Spinal astrocyte glutamate receptor 1 overexpression after ischemic insult facilitates behavioral signs of spasticity and rigidity.
Using a rat model of ischemic paraplegia, we examined the expression of spinal AMPA receptors and their role in mediating spasticity and rigidity. Spinal ischemia was induced by transient occlusion of the descending aorta combined with systemic hypotension. Spasticity/rigidity were identified by simultaneous measurements of peripheral muscle resistance (PMR) and electromyography (EMG) before and during ankle flexion. In addition, Hoffman reflex (H-reflex) and motor evoked potentials (MEPs) were recorded from the gastrocnemius muscle. Animals were implanted with intrathecal catheters for drug delivery and injected with the AMPA receptor antagonist NGX424 (tezampanel), glutamate receptor 1 (GluR1) antisense, or vehicle. Where intrathecal vehicle had no effect, intrathecal NGX424 produced a dose-dependent suppression of PMR [ED50 of 0.44 microg (0.33-0.58)], as well as tonic and ankle flexion-evoked EMG activity. Similar suppression of MEP and H-reflex were also seen. Western blot analyses of lumbar spinal cord tissue from spastic animals showed a significant increase in GluR1 but decreased GluR2 and GluR4 proteins. Confocal and electron microscopic analyses of spinal cord sections from spastic animals revealed increased GluR1 immunoreactivity in reactive astrocytes. Selective GluR1 knockdown by intrathecal antisense treatment resulted in a potent reduction of spasticiy and rigidity and concurrent downregulation of neuronal/astrocytic GluR1 in the lumbar spinal cord. Treatment of rat astrocyte cultures with AMPA led to dose-dependent glutamate release, an effect blocked by NGX424. These data suggest that an AMPA/kainate receptor antagonist can represent a novel therapy in modulating spasticity/rigidity of spinal origin and that astrocytes may be a potential target for such treatment.
Hefferan
Michael P
MP
Anesthesiology Research Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0695, USA. mhefferan@ucsd.edu
Kucharova
Karolina
K
Kinjo
Kiyohiko
K
Kakinohana
Osamu
O
Sekerkova
Gabriella
G
Nakamura
Seiya
S
Fuchigami
Tatsuya
T
Tomori
Zoltan
Z
Yaksh
Tony L
TL
Kurtz
Neil
N
Marsala
Martin
M
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D008297:Male; D009127:Muscle Rigidity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D009128:Muscle Spasticity / Q000209:etiology / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D020760:Spinal Cord Ischemia / Q000150:complications / Q000235:genetics / Q000378:metabolism*
D018091:Receptors, AMPA