title: AC105 Increases Extracellular Magnesium Delivery and Reduces Excitotoxic Glutamate Exposure within Injured Spinal Cords in Rats.
abstract: Magnesium (Mg2+) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg2+contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg2+supplementation have been reported in many animal models. Recent studies found that lower Mg2+doses also improved neurologic outcomes when Mg2+was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg2+formulation might increase Mg2+delivery to the injured spinal cord, compared with that of MgSO4alone. Here, we assessed spinal extracellular Mg2+and glutamate levels following SCI in rats using microdialysis. Basal levels of extracellular Mg2+(∼0.5 mM) were significantly reduced to 0.15 mM in the core and 0.12 mM in the rostral peri-lesion area after SCI. A single intravenous infusion of saline or of MgSO4at 192 μmoL/kg did not significantly change extracellular Mg2+concentrations. However, a single infusion of AC105 (a MgCl2in PEG) at an equimolar Mg2+dose significantly increased the Mg2+concentration to 0.3 mM (core area) and 0.25 mM (rostral peri-lesion area). Moreover, multiple AC105 treatments completely restored the depleted extracellular Mg2+concentrations after SCI to levels in the uninjured spinal cord. Repeated MgSO4infusions slightly increased the Mg2+concentrations while saline infusion had no effect. In addition, AC105 treatment significantly reduced extracellular glutamate levels in the lesion center after SCI. These results indicate that intravenous infusion of PEG-formulated Mg2+normalized the Mg2+homeostasis following SCI and reduced potentially neurotoxic glutamate levels, consistent with a neuroprotective mechanism of blocking excitotoxicity.
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Zhihong
authors: Z
authors: Huang
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Zoran
authors: Z
authors: Filipovic
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Nandakumar
authors: N
authors: Mp
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Chia
authors: C
authors: Ung
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Erika L
authors: EL
authors: Troy
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Raymond W
authors: RW
authors: Colburn
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Jennifer F
authors: JF
authors: Iaci
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Craig
authors: C
authors: Hackett
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Donald C
authors: DC
authors: Button
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Anthony O
authors: AO
authors: Caggiano
authors: Acorda Therapeutics, Inc. , Ardsley, New York.
authors: Tom J
authors: TJ
authors: Parry
mesh_terms: D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D018690:Excitatory Amino Acid Agonists; D045604:Extracellular Fluid / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018698:Glutamic Acid / Q000378:metabolism*; D007262:Infusions, Intravenous; D008278:Magnesium Sulfate / Q000008:administration & dosage* / Q000378:metabolism; D017551:Microdialysis / Q000379:methods; D011092:Polyethylene Glycols / Q000008:administration & dosage* / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D013119:Spinal Cord Injuries / Q000188:drug therapy / Q000378:metabolism*; D013904:Thoracic Vertebrae
chemical_list: D018690:Excitatory Amino Acid Agonists; D018698:Glutamic Acid; D011092:Polyethylene Glycols; D008278:Magnesium Sulfate
keywords: magnesium; microdialysis; polyethylene glycol; rat; spinal cord injury