scholarly journals Striatal Acetylcholine Helps to Preserve Functional Outcomes in a Mouse Model of Stroke

ASN NEURO ◽  
2020 ◽  
Vol 12 ◽  
pp. 175909142096161
Author(s):  
Daniela F. Goncalves ◽  
Monica S. Guzman ◽  
Robert Gros ◽  
André R. Massensini ◽  
Robert Bartha ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Functional Recovery ◽  
Functional Outcomes ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Lesion Volume ◽  
Functional Impairments ◽  
Ach Release ◽  
Cholinergic Interneurons ◽  
Blood Brain

Acetylcholine (ACh) has been suggested to facilitate plasticity and improve functional recovery after different types of brain lesions. Interestingly, numerous studies have shown that striatal cholinergic interneurons are relatively resistant to acute ischemic insults, but whether ACh released by these neurons enhances functional recovery after stroke is unknown. We investigated the role of endogenous striatal ACh in stroke lesion volume and functional outcomes following middle cerebral artery occlusion to induce focal ischemia in striatum-selective vesicular acetylcholine transporter-deficient mice (stVAChT-KO). As transporter expression is almost completely eliminated in the striatum of stVAChT-KO mice, ACh release is nearly abolished in this area. Conversely, in other brain areas, VAChT expression and ACh release are preserved. Our results demonstrate a larger infarct size after ischemic insult in stVAChT-KO mice, with more pronounced functional impairments and increased mortality than in littermate controls. These changes are associated with increased activation of GSK-3, decreased levels of β-catenin, and a higher permeability of the blood–brain barrier in mice with loss of VAChT in striatum neurons. These results support a framework in which endogenous ACh secretion originating from cholinergic interneurons in the striatum helps to protect brain tissue against ischemia-induced damage and facilitates brain recovery by supporting blood–brain barrier function.

scholarly journals Netrin-4 Enhances Angiogenesis and Neurologic Outcome after Cerebral Ischemia

2008 ◽  
Vol 29 (2) ◽  
pp. 385-397 ◽  
Author(s):  
Stanley Hoang ◽  
Jason Liauw ◽  
Matthew Choi ◽  
Michael Choi ◽  
Raphael G Guzman ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Vessel ◽  
Blood Brain Barrier ◽  
Functional Recovery ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Vascular Networks ◽  
Behavioral Recovery ◽  
Deleted In Colorectal Cancer ◽  
Blood Brain

Functional recovery after cerebral ischemia is mediated by the regeneration of vascular networks and the restoration of synaptic architecture. Netrins have been implicated in neuronal pathfinding and angiogenesis. In this study, we investigated the expression of Netrin-4 and its putative receptors, deleted in colorectal cancer (DCC), Unc5A, and Unc5B after distal middle cerebral artery occlusion in mice. Netrin-4 protein was also administered intracerebroventricularly to examine its effect on angiogenesis and behavioral recovery. Netrin-4 protein was highly upregulated in the ischemic core as soon as 1 day after cerebral ischemia, with subsequent downregulation after 1 week. Its expression was limited to the area of blood—brain barrier damage and was seen on both blood vessels and astrocytic foot processes. Although there was not a significant upregulation of the putative Netrin-4 receptor Unc5A and Unc5B, there was a significant increase in expression of the DCC receptor on neuronal processes in the peri-infarct cortex. Intracerebroventricular administration of Netrin-4 into the ischemic brain increased blood vessel density, endothelial proliferation, and improved behavioral recovery at 1 week after stroke, but did not have an effect on blood—brain barrier permeability or infarct size. These findings suggest that Netrin-4 may improve poststroke functional recovery by enhancing blood vessel proliferation.

scholarly journals The Neuroprotective Effects of Necrostatin-1 on Subarachnoid Hemorrhage in Rats Are Possibly Mediated by Preventing Blood–Brain Barrier Disruption and RIP3-Mediated Necroptosis

2019 ◽  
Vol 28 (11) ◽  
pp. 1358-1372 ◽  
Author(s):  
Jingsen Chen ◽  
Hanghuang Jin ◽  
Hangzhe Xu ◽  
Yucong Peng ◽  
Liyong Jie ◽  
...  
Keyword(s):  
Subarachnoid Hemorrhage ◽  
Blood Brain Barrier ◽  
New Drugs ◽  
Brain Barrier ◽  
Lesion Volume ◽  
Brain Swelling ◽  
Neuroprotective Effects ◽  
Pharmaceutical Therapy ◽  
Blood Brain

