Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Dietrich, Kristen; Hackett, Mark J.; Caine, Sally; Nadeau, Colby A.; Aziz, Jasmine R.; Nichol, Helen; Paterson, Phyllis G.; Colbourne, Frederick

doi:10.1161/strokeaha.116.015404

Cited by 38 publications

(57 citation statements)

References 29 publications

(71 reference statements)

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“…19,20 Briefly, 219 adult male Sprague-Dawley rats (350-400g; Charles River Laboratories, Montreal, Quebec, Canada) were used in several studies to examine the effects of NAC (40 or 75mg/kg given intraperitoneally [IP] 2 hours after collagenase infusion and thereafter as in the mice efficacy studies, versus saline control). Homozygous ALOX5 knockout (ALOX-5 -/-) mice were obtained from The Jackson Laboratory (Bar Harbor, ME).…”

Section: Methodsmentioning

confidence: 99%

“…Rat experiments were approved and conducted at the University of Alberta (Edmonton, Alberta, Canada) according to published methods. 19,20 Briefly, 219 adult male Sprague-Dawley rats (350-400g; Charles River Laboratories, Montreal, Quebec, Canada) were used in several studies to examine the effects of NAC (40 or 75mg/kg given intraperitoneally [IP] 2 hours after collagenase infusion and thereafter as in the mice efficacy studies, versus saline control). We assessed body temperature, edema, eicosanoids, cerebral bleeding, behavior, and lesion volume (out to a 28-day survival).…”

Section: Methodsmentioning

confidence: 99%

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N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Karuppagounder

Alin

Chen

et al. 2018

Annals of Neurology

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204

167

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Objectives N‐acetylcysteine (NAC) is a clinically approved thiol‐containing redox modulatory compound currently in trials for many neurological and psychiatric disorders. Although generically labeled as an “antioxidant,” poor understanding of its site(s) of action is a barrier to its use in neurological practice. Here, we examined the efficacy and mechanism of action of NAC in rodent models of hemorrhagic stroke. Methods Hemin was used to model ferroptosis and hemorrhagic stroke in cultured neurons. Striatal infusion of collagenase was used to model intracerebral hemorrhage (ICH) in mice and rats. Chemical biology, targeted lipidomics, arachidonate 5‐lipoxygenase (ALOX5) knockout mice, and viral‐gene transfer were used to gain insight into the pharmacological targets and mechanism of action of NAC. Results NAC prevented hemin‐induced ferroptosis by neutralizing toxic lipids generated by arachidonate‐dependent ALOX5 activity. NAC efficacy required increases in glutathione and is correlated with suppression of reactive lipids by glutathione‐dependent enzymes such as glutathione S ‐transferase. Accordingly, its protective effects were mimicked by chemical or molecular lipid peroxidation inhibitors. NAC delivered postinjury reduced neuronal death and improved functional recovery at least 7 days following ICH in mice and can synergize with clinically approved prostaglandin E 2 (PGE 2 ). Interpretation NAC is a promising, protective therapy for ICH, which acted to inhibit toxic arachidonic acid products of nuclear ALOX5 that synergized with exogenously delivered protective PGE 2 in vitro and in vivo. The findings provide novel insight into a target for NAC, beyond the generic characterization as an antioxidant, resulting in neuroprotection and offer a feasible combinatorial strategy to optimize efficacy and safety in dosing of NAC for treatment of neurological disorders involving ferroptosis such as ICH. Ann Neurol 2018;84:854–872

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Karuppagounder

Alin

Chen

et al. 2018

Annals of Neurology

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204

167

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“…Primary somatosensory cortex was closer to the hematoma, but we did not assess tissue in the needle path or any tissue infiltrated with blood. We chose not to assess peri-hematoma regions to avoid confounds of ongoing injury, cell death, and edema [21–23]. …”

Section: Methodsmentioning

confidence: 99%

Evidence for Decreased Brain Parenchymal Volume After Large Intracerebral Hemorrhages: a Potential Mechanism Limiting Intracranial Pressure Rises

Colbourne

2017

Transl. Stroke Res.

