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The Journal of Neuroscience, October 17, 2007, 27(42):11179-11191; doi:10.1523/JNEUROSCI.0989-07.2007

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Cellular/Molecular
Spinal Astrocyte Glutamate Receptor 1 Overexpression after Ischemic Insult Facilitates Behavioral Signs of Spasticity and Rigidity

Michael P. Hefferan,¹ Karolina Kucharova,^1,4 Kiyohiko Kinjo,¹ Osamu Kakinohana,¹ Gabriella Sekerkova,² Seiya Nakamura,^1,3 Tatsuya Fuchigami,^1,3 Zoltan Tomori,⁵ Tony L. Yaksh,¹ Neil Kurtz,⁶ and Martin Marsala^1,4

¹Anesthesiology Research Laboratory, Department of Anesthesiology, University of California, San Diego, La Jolla, California 92093-0695, ²Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60208, ³Department of Anesthesiology, University of the Ryukyus, Okinawa, Japan 903-0213, Institutes of ⁴Neurobiology and ⁵Experimental Physics, Slovak Academy of Sciences, 04001 Kosice, Slovakia, and ⁶TorreyPines Therapeutics, La Jolla, California 92037

Correspondence should be addressed to Dr. Michael P. Hefferan, Anesthesiology Research Laboratory, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0695. Email: mhefferan{at}ucsd.edu

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 µg (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.

Key words: ischemia; spinal cord injury; astrocytes; AMPA receptor; spasticity; rigidity

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Received Jan. 24, 2006; revised June 27, 2007; accepted June 28, 2007.

Correspondence should be addressed to Dr. Michael P. Hefferan, Anesthesiology Research Laboratory, Department of Anesthesiology, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0695. Email: mhefferan{at}ucsd.edu

This article has been cited by other articles:

				S. Codeluppi, C. I. Svensson, M. P. Hefferan, F. Valencia, M. D. Silldorff, M. Oshiro, M. Marsala, and E. B. Pasquale The Rheb-mTOR Pathway Is Upregulated in Reactive Astrocytes of the Injured Spinal Cord J. Neurosci., January 28, 2009; 29(4): 1093 - 1104. [Abstract] [Full Text] [PDF]

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