There has therefore been much interest in treatments that will aid the spontaneous recovery of function observed in the first few months following a stroke.
Researchers at Carver College of Medicine and College of Public Health (Ms Acion), University of Iowa, Iowa City, have now reported results from a clinical trial with escitalopram, a selective serotonin-reuptake inhibitor (SSRI) antidepressant. The team hypothesised that treatment with antidepressants may be beneficial because of their ability to stimulate production of compounds essential for nerve growth.
In the randomised trial, 43 patients were assigned to take 5 to 10 milligrams of escitalopram daily, 45 to take placebo daily and 41 to participate in a problem-solving therapy program developed for patients with depression. After 12 weeks of treatment, patients taking escitalopram had higher scores on neuropsychological tests assessing overall cognitive function, specifically on those measuring verbal and visual memory. The beneficial effect of escitalopram on cognitive recovery was independent of its effect on depressive symptoms and was not influenced by stroke type or mechanism of ischemic stroke. In addition, escitalopram was well tolerated and the frequency of adverse effects similar to those of patients receiving placebo.
The authors of the study, published in the February issue of Archives of General Psychiatry, suggest that the utility of antidepressant therapy in post-stroke recovery warrants further investigation.
Ischaemic stroke is a leading cause of adult disability and death. Glutamate plays an essential role in neural development, excitatory synaptic transmission, and plasticity but, during a stroke, glutamate accumulates at synapses, resulting in neuronal death. Excessive influx of Ca2+ ions through N-methyl-D-aspartate (NMDA) glutamate receptors is a major contributor to cell death and brain damage following ischaemic stroke.
So far, directly targeting glutamate receptors has not proved to be an effective way of treating stroke but scientists at the University of Central Florida and Louisiana State University have discovered that uncoupling a kinase from the NR2B subunit of the NMDA receptor blocks damaging Ca2+ influx through the receptor channels and protects neurons against the harmful effects of ischemia. Death-associated protein kinase 1 (DAPK1) is recruited into the NMDA receptor NR2B protein complex during ischaemia and phosphorylates NR2B at Ser-1303, enhancing the NR1/NR2B channel conductance. Genetic deletion of DAPK1 or administration of the peptide, NR2BCT – which blocks the interaction of DAPK1 with the NR2B subunit – protected mice from the damaging effects of cerebral ischaemia. NR2BCT did not affect the catalytic activity of DAPK-1 or the normal physiological functioning of NMDA receptors and the authors hope that, as well as providing new insights into the mechanisms of stroke damage, their discovery will provide a new target for the treatment of stroke which could show advantage over NMDA antagonists.
The study is published in the January 22nd issue of Cell.
Stroke and brain trauma are leading causes of death and disability worldwide. The most common type of stroke, ischaemic stroke, is caused by blood clots which cut off the supply of blood to the brain. Although people who have had an ischaemic stroke can be treated with ‘clot-busting’ medicines, the window of opportunity for effective thrombolysis is only about 3 hours from the onset of stroke. Following a stroke, levels of glutamate increase rapidly, leading to over-activation of N-methyl-D-aspartic acid receptors (NMDARs) and neuronal excitotoxicity. Although this pathway is believed to be a major contributor to neuronal injury after stroke and brain trauma, NMDAR antagonists have not proved effective in reducing brain injury after stroke. Some of the limitations of NMDAR antagonists, including interference with the normal physiological function of NMDARs and a narrow therapeutic window, might be overcome by targeting downstream signalling pathways and scientists at the Brain Research Centre, University of British Columbia and the China Medical University Hospital, Taiwan have identified one such pathway.
Over-activation of NR2B subunit–containing NMDARs was found to activate SREBP-1, a transcription factor that regulates genes involved in lipid biosynthesis. Activation of SREBP-1 requires cleavage of an inactive membrane-bound precursor protein by two dedicated proteases in the Golgi apparatus, releasing an N-terminal fragment which translocates to the nucleus. Under basal, unstimulated conditions, immature SREBPs form a stable complex with SREBP cleavage–activating protein (SCAP) and are retained in the endoplasmic reticulum (ER) by the interaction between SCAP and the ER membrane–resident protein, Insig-1. Treatment of neuronal cultures with Insig-1–specific siRNA resulted in a 40% reduction in Insig-1 and a corresponding increase in active SREBP-1. Challenging these neurons with excitotoxic NMDA stimuli resulted in increased cell death compared to controls, supporting a crucial role for the degradation of Insig-1 in mediating NMDAR-dependent SREBP-1 activation and excitotoxicity, and also suggesting that inhibition of Insig-1 degradation may be neuroprotective. Insig-1 is degraded by the proteasome after ubiquitination, and an Insig-1–derived interference peptide (Indip) that competes for ubiquitination was found to block NMDA-induced degradation of Insig-1 and reduce cell death.
In animal studies, prophylactic Indip treatment 45 minutes before 90-min transient middle cerebral artery occlusion (MCAo) reduced the size of the infarct compared to saline-injected animals and also markedly improved the combined behavioral outcome 24 h post-ischemia. In an experiment more closely resembling clinical intervention, Indip administered 2 h after 90-min transient MCAo also produced significantly reduced brain infarct volume 7 days later. Although the details of exactly how SREBP-1 activation leads to neuronal damage have not been fully established, the study suggests that agents that reduce activation may be neuroprotective after stroke. Since excitotoxicity is also believed to be associated with chronic neurodegenerative disorders such as Huntington’s disease and Parkinson’s disease, reducing SREBP-1 activation may also be of benefit in these conditions.