Systemic administration of an antagonist of the ATP-sensitive receptor P2X7 improves recovery after spinal cord injury.
Traumatic spinal cord injury is characterized by an immediate, irreversible loss of tissue at the lesion site, as well as a secondary expansion of tissue damage over time. Although secondary injury should, in principle, be preventable, no effective treatment options currently exist for patients with acute spinal cord injury (SCI). Excessive release of ATP by the traumatized tissue, followed by activation of high-affinity P2X7 receptors, has previously been implicated in secondary injury, but no clinically relevant strategy by which to antagonize P2X7 receptors has yet, to the best of our knowledge, been reported. Here we have tested the neuroprotective effects of a systemically administered P2X7R antagonist, Brilliant blue G (BBG), in a weight-drop model of thoracic SCI in rats. Administration of BBG 15 min after injury reduced spinal cord anatomic damage and improved motor recovery without evident toxicity. Moreover, BBG treatment directly reduced local activation of astrocytes and microglia, as well as neutrophil infiltration. These observations suggest that BBG not only protected spinal cord neurons from purinergic excitotoxicity, but also reduced local inflammatory responses. Importantly, BBG is a derivative of a commonly used blue food color (FD&C blue No. 1), which crosses the blood-brain barrier. Systemic administration of BBG may thus comprise a readily feasible approach by which to treat traumatic SCI in humans.
Peng
Weiguo
W
Department of Neurosurgery, Division of Glial Disease and Therapeutics, Center for Translational Neuromedicine, University of Rochester Medical Center, Rochester, NY 14642, USA.
Cotrina
Maria L
ML
Han
Xiaoning
X
Yu
Hongmei
H
Bekar
Lane
L
Blum
Livnat
L
Takano
Takahiro
T
Tian
Guo-Feng
GF
Goldman
Steven A
SA
Nedergaard
Maiken
M
D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D004195:Disease Models, Animal; D006801:Humans; D007202:Indicators and Reagents / Q000008:administration & dosage / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D058919:Purinergic P2 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D018048:Receptors, Purinergic P2 / Q000378:metabolism; D058486:Receptors, Purinergic P2X7; D020127:Recovery of Function / Q000187:drug effects; D012394:Rosaniline Dyes / Q000008:administration & dosage / Q000494:pharmacology*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
D007202:Indicators and Reagents; D018696:Neuroprotective Agents; C546468:P2RX7 protein, human; D058919:Purinergic P2 Receptor Antagonists; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7; D012394:Rosaniline Dyes; D000255:Adenosine Triphosphate; C004692:coomassie Brilliant Blue