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1.
Brain Res ; 1802: 148207, 2023 Mar 01.
Article in English | MEDLINE | ID: mdl-36549360

ABSTRACT

Erythropoietin (EPO) has neuroprotective effects in central nervous system injury models. In clinical trials EPO has shown beneficial effects in traumatic brain injury (TBI) as well as in ischemic stroke. We have previously shown that EPO has short-term effects on astrocyte glutamatergic signaling in vitro and that administration of EPO after experimental TBI decreases early cytotoxic brain edema and preserves structural and functional properties of the blood-brain barrier. These effects have been attributed to preserved or restored astrocyte function. Here we explored the effects of EPO on astrocytes undergoing oxygen-glucose-deprivation, an in vitro model of ischemia. Measurements of glutamate uptake, intracellular pH, intrinsic NADH fluorescence, Na,K-ATPase activity, and lactate release were performed. We found that EPO within minutes caused a Na,K-ATPase-dependent increase in glutamate uptake, restored intracellular acidification caused by glutamate and increased lactate release. The effects on intracellular pH were dependent on the sodium/hydrogen exchanger NHE. In neuron-astrocyte co-cultures, EPO increased NADH production both in astrocytes and neurons, however the increase was greater in astrocytes. We suggest that EPO preserves astrocyte function under ischemic conditions and thus may contribute to neuroprotection in ischemic stroke and brain ischemia secondary to TBI.


Subject(s)
Brain Injuries, Traumatic , Erythropoietin , Ischemic Stroke , Humans , Astrocytes , Sodium-Potassium-Exchanging ATPase , NAD , Ischemia , Glutamic Acid/pharmacology , Models, Theoretical
2.
J Neurotrauma ; 35(4): 671-680, 2018 02 15.
Article in English | MEDLINE | ID: mdl-29179621

ABSTRACT

Erythropoietin (EPO) has neuroprotective effects in multiple central nervous system (CNS) injury models; however EPO's effects on traumatic brain edema are elusive. To explore EPO as an intervention in traumatic brain edema, male Sprague-Dawley (SD) rats were subjected to blunt, controlled traumatic brain injury (TBI). Animals were randomized to EPO 5000 IU/kg or saline (control group) intraperitoneally within 30 min after trauma and once daily for 4 consecutive days. Brain MRI, immunohistofluorescence, immunohistochemistry, and quantitative protein analysis were performed at days 1 and 4 post- trauma. EPO significantly prevented the loss of the tight junction protein zona occludens 1 (ZO-1) observed in control animals after trauma. The decrease of ZO-1 in the control group was associated with an immunoglobulin (Ig)G increase in the perilesional parenchyma, indicating blood-brain barrier (BBB) dysfunction and increased permeability. EPO treatment attenuated decrease in apparent diffusion coefficient (ADC) after trauma, suggesting a reduction of cytotoxic edema, and reduced the IgG leakage, indicating that EPO contributed to preserve BBB integrity and attenuated vasogenic edema. Animals treated with EPO demonstrated conserved levels of aquaporin 4 (AQP4) protein expression in the perilesional area, whereas control animals showed a reduction of AQP4. We show that post TBI administration of EPO decreases early cytotoxic brain edema and preserves structural and functional properties of the BBB, leading to attenuation of the vasogenic edema response. The data support that the mechanisms involve preservation of the tight junction protein ZO-1 and the water channel AQP4, and indicate that treatment with EPO may have beneficial effects on the brain edema response following TBI.


Subject(s)
Brain Edema/pathology , Brain Injuries, Traumatic/pathology , Brain/drug effects , Epoetin Alfa/pharmacology , Hematinics/pharmacology , Animals , Blood-Brain Barrier/drug effects , Brain/pathology , Brain Edema/etiology , Brain Injuries, Traumatic/complications , Male , Random Allocation , Rats , Rats, Sprague-Dawley
3.
Scand J Trauma Resusc Emerg Med ; 25(1): 73, 2017 Jul 17.
Article in English | MEDLINE | ID: mdl-28716150

