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Abstract Cell specific-targeted therapy (CSTT) for acute ischemic stroke remains underdeveloped. Cerebrovascular endothelial cells (CECs) are key components of the blood–brain barrier and are the first brain cells affected by ischemic stroke. After stroke, CEC injury causes insufficient energy supply to neurons and leads to cytotoxic and vasogenic brain edema. Aptamers are short single-stranded RNA or DNA molecules that can bind to specific ligands for cell specific delivery. The expression of vascular cell adhesion molecule-1 (VCAM-1) is increased on CECs after stroke. Herein, we report that an RNA-based VCAM-1-aptamer can specifically target CECs in stroke brains following transient middle cerebral artery occlusion in mice. Our data demonstrate the potential of an RNA-based aptamer as an effective delivery platform to target CECs after stroke. We believe this method will allow for the development of CSTT for treatment of patients with stroke.
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Neuronal activity reorganization in motor cortex for successful locomotion after a lesion in the ventrolateral thalamus
This is the first study to analyze reorganization of the activity of single neurons and subpopulations of neurons related to the shoulder, elbow, or wrist, as well as fast- and slow-conducting pyramidal tract neurons, in the motor cortex of animals walking before and after inactivation or lesion in the thalamus. The results offer unique insights into the mechanisms of spontaneous recovery after thalamic stroke, potentially providing guidance for new strategies to alleviate locomotor deficits after stroke.
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- Award ID(s):
- 1912557
- PAR ID:
- 10482025
- Publisher / Repository:
- American Physiological Society
- Date Published:
- Journal Name:
- Journal of Neurophysiology
- Volume:
- 127
- Issue:
- 1
- ISSN:
- 0022-3077
- Page Range / eLocation ID:
- 56 to 85
- Subject(s) / Keyword(s):
- cat diaschisis inactivation limb control pyramidal tract neuron
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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BackgroundUpper limb proprioceptive impairments are common after stroke and affect daily function. Recent work has shown that stroke survivors have difficulty using visual information to improve proprioception. It is unclear how eye movements are impacted to guide action of the arm after stroke. Here, we aimed to understand how upper limb proprioceptive impairments impact eye movements in individuals with stroke. MethodsControl (N = 20) and stroke participants (N = 20) performed a proprioceptive matching task with upper limb and eye movements. A KINARM exoskeleton with eye tracking was used to assess limb and eye kinematics. The upper limb was passively moved by the robot and participants matched the location with either an arm or eye movement. Accuracy was measured as the difference between passive robot movement location and active limb matching (Hand-End Point Error) or active eye movement matching (Eye-End Point Error). ResultsWe found that individuals with stroke had significantly larger Hand (2.1×) and Eye-End Point (1.5×) Errors compared to controls. Further, we found that proprioceptive errors of the hand and eye were highly correlated in stroke participants ( r = .67, P = .001), a relationship not observed for controls. ConclusionsEye movement accuracy declined as a function of proprioceptive impairment of the more-affected limb, which was used as a proprioceptive reference. The inability to use proprioceptive information of the arm to coordinate eye movements suggests that disordered proprioception impacts integration of sensory information across different modalities. These results have important implications for how vision is used to actively guide limb movement during rehabilitation.more » « less
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The neurovascular unit (NVU) is composed of vascular cells, glia, and neurons that form the basic component of the blood brain barrier. This intricate structure rapidly adjusts cerebral blood flow to match the metabolic needs of brain activity. However, the NVU is exquisitely sensitive to damage and displays limited repair after a stroke. To effectively treat stroke, it is therefore considered crucial to both protect and repair the NVU. Mitochondrial calcium (Ca2+) uptake supports NVU function by buffering Ca2+and stimulating energy production. However, excessive mitochondrial Ca2+uptake causes toxic mitochondrial Ca2+overloading that triggers numerous cell death pathways which destroy the NVU. Mitochondrial damage is one of the earliest pathological events in stroke. Drugs that preserve mitochondrial integrity and function should therefore confer profound NVU protection by blocking the initiation of numerous injury events. We have shown that mitochondrial Ca2+uptake and efflux in the brain are mediated by the mitochondrial Ca2+uniporter complex (MCUcx) and sodium/Ca2+/lithium exchanger (NCLX), respectively. Moreover, our recent pharmacological studies have demonstrated that MCUcxinhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+overloading. These