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 MCUcx inhibition and NCLX activation suppress ischemic and excitotoxic neuronal cell death by blocking mitochondrial Ca2+overloading. These findings suggest that combining MCUcx inhibition 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 MCUcx inhibition 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
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.
more » « less- Award ID(s):
- 1912557
- NSF-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
More Like this
-
-
more » « less
Abstract In 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 points Ischaemic 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.
-
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.more » « less
-
null (Ed.)Background The rhythm of music can entrain neurons in motor cortex by way of direct connections between auditory and motor brain regions. Objective We sought to automate an individualized and progressive music-based, walking rehabilitation program using real-time sensor data in combination with decision algorithms. Methods A music-based digital therapeutic was developed to maintain high sound quality while modulating, in real-time, the tempo (ie, beats per minute, or bpm) of music based on a user’s ability to entrain to the tempo and progress to faster walking cadences in-sync with the progression of the tempo. Eleven individuals with chronic hemiparesis completed one automated 30-minute training visit. Seven returned for 2 additional visits. Safety, feasibility, and rehabilitative potential (ie, changes in walking speed relative to clinically meaningful change scores) were evaluated. Results A single, fully automated training visit resulted in increased usual (∆ 0.085 ± 0.027 m/s, P = .011) and fast (∆ 0.093 ± 0.032 m/s, P = .016) walking speeds. The 7 participants who completed additional training visits increased their usual walking speed by 0.12 ± 0.03 m/s after only 3 days of training. Changes in walking speed were highly related to changes in walking cadence ( R 2 > 0.70). No trips or falls were noted during training, all users reported that the device helped them walk faster, and 70% indicated that they would use it most or all of the time at home. Conclusions In this proof-of-concept study, we show that a sensor-automated, progressive, and individualized rhythmic locomotor training program can be implemented safely and effectively to train walking speed after stroke. Music-based digital therapeutics have the potential to facilitate salient, community-based rehabilitation.more » « less
-
The mitochondrial calcium (Ca2+) uniporter (MCU) mediates high-capacity mitochondrial Ca2+ uptake implicated in ischemic/reperfusion cell death. We have recently shown that inducible MCU ablation in Thy1-expressing neurons renders mice resistant to sensorimotor deficits and forebrain neuron loss in a model of hypoxic/ischemic (HI) brain injury. These findings encouraged us to compare the neuroprotective effects of Ru360 and the recently identified cell permeable MCU inhibitor Ru265. Unlike Ru360, Ru265 (2-10 µM) reached intracellular concentrations in cultured cortical neurons that preserved cell viability, blocked the protease activity of Ca2+-dependent calpains and maintained mitochondrial respiration and glycolysis after a lethal period of oxygen-glucose deprivation (OGD). Intraperitoneal (i.p.) injection of adult male C57Bl/6 mice with Ru265 (3 mg/kg) also suppressed HI-induced sensorimotor deficits and brain injury. However, higher doses of Ru265 (10 and 30 mg/kg, i.p.) produced dose-dependent increases in the frequency of seizure-like behaviours and the duration of clonic convulsions. Ru265 is proposed to promote convulsions by reducing Ca2+ buffering and energy production in highly energetic interneurons that suppress brain seizure activity. These findings support the potential therapeutic utility of MCU inhibition in the acute management of ischemic stroke but also indicate that such clinical translation will require drug delivery strategies which mitigate the pro-convulsant effects of Ru265.more » « less
- Free Publicly Accessible Full Text
-
Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1152/jn.00191.2021