ABSTRACT

BACKGROUND: Accidental hypothermia with cardiac arrest represents a challenge for pre-hospital rescuers as well as in-hospital staff. For pre-hospital personnel, the main focus is to get the patient to the correct destination without unnecessary delay. For in-hospital personnel early information is vital to assess the possibility for resuscitation with extracorporeal re-warming. The challenge is augmented when rescuers must cross national borders to reach and/or deliver the patients. We present a case where three adolescent boys suffered severe hypothermia after a canoeing accident in Sweden. CASE PRESENTATION: Three 14-year-old boys were canoeing a mountain lake close to the Norwegian border when their boat capsized and they all fell into the cold water. The rescue operation was hampered by rough weather conditions, and immersion times spanned from 63 to 125 min. Flight times from the scene of accident to the nearest ECMO center in Norway (Trondheim) and Sweden (Umeå) were about 30 and 90 min respectively. Two of the victims showed no vital signs after retrieval from the water and had extremely low body temperatures. They were brought to Trondheim University Hospital where they were resuscitated successfully with extracorporeal re-warming. Unable to be weaned from ECMO in the initial phase, both patients were retrieved by mobile ECMO teams to Karolinska University Hospital, from where they were discharged to their homes with good outcomes, although with some sequelae. A third victim with moderate to severe hypothermia without cardiac arrest was treated at a local hospital, from where he after a short stay was discharged without physical sequelae. CONCLUSION: These cases are a reminder of the traditional mantra that «no one is dead until warm and dead¼. Good communication between pre- and in-hospital staff can be vital for optimizing patient treatment when handling victims of severe hypothermia, and especially when there is multiple victims. Communication between neighboring countries, but even neighboring regions within the same country, can be challenging. We encourage regions similar to ours to review protocols regarding hypothermia management, making them more robust before incidents like this take place.


Subject(s)
Heart Arrest/therapy , Hypothermia/therapy , Accidents , Adolescent , Communication , Extracorporeal Membrane Oxygenation , Humans , Male , Norway , Resuscitation , Rewarming , Sweden , Transportation of Patients
4.
Sci Rep ; 6: 22047, 2016 Feb 25.
Article in English | MEDLINE | ID: mdl-26911348

ABSTRACT

Migraine is a complex brain disorder, and understanding the complexity of this prevalent disease could improve quality of life for millions of people. Familial Hemiplegic Migraine type 2 (FHM2) is a subtype of migraine with aura and co-morbidities like epilepsy/seizures, cognitive impairments and psychiatric manifestations, such as obsessive-compulsive disorder (OCD). FHM2 disease-mutations locate to the ATP1A2 gene encoding the astrocyte-located α2-isoform of the sodium-potassium pump (α2Na(+)/K(+)-ATPase). We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (α2(+/G301R)) phenocopy several FHM2-relevant disease traits e.g., by mimicking mood depression and OCD. In vitro studies showed impaired glutamate uptake in hippocampal mixed astrocyte-neuron cultures from α2(G301R/G301R) E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in reduced recovery in α2(+/G301R) male mice. Moreover, NMDA-type glutamate receptor antagonists or progestin-only treatment reverted specific α2(+/G301R) behavioral phenotypes. Our findings demonstrate that studies of an in vivo relevant FHM2 disease knock-in mouse model provide a link between the female sex hormone cycle and the glutamate system and a link to co-morbid psychiatric manifestations of FHM2.


Subject(s)
Glutamic Acid/metabolism , Migraine with Aura/genetics , Migraine with Aura/metabolism , Mutation , Phenotype , Acoustic Stimulation , Animals , Behavior, Animal , Biological Transport , Cerebrovascular Circulation , Computational Biology/methods , Cortical Spreading Depression/genetics , Disease Models, Animal , Female , Gonadal Steroid Hormones/metabolism , Male , Mice , Mice, Transgenic , Migraine with Aura/diagnosis , Migraine with Aura/drug therapy , Motor Activity , Reaction Time , Sodium-Potassium-Exchanging ATPase/genetics , Stress, Physiological
5.
Brain Res ; 1611: 18-28, 2015 Jun 22.
Article in English | MEDLINE | ID: mdl-25770057

