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After traumatic brain injury (TBI), glial cells have both beneficial and deleterious roles in injury progression and recovery. However, few studies have examined the influence of reactive astrocytes in the tripartite synapse following TBI. Here, we have demonstrated that hippocampal synaptic damage caused by controlled cortical impact (CCI) injury in mice results in a switch from neuronal to astrocytic d-serine release. Under nonpathological conditions, d-serine functions as a neurotransmitter and coagonist for NMDA receptors and is involved in mediating synaptic plasticity. The phasic release of neuronal d-serine is important in maintaining synaptic function, and deficiencies lead to reductions in synaptic function and plasticity. Following CCI injury, hippocampal neurons downregulated d-serine levels, while astrocytes enhanced production and release of d-serine. We further determined that this switch in the cellular source of d-serine, together with the release of basal levels of glutamate, contributes to synaptic damage and dysfunction. Astrocyte-specific elimination of the astrocytic d-serine-synthesizing enzyme serine racemase after CCI injury improved synaptic plasticity, brain oscillations, and learning behavior. We conclude that the enhanced tonic release of d-serine from astrocytes after TBI underlies much of the synaptic damage associated with brain injury.

Despite ischemic stroke being the fifth leading cause of death in the USA, there are few therapeutic options available. We recently showed that the neuroprotective compound P7C3-A20 reduced brain atrophy, increased neurogenesis, and improved functional recovery when treatment was initiated immediately post-reperfusion after a 90-min middle cerebral artery occlusion (MCAO). In the present study, we investigated a more clinically relevant therapeutic window for P7C3-A20 treatment after ischemic stroke. MCAO rats were administered P7C3-A20 for 1 week, beginning immediately or at a delayed point, 6 h post-reperfusion. Delayed P7C3-A20 treatment significantly improved stroke-induced sensorimotor deficits in motor coordination and symmetry, as well as cognitive deficits in hippocampal-dependent spatial learning, memory retention, and working memory. In the cerebral cortex, delayed P7C3-A20 treatment significantly increased tissue sparing 7 weeks after stroke and reduced hemispheric infarct volumes 48 h after reperfusion. Despite no reduction in striatal infarct volumes acutely, there was a significant increase in spared tissue volume chronically. In the hippocampus, only immediately treated P7C3-A20 animals had a significant increase in tissue sparing compared to vehicle-treated stroke animals. This structural protection translated into minimal hippocampal-dependent behavioral improvements with delayed P7C3-A20 treatment. However, all rats treated with delayed P7C3-A20 demonstrated a significant improvement in both sensorimotor tasks compared to vehicle controls, suggesting a somatosensory-driven recovery. These results demonstrate that P7C3-A20 improves chronic functional and histopathological outcomes after ischemic stroke with an extended therapeutic window.

An online survey was conducted in the USA to obtain information about the knowledge and experiences of patients with painful diabetic peripheral neuropathy (pDPN). 506 adults with diabetes and pDPN affecting the feet for ≥6 months, for which pain medication had been prescribed for ≥6 months, completed an online survey questionnaire in March 2021. 79% of respondents had type 2 diabetes, 60% were male, 82% were Caucasian and 87% had comorbidities. Pain was significant to severe in 49% of respondents, and 66% had disability due to nerve pain. Anticonvulsants, over-the-counter pills and supplements were the most commonly used medications. Topical creams/patches were prescribed in 23% of respondents. 70% had tried multiple medications for their pain. 61% of respondents had to see ≥2 doctors before receiving a correct diagnosis of pDPN. 85% of respondents felt that the doctor understood their pain and its impact on their life. 70% had no difficulty finding the information they wanted. 34% felt insufficiently informed about their condition. A medical professional was the primary, and most trusted, source of information. Frustration, worry, anxiety and uncertainty were the most commonly reported emotions. Respondents were generally eager to find new medications for pain relief and desperate for a cure. Lifestyle changes because of nerve pain were most commonly associated with physical disabilities and sleep disturbance. Better treatments and freedom from pain were the overriding perspectives when considering the future. Patients with pDPN are generally well informed about their pain and trust their doctor but remain unsatisfied with their current treatment and struggle to find a lasting solution for their pain. Early identification and diagnosis of pain in diabetics, and education about treatments, is important to minimize the impact of pain on quality of life and emotional well-being.