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Potentially fatal intracranial pressure (ICP) rises commonly occur after large intracerebral hemorrhages (ICH). We monitored ICP after infusing 100–160 μL of autologous blood (vs. 0 μL control) into the striatum of rats in order to test the validity of this common model with regard to ICP elevations. Other endpoints included body temperature, behavioral impairment, lesion volume, and edema. Also, we evaluated hippocampal CA1 sector and somatosensory cortical neuron morphology to assess whether global ischemic injury occurred. Despite massive blood infusions, ICP only modestly increased (160 μL 10.8 ± 2.1 mmHg for <36 h vs. control 3.4 ± 0.5 mmHg), with little peri-hematoma edema at 3 days. Body temperature was not affected. Behavioral deficits and tissue loss were infusion volume-dependent. There was no histological evidence of hippocampal or cortical injury, indicating that cell death was confined to the hematoma and closely surrounding tissue. Surprisingly, the most severe hemorrhages significantly increased cell density (~15–20%) and reduced cell body size (~30%) in regions outside the injury site. Additionally, decreased cell size and increased density were observed after collagenase-induced ICH. Parenchymal volume is seemingly reduced after large ICH. Thus, in addition to well-known compliance mechanisms (e.g., displacement of cerebrospinal fluid and cerebral blood), reduced brain parenchymal volume appears to limit ICP rises in rodents with very large mass lesions.

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“…Direct elemental mapping techniques include X-ray Fluorescence Microscopy (XFM), Proton Induced X-ray Emission (PIXE), Laser Ablation Inductively Coupled Plasma Mass Spectrometry (LA-ICP-MS), and Secondary Ion Mass Spectrometry (SIMS). These techniques (shown schematically in Figure 1), have enabled neuroscientists to directly study the distribution of Na + , K + , Mg 2+ , Ca 2+ , and Cl − , in situ within ex vivo tissue sections at cellular and sub-cellular spatial resolution, in conditions such as traumatic brain injury (Chwiej et al, 2011;Lozić et al, 2014), ischemic stroke (Caine et al, 2016;Pushie et al, 2018), hemorrhagic stroke (Hackett et al, 2015b;Williamson et al, 2016), schizophrenia (Lins et al, 2016), and epilepsy (Inamura et al, 1990;Ren et al, 1999;Chwiej et al, 2008;Chwiej et al, 2012a), to name a few (Figure 2). This mini-review highlights the recent applications of XFM, PIXE, LA-ICP-MS, and SIMS, to study the role of ions in healthy brain function and during disease or injury.…”

Section: Introductionmentioning

confidence: 99%

A Review of ex vivo Elemental Mapping Methods to Directly Image Changes in the Homeostasis of Diffusible Ions (Na+, K+, Mg2 +, Ca2 +, Cl–) Within Brain Tissue

et al. 2020

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Diffusible ions (Na + , K + , Mg 2+ , Ca 2+ , Cl −) are vital for healthy function of all cells, especially brain cells. Unfortunately, the diffusible nature of these ions renders them difficult to study with traditional microscopy in situ within ex vivo brain tissue sections. This mini-review examines the recent progress in the field, using direct elemental mapping techniques to study ion homeostasis during normal brain physiology and pathophysiology, through measurement of ion distribution and concentration in ex vivo brain tissue sections. The mini-review examines the advantages and limitations of specific techniques: proton induced X-ray emission (PIXE), X-ray fluorescence microscopy (XFM), secondary ion mass spectrometry (SIMS), laser-ablation inductively coupled plasma mass spectrometry (LA-ICP-MS), and the sample preparation requirements to study diffusible ions with these methods.

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Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Cited by 38 publications

References 29 publications

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Evidence for Decreased Brain Parenchymal Volume After Large Intracerebral Hemorrhages: a Potential Mechanism Limiting Intracranial Pressure Rises

A Review of ex vivo Elemental Mapping Methods to Directly Image Changes in the Homeostasis of Diffusible Ions (Na+, K+, Mg2 +, Ca2 +, Cl–) Within Brain Tissue

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Rehabilitation Augments Hematoma Clearance and Attenuates Oxidative Injury and Ion Dyshomeostasis After Brain Hemorrhage

Cited by 38 publications

References 29 publications

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E2 to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

Evidence for Decreased Brain Parenchymal Volume After Large Intracerebral Hemorrhages: a Potential Mechanism Limiting Intracranial Pressure Rises

A Review of ex vivo Elemental Mapping Methods to Directly Image Changes in the Homeostasis of Diffusible Ions (Na+, K+, Mg2 +, Ca2 +, Cl–) Within Brain Tissue

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N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice

N‐acetylcysteine targets 5 lipoxygenase‐derived, toxic lipids and can synergize with prostaglandin E₂ to inhibit ferroptosis and improve outcomes following hemorrhagic stroke in mice