ABSTRACT

Traumatic brain injury (TBI) is a major contributor to mortality and morbidity. The pathophysiology involves development of brain edema. Therapeutic options are limited as the mechanisms are not fully understood. Changes in the function of the blood-brain barrier (BBB), as well as variations in aquaporin expression, have been proposed to be involved in the development of the edema but the contribution of each factor has not been fully elucidated. In order to evaluate these mechanisms, in a potential window of opportunity, the early dynamic response was studied using an animal model causing a moderate TBI. Sprague-Dawley rats were subjected to blunt controlled head trauma and followed for up to four days by magnetic-resonance-imaging, immunohistofluorescence, immunohistochemistry, and quantitative protein analysis. Non-traumatized animals served as controls. TBI resulted in a midline shift and a decrease in Apparent Diffusion Coefficient, indicating a hemispheric enlargement due to cytotoxic edema. The tight junction protein Zona Occludens-1 was decreased (-25%) and associated with an increased IgG permeability (+20%) in the perilesional brain tissue in accordance with a BBB breakdown. The total amount of AQP4 protein decreased (-20%). The disruption of the BBB lasted for 4 days while the impact on AQP4 levels disappeared between day 1 and 4. Our findings shows that blunt focal brain injury results in an early development of brain edema involving both cytotoxic and vasogenic components, a persistent BBB breakdown and a temporary decrease in AQP4, and indicates that both types of edemas and mechanisms should be targeted in TBI treatment.


Subject(s)
Aquaporin 4/metabolism , Blood-Brain Barrier/metabolism , Brain Edema/metabolism , Brain Injuries/complications , Animals , Brain Edema/etiology , Brain Edema/pathology , Immunoglobulin G/metabolism , Permeability , Rats , Rats, Sprague-Dawley , Zonula Occludens-1 Protein/metabolism
6.
PLoS One ; 9(6): e98469, 2014.
Article in English | MEDLINE | ID: mdl-24901986

ABSTRACT

Glutamate released during neuronal activity is cleared from the synaptic space via the astrocytic glutamate/Na(+) co-transporters. This transport is driven by the transmembrane Na(+) gradient mediated by Na,K-ATPase. Astrocytes express two isoforms of the catalytic Na,K-ATPase α subunits; the ubiquitously expressed α1 subunit and the α2 subunit that has a more specific expression profile. In the brain α2 is predominantly expressed in astrocytes. The isoforms differ with regard to Na+ affinity, which is lower for α2. The relative roles of the α1 and α2 isoforms in astrocytes are not well understood. Here we present evidence that the presence of the α2 isoform may contribute to a more efficient restoration of glutamate triggered increases in intracellular sodium concentration [Na(+)]i. Studies were performed on primary astrocytes derived from E17 rat striatum expressing Na,K-ATPase α1 and α2 and the glutamate/Na(+) co-transporter GLAST. Selective inhibition of α2 resulted in a modest increase of [Na(+)]i accompanied by a disproportionately large decrease in uptake of aspartate, an indicator of glutamate uptake. To compare the capacity of α1 and α2 to handle increases in [Na(+)]i triggered by glutamate, primary astrocytes overexpressing either α1 or α2 were used. Exposure to glutamate 200 µM caused a significantly larger increase in [Na(+)]i in α1 than in α2 overexpressing cells, and as a consequence restoration of [Na(+)]i, after glutamate exposure was discontinued, took longer time in α1 than in α2 overexpressing cells. Both α1 and α2 interacted with astrocyte glutamate/Na(+) co-transporters via the 1st intracellular loop.


Subject(s)
Astrocytes/metabolism , Glutamic Acid/metabolism , Sodium-Potassium-Exchanging ATPase/metabolism , Animals , Aspartic Acid/metabolism , Biological Transport , Excitatory Amino Acid Transporter 1/metabolism , Excitatory Amino Acid Transporter 2/metabolism , Gene Expression , Intracellular Space/metabolism , Isoenzymes , Protein Binding , Rats , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/genetics
7.
PLoS One ; 7(4): e34936, 2012.
Article in English | MEDLINE | ID: mdl-22493723

ABSTRACT

Astrocytes express potassium and water channels to support dynamic regulation of potassium homeostasis. Potassium kinetics can be modulated by aquaporin-4 (AQP4), the essential water channel for astrocyte water permeability regulation. We investigated whether extracellular potassium ([K(+)](o)) can regulate astrocyte water permeability and the mechanisms of such an effect. Studies were performed on rat primary astrocytes and a rat astrocyte cell line transfected with AQP4. We found that 10 mM [K(+)](o) caused an immediate, more than 40%, increase in astrocyte water permeability which was sustained in 5 min. The water channel AQP4 was a target for this regulation. Potassium induced a significant increase in intracellular cAMP as measured with a FRET based method and with enzyme immunoassay. We found that protein kinase A (PKA) could phosphorylate AQP4 in vitro. Further elevation of [K(+)](o) to 35 mM induced a global intracellular calcium response and a transient water permeability increase that was abolished in 5 min. When inwardly rectifying potassium (Kir)-channels were blocked, 10 mM [K(+)](o) also induced a calcium increase and the water permeability increase no longer persisted. In conclusion, we find that elevation of extracellular potassium regulates AQP4 and astrocyte water permeability via intracellular signaling involving cAMP. A prolonged increase of astrocyte water permeability is Kir-channel dependent and this response can be impeded by intracellular calcium signaling. Our results support the concept of coupling between AQP4 and potassium handling in astrocytes.