Despite the substantial efforts to elucidate the role of early brain injury in subarachnoid hemorrhage (SAH), an effective pharmaceutical therapy for patients with SAH continues to be unavailable. This study aims to reveal the role of necroptosis after SAH, and explore whether the disruption of the blood–brain barrier (BBB) and RIP3-mediated necroptosis following SAH in a rat SAH model are altered by necrostatin-1 via its selective inhibition of receptor-interacting protein kinase 1 (RIP1). Sixty-five rats were used in the experiments. The SAH model was established using endovascular perforation. Necrostatin-1 was intracerebroventricularly injected 1 h before SAH induction. The neuroprotective effects of necrostatin-1 were evaluated with multiple methods such as magnetic resonance imaging (MRI) scanning, immunohistochemistry, propidium iodide (PI) labeling, and western blotting. Pretreatment with necrostatin-1 attenuated brain swelling and reduced the lesion volume on T2 sequence and ventricular volume on MRI 72 h after SAH induction. Albumin leakage and the degradation of tight junction proteins were also ameliorated by necrostatin-1 administration. In addition, necrostatin-1 decreased the number of PI-positive cells in the basal cortex, reduced the levels of the RIP3 and MLKL proteins, and inhibited the production of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α. Based on the findings from the present study, the selective RIP1 inhibitor necrostatin-1 functioned as a neuroprotective agent after SAH by attenuating brain swelling and BBB disruption. Moreover, the necrostatin-1 pretreatment prevented SAH-induced necroptosis by suppressing the activity of the RIP3/MLKL signaling pathway. These results will provide insights into new drugs and pharmacological targets to manage SAH, which are worth further study.

scholarly journals EphrinB2 Activation Enhances Vascular Repair Mechanisms and Reduces Brain Swelling After Mild Cerebral Ischemia

2017 ◽  
Vol 37 (5) ◽  
pp. 867-878 ◽  
Author(s):  
Adnan Ghori ◽  
Florian B. Freimann ◽  
Melina Nieminen-Kelhä ◽  
Irina Kremenetskaia ◽  
Karen Gertz ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Blood Brain Barrier ◽  
Major Complication ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Tyrosine Kinase Receptor ◽  
Vascular Repair ◽  
Brain Swelling ◽  
Blood Brain ◽  
Repair Mechanisms

Objective— Cerebral edema caused by the disruption of the blood–brain barrier is a major complication after stroke. Therefore, strategies to accelerate and enhance neurovascular recovery after stroke are of prime interest. Our main aim was to study the role of ephrinB2/EphB4 signaling in mediating the vascular repair and in blood–brain barrier restoration after mild cerebral ischemia occlusion/reperfusion. Approach and Results— Here, we show that the guidance molecule ephrinB2 plays a key role in neurovascular protection and blood–brain barrier restoration after stroke. In a focal stroke model, we characterize the stroke-induced damage to cerebral blood vessels and their subsequent endogenous repair on a cellular, molecular, and functional level. EphrinB2 and its tyrosine kinase receptor EphB4 are upregulated early after stroke by endothelial cells and perivascular support cells, in parallel to their reassembly during neurovascular recovery. Using both retroviral and pharmacological approaches, we show that the inhibition of ephrinB2/EphB4 signaling suppresses post-middle cerebral artery occlusion neurovascular repair mechanisms resulting in an aggravation of brain swelling. In contrast, the activation of ephrinB2 after brain ischemia leads to an increased pericyte recruitment and increased endothelial–pericyte interaction, resulting in an accelerated neurovascular repair after ischemia. Conclusions— We show that reducing swelling could result in improved outcome because of reduction in damaged brain tissue. We also identify a novel role for ephrinB2/EphB4 signaling in the maintenance of the neurovascular homeostasis and provide a novel therapeutic approach in reducing brain swelling after stroke.

scholarly journals Selective Liposomal Transport Through Blood Brain Barrier Disruption in Ischaemic Stroke Reveals Two Distinct Therapeutic Opportunities

