O-Desulfated Heparin Improves Outcome After Rat Cerebral Ischemia/Reperfusion Injury

Mocco, J; Shelton, Corbett; Sergot, Paulina; Ducruet, Andrew F.; Komotar, Ricardo J.; Otten, Marc L.; Sosunov, Sergei A.; MacArthur, Robert B.; Kennedy, Thomas P.; Connolly, E. Sander

doi:10.1227/01.neu.0000306109.55174.e6

Cited by 19 publications

(18 citation statements)

References 65 publications

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“…Current therapeutic interventions used for the early treatment of ischaemic stroke involve administration of tissue plasminogen activator (tPA, thrombolytic therapy), aspirin, dipyridamole and clopidogrel (antiplatelet therapy), and heparin, warfarin and dabigatran (anticoagulant therapy) (Mocco et al . ; Whitehead et al . ; Melani et al .…”

Section: Discussionmentioning

confidence: 99%

Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain

Ghatak

Banerjee

Sikdar

2015

The Journal of Physiology

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Key pointsr The physiological metabolite, lactate and the two-pore domain leak potassium channel, TREK1 are known neuroprotectants against cerebral ischaemia. However, it is not known whether lactate interacts with TREK1 channel to provide neuroprotection.r In this study we show that lactate increases TREK1 channel activity and hyperpolarizes CA1 stratum radiatum astrocytes in hippocampal slices.r Lactate increases open probability and decreases longer close time of the human (h)TREK1 channel in a concentration dependent manner.r Lactate interacts with histidine 328 (H328) in the carboxy terminal domain of hTREK1 channel to decrease its dwell time in the longer closed state. This interaction was dependent on the charge on H328.r Lactate-insensitive mutant H328A hTREK1 showed pH sensitivity similar to wild-type hTREK1, indicating that the effect of lactate on hTREK1 is independent of pH change.Abstract A rise in lactate concentration and the leak potassium channel TREK1 have been independently associated with cerebral ischaemia. Recent literature suggests lactate to be neuroprotective and TREK1 knockout mice show an increased sensitivity to brain and spinal cord ischaemia; however, the connecting link between the two is missing. Therefore we hypothesized that lactate might interact with TREK1 channels. In the present study, we show that lactate at ischaemic concentrations (15-30 mM) at pH 7.4 increases TREK1 current in CA1 stratum radiatum astrocytes and causes membrane hyperpolarization. We confirm the intracellular action of lactate on TREK1 in hippocampal slices using monocarboxylate transporter blockers and at single channel level in cell-free inside-out membrane patches. The intracellular effect of lactate on TREK1 is specific since other monocarboxylates such as pyruvate and acetate at pH 7.4 failed to increase TREK1 current. Deletion and point mutation experiments suggest that lactate decreases the longer close dwell time incrementally with increase in lactate concentration by interacting with the histidine residue at position 328 (H328) in the carboxy terminal domain of the TREK1 channel. The interaction of lactate with H328 is dependent on the charge on the histidine residue since isosteric mutation of H328 to glutamine did not show an increase in TREK1 channel activity with lactate. This is the first demonstration of a direct effect of lactate on ion channel activity. The action of lactate on the TREK1 channel signifies a separate neuroprotective mechanism in ischaemia since it was found to be independent of the effect of acidic pH on channel activity.S. Ghatak and A. Banerjee contributed equally to this work.

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Section: Discussionmentioning

confidence: 99%

Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain

Ghatak

Banerjee

Sikdar

2015

The Journal of Physiology

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“…Neuroprotectants are agents that antagonize, halt, or impede the molecular and biochemical events that induce ischemic damage. Numerous agents afford neuroprotection in animal models by modulating cerebral blood flow, including thrombolytics [101, 102], anti-thrombotytics [103, 104], anti-platelets [105, 106], and fibrinogen-depleting agents [107]. Hypothermia, the only widely clinically used method of neuroprotection after ischemia [108, 109]; reviewed in [110], improves cortical blood flow [111, 112], decreases neuronal activity and oxygen consumption [113], reduces free radical production [114], and reduces inflammatory signaling for neuroprotection [115].…”

Section: Synaptic Neuroprotectionmentioning

confidence: 99%

Global Cerebral Ischemia: Synaptic and Cognitive Dysfunction

Neumann¹,

Cohan²,

Dave³

et al. 2013

Current Drug Targets

111

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Cardiopulmonary arrest is one of the leading causes of death and disability, primarily occurring in the aged population. Numerous global cerebral ischemia animal models induce neuronal damage similar to cardiac arrest. These global cerebral ischemia models range from vessel occlusion to total cessation of cardiac function, both of which have allowed for the investigation of this multifaceted disease and detection of numerous agents that are neuroprotective. Synapses endure a variety of alterations after global cerebral ischemia from the resulting excitotoxicity and have been a major target for neuroprotection; however, neuroprotective agents have proven unsuccessful in clinical trials, as neurological outcomes have not displayed significant improvements in patients. A majority of these neuroprotective agents have specific neuronal targets, where the success of future neuroprotective agents may depend on non-specific targets and numerous cognitive improvements. This review focuses on the different models of global cerebral ischemia, neuronal synaptic alterations, synaptic neuroprotection and behavioral tests that can be used to determine deficits in cognitive function after global cerebral ischemia.

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“…The protective effects of heparin and its derivatives in IR injury have been evaluated in various systems including hepatic, gastrointestinal, urogenital systems and in pancreas, lungs and heart (Yagmurdur et al ., ; Mocco et al ., ; Taha et al ., ; Gedik et al ., ; Ghadie et al ., ; Warzecha et al ., ). But, no previous study has addressed the effect of heparin in the prevention of IR injury in the testes.…”

Section: Introductionmentioning

confidence: 98%

Protective role of methylprednisolone and heparin in ischaemic-reperfusion injury of the rat testicle

et al. 2015

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This study evaluated the therapeutic efficacy of heparin and methylprednisolone in the treatment of ischaemic reperfusion (IR) injury of the testis. Twenty-four male Sprague-Dawley rats were allocated equally into three groups of eight animals each. The left testes were rotated 720° for 2 h in the rats in the torsion-detorsion group. Rats in the treatment groups underwent the same surgical procedure as the torsion-detorsion group but were also given methylprednisolone (group II) or heparin (group III) by an intraperitoneal route 30 min prior to detorsion. Left orchiectomy was performed in all rats from each experimental animal at 2 h after detorsion, and the tissue was harvested for the measurement of malondialdehyde (MDA), protein carbonyl (PC) and nitric oxide (NO) and the endogenous antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase. Additional tissue was evaluated using histopathological and immunohistochemical changes. PC and MDA levels were significantly reduced in the treated groups compared to the control group. There was no statistically significant difference in NO level or SOD, GSH-Px and catalase activity among the treatment groups. Histopathological and immunohistochemical findings supported biochemical changes. It is concluded that pre-treatment with methylprednisolone or heparin protects the testis in ischaemic reperfusion injury caused by testicular torsion-detorsion.

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O-Desulfated Heparin Improves Outcome After Rat Cerebral Ischemia/Reperfusion Injury

Abstract: Our findings indicate that ODSH can be administered at a dose that provides postischemic anti-inflammatory neuroprotection without an increased risk of intracerebral hemorrhage.

Cited by 19 publications

References 65 publications

Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain

Ischaemic concentrations of lactate increase TREK1 channel activity by interacting with a single histidine residue in the carboxy terminal domain

Global Cerebral Ischemia: Synaptic and Cognitive Dysfunction

Protective role of methylprednisolone and heparin in ischaemic-reperfusion injury of the rat testicle

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