Subject(s)
Aquaporin 4/metabolism , Astrocytes/metabolism , Cyclic AMP/metabolism , Potassium Channels, Inwardly Rectifying/metabolism , Potassium/metabolism , Water/metabolism , Animals , Aquaporin 4/genetics , Astrocytes/cytology , Calcium/metabolism , Cell Line , Cerebellum/cytology , Cerebellum/metabolism , Cyclic AMP-Dependent Protein Kinases/metabolism , Fluorescence Resonance Energy Transfer , Homeostasis , Mice , Permeability , Phosphorylation , Primary Cell Culture , Rats , Signal Transduction , Transfection
8.
Proc Natl Acad Sci U S A ; 106(5): 1602-7, 2009 Feb 03.
Article in English | MEDLINE | ID: mdl-19164545

ABSTRACT

Disturbed brain water homeostasis with swelling of astroglial cells is a common complication in stroke, trauma, and meningitis and is considered to be a major cause of permanent brain damage. Astroglial cells possess the water channel aquaporin 4 (AQP4). Recent studies from our laboratory have shown that glutamate, acting on group I metabotropic glutamate receptors (mGluRs), increases the permeability of astrocyte AQP4, which, in situations of hypoxia-ischemia, will increase astrocyte water uptake. Here we report that erythropoietin (EPO), which in recent years has emerged as a potent neuro-protective agent, antagonizes the effect of a group I mGluR agonist on astrocyte water permeability. Activation of group I mGluRs triggers fast and highly regular intracellular calcium oscillations and we show that EPO interferes with this signaling event by altering the frequency of the oscillations. These effects of EPO are immediate, in contrast to the neuroprotective effects of EPO that are known to depend upon gene activation. Our findings indicate that EPO may directly reduce the risk of astrocyte swelling in stroke and other brain insults. In support of this conclusion we found that EPO reduced the neurological symptoms in a mouse model of primary brain edema known to depend upon AQP4 water transport.


Subject(s)
Astrocytes/metabolism , Erythropoietin/physiology , Water/metabolism , Animals , Aquaporin 4/metabolism , Brain Edema/physiopathology , Calcium Signaling , Cells, Cultured , Female , Hippocampus/metabolism , In Vitro Techniques , Mice , Mice, Inbred C3H , Permeability , Rats , Receptors, Glutamate/metabolism
9.
Glia ; 56(6): 587-96, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18286643

ABSTRACT

Astrocytes play a key role for maintenance of brain water homeostasis, but little is known about mechanisms of short-term regulation of astrocyte water permeability. Here, we report that glutamate increases astrocyte water permeability and that the molecular target for this effect is the aquaporin-4 (AQP4) serine 111 residue, which is in a strategic position for control of the water channel gating. The glutamate effect involves activation of group I metabotropic glutamate receptors (mGluR), intracellular calcium release, and activation of calcium/calmodulin-dependent protein kinase II (CaMKII) and nitric oxide synthase (NOS). The physiological impact of our results is underlined by the finding that mGluR activation increases the rate of hypoosmotic tissue swelling in acute rat hippocampal slices. Cerebral ischemia is associated with an excessive release of glutamate, and in postischemic cerebral edema ablation of AQP4 attenuates the degree of damage. Thus, we have identified AQP4 as the molecular target for drugs that may attenuate the development of brain edema.


Subject(s)
Aquaporin 4/metabolism , Astrocytes/drug effects , Glutamic Acid/pharmacology , Water/metabolism , Animals , Animals, Newborn , Astrocytes/physiology , Benzylamines/pharmacology , Calcium/metabolism , Cell Line, Transformed , Dose-Response Relationship, Drug , Enzyme Inhibitors/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Green Fluorescent Proteins/metabolism , Hippocampus/drug effects , Hippocampus/physiology , In Vitro Techniques , Methoxyhydroxyphenylglycol/analogs & derivatives , Methoxyhydroxyphenylglycol/pharmacology , N-Methylaspartate/pharmacology , Permeability/drug effects , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/metabolism , Serine/metabolism , Sulfonamides/pharmacology , Transfection/methods
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