2019 ◽  
Author(s):  
Zahraa S. Al-Ahmady ◽  
Dhifaf Jasim ◽  
Sabahuddin Syed Ahmad ◽  
Raymond Wong ◽  
Michael Haley ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Inflammatory Responses ◽  
Neurovascular Unit ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Experimental Stroke ◽  
Blood Brain Barrier Disruption ◽  
Blood Brain ◽  
Ischaemic Brain

AbstractThe development of new therapies for stroke continues to face repeated translational failures. Brain endothelial cells form paracellular and transcellular barriers to many blood-borne therapies and the development of efficient delivery strategies is highly warranted. Here, in a mouse model of stroke, we show selective recruitment of clinically used liposomes into the ischaemic brain that correlates with biphasic blood brain barrier (BBB) breakdown. Intravenous administration of liposomes into mice exposed to transient middle cerebral artery occlusion took place at early (0.5h and 4h) and delayed (24h and 48h) timepoints, covering different phases of BBB disruption after stroke. Using a combination of in vivo real-time imaging and histological analysis we show that selective liposomal brain accumulation coincides with biphasic enhancement in transcellular transport followed by a delayed impairment to the paracellular barrier. This process precedes neurological damage in the acute phase and maintains long-term liposomal co-localisation within the neurovascular unit, which could have great potential for neuroprotection. Levels of liposomal uptake by glial cells are similarly selectively enhanced in the ischaemic region late after experimental stroke (2-3 days), highlighting their potential for blocking delayed inflammatory responses or shifting the polarization of microglia/macrophages towards brain repair.These findings demonstrate the capability of liposomes to maximise selective translocation into the brain after stroke and identify for the first time two windows for therapeutic manipulation. This emphasizes the benefits of selective drug delivery for efficient tailoring of new stroke treatments.

High glucose-induced effects on Na+-K+-Cl- cotransport and Na+/H+ exchange of blood-brain barrier endothelial cells: involvement of SGK1, PKCβII and SPAK/OSR1

2021 ◽  
Author(s):  
Nicholas R. Klug ◽  
Olga V. Chechneva ◽  
Benjamin Y. Hung ◽  
Martha E. O'Donnell
Keyword(s):  
Blood Brain Barrier ◽  
High Glucose ◽  
Artery Occlusion ◽  
Brain Barrier ◽  
Microvascular Endothelial Cell ◽  
Edema Formation ◽  
Kinase C ◽  
Blood Brain ◽  
Transport Of Ions ◽  
Cerebral Artery Occlusion

Hyperglycemia exacerbates edema formation and worsens neurological outcome in ischemic stroke. Edema formation in the early hours of stroke involves transport of ions and water across an intact blood-brain barrier (BBB), and swelling of astrocytes. We showed previously that high glucose (HG) exposures of 24 hours to 7 days increase abundance and activity of BBB Na+-K+-2Cl- cotransport (NKCC) and Na+/H+ exchange 1 (NHE1). Further, bumetanide and HOE-642 inhibition of these transporters significantly reduces edema and infarct following middle cerebral artery occlusion in hyperglycemic rats, suggesting that NKCC and NHE1 are effective therapeutic targets for reducing edema in hyperglycemic stroke. The mechanisms underlying hyperglycemia effects on BBB NKCC and NHE1 are not known. In the present study we investigated whether serum-glucocorticoid regulated kinase 1 (SGK1) and protein kinase C beta II (PKCβII) are involved in HG effects on BBB NKCC and NHE1. We found transient increases in phosphorylated SGK1 and PKCβII within the first hour of HG exposure, after 5-60 min for SGK1 and 5 min for PKCβII. However, no changes were observed in cerebral microvascular endothelial cell SGK1 or PKCβII abundance or phosphorylation (activity) after 24 or 48 hr HG exposures. Further, we found that HG-induced increases in NKCC and NHE1 abundance were abolished by inhibition of SGK1 but not PKCβII, whereas the increases in NKCC and NHE activity were abolished by inhibition of either kinase. Finally, we found evidence that STE20/SPS1-related proline/alanine-rich kinase and oxidative stress-responsive kinase-1 (SPAK/OSR1) participate in the HG-induced effects on BBB NKCC.

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