findings suggest that combining MCUcxinhibition with NCLX activation should markedly protect the NVU. In terms of promoting NVU repair, nuclear hormone receptor activation is a promising approach. Retinoid X receptor (RXR) and thyroid hormone receptor (TR) agonists activate complementary transcriptional programs that stimulate mitochondrial biogenesis, suppress inflammation, and enhance the production of new vascular cells, glia, and neurons. RXR and TR agonism should thus further improve the clinical benefits of MCUcxinhibition and NCLX activation by increasing NVU repair. However, drugs that either inhibit the MCUcx, or stimulate the NCLX, or activate the RXR or TR, suffer from adverse effects caused by undesired actions on healthy tissues. To overcome this problem, we describe the use of nanoparticle drug formulations that preferentially target metabolically compromised and damaged NVUs after an ischemic or hemorrhagic stroke. These nanoparticle-based approaches have the potential to improve clinical safety and efficacy by maximizing drug delivery to diseased NVUs and minimizing drug exposure in healthy brain and peripheral tissues.more » « less
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AbstractIn stroke, the sudden deprivation of oxygen to neurons triggers a profuse release of glutamate that induces anoxic depolarization (AD) and leads to rapid cell death. Importantly, the latency of the glutamate‐driven AD event largely dictates subsequent tissue damage. Although the contribution of synaptic glutamate during ischaemia is well‐studied, the role of tonic (ambient) glutamate has received far less scrutiny. The majority of tonic, non‐synaptic glutamate in the brain is governed by the cystine/glutamate antiporter, system xc−. Employing hippocampal slice electrophysiology, we showed that transgenic mice lacking a functional system xc−display longer latencies to AD and altered depolarizing waves compared to wild‐type mice after total oxygen deprivation. Experiments which pharmacologically inhibited system xc−, as well as those manipulating tonic glutamate levels and those antagonizing glutamate receptors, revealed that the antiporter's putative effect on ambient glutamate precipitates the ischaemic cascade. As such, the current study yields novel insight into the pathogenesis of acute stroke and may direct future therapeutic interventions.image Key pointsIschaemic stroke remains the leading cause of adult disability in the world, but efforts to reduce stroke severity have been plagued by failed translational attempts to mitigate glutamate excitotoxicity.Elucidating the ischaemic cascade, which within minutes leads to irreversible tissue damage induced by anoxic depolarization, must be a principal focus.Data presented here show that tonic, extrasynaptic glutamate supplied by system xc−synergizes with ischaemia‐induced synaptic glutamate release to propagate AD and exacerbate depolarizing waves.Exploiting the role of system xc−and its obligate release of ambient glutamate could, therefore, be a novel therapeutic direction to attenuate the deleterious effects of acute stroke.more » « less
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Abstract BackgroundPrevious work has shown that ~ 50–60% of individuals have impaired proprioception after stroke. Typically, these studies have identified proprioceptive impairments using a narrow range of reference movements. While this has been important for identifying the prevalence of proprioceptive impairments, it is unknown whether these error responses are consistent for a broad range of reference movements. The objective of this study was to characterize proprioceptive accuracy as function of movement speed and distance in stroke. MethodsStroke (N = 25) and controls (N = 21) completed a robotic proprioception test that varied movement speed and distance. Participants mirror-matched various reference movement speeds (0.1–0.4 m/s) and distances (7.5–17.5 cm). Spatial and temporal parameters known to quantify proprioception were used to determine group differences in proprioceptive accuracy, and whether patterns of proprioceptive error were consistent across testing conditions within and across groups. ResultsOverall, we found that stroke participants had impaired proprioception compared to controls. Proprioceptive errors related to tested reference movement scaled similarly to controls, but some errors showed amplified scaling (e.g., significantly overshooting or undershooting reference speed). Further, interaction effects were present for speed and distance reference combinations at the extremes of the testing distribution. ConclusionsWe found that stroke participants have impaired proprioception and that some proprioceptive errors were dependent on characteristics of the movement (e.g., speed) and that reference movements at the extremes of the testing distribution resulted in significantly larger proprioceptive errors for the stroke group. Understanding how sensory information is utilized across a broad spectrum of movements after stroke may aid design of rehabilitation programs.more » « less
- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1152/jn.00191.2021
