Thoracic 9 Spinal Transection-Induced Model of Muscle Spasticity in the Rat: A Systematic Electrophysiological and Histopathological Characterization.

Jose A Corleto,Michael R Navarro,Oleksandr Platoshyn,Camila Santucci,Mariana Bravo-Hernández,Kota Kamizato,Martin Marsala,Osamu Kakinohana,Julian Taylor,Dasa Cizkova,Nadezda Lukacova,Michael G Fehlings

doi:10.1371/journal.pone.0144642

Abstract

The development of spinal hyper-reflexia as part of the spasticity syndrome represents one of the major complications associated with chronic spinal traumatic injury (SCI). The primary mechanism leading to progressive appearance of muscle spasticity is multimodal and may include loss of descending inhibitory tone, alteration of segmental interneuron-mediated inhibition and/or increased reflex activity to sensory input. Here, we characterized a chronic thoracic (Th 9) complete transection model of muscle spasticity in Sprague-Dawley (SD) rats. Isoflurane-anesthetized rats received a Th9 laminectomy and the spinal cord was transected using a scalpel blade. After the transection the presence of muscle spasticity quantified as stretch and cutaneous hyper-reflexia was identified and quantified as time-dependent changes in: i) ankle-rotation-evoked peripheral muscle resistance (PMR) and corresponding electromyography (EMG) activity, ii) Hoffmann reflex, and iii) EMG responses in gastrocnemius muscle after paw tactile stimulation for up to 8 months after injury. To validate the clinical relevance of this model, the treatment potency after systemic treatment with the clinically established anti-spastic agents baclofen (GABAB receptor agonist), tizanidine (α2-adrenergic agonist) and NGX424 (AMPA receptor antagonist) was also tested. During the first 3 months post spinal transection, a progressive increase in ankle rotation-evoked muscle resistance, Hoffmann reflex amplitude and increased EMG responses to peripherally applied tactile stimuli were consistently measured. These changes, indicative of the spasticity syndrome, then remained relatively stable for up to 8 months post injury. Systemic treatment with baclofen, tizanidine and NGX424 led to a significant but transient suppression of spinal hyper-reflexia. These data demonstrate that a chronic Th9 spinal transection model in adult SD rat represents a reliable experimental platform to be used in studying the pathophysiology of chronic spinal injury-induced spasticity. In addition a consistent anti-spastic effect measured after treatment with clinically effective anti-spastic agents indicate that this model can effectively be used in screening new anti-spasticity compounds or procedures aimed at modulating chronic spinal trauma-associated muscle spasticity.

Highlights

The progressive development of muscle spasticity represents a serious complication associated with chronic traumatic spinal cord injury
The ankle was rotated from a baseline position of 0° to 40° or 0° to 80° at a progressively increased velocity of ankle rotation (40, 200 and 400° /sec) and resulting changes in ankle resistance (PMR-peripheral muscle resistance) and gastrocnemius muscle activity (EMG) measured (Fig 2A and 2B)
This was expressed as ankle rotation-velocity-dependent increase in EMG and Peripheral muscle resistance (PMR) and with most pronounced and consistent spastic response measured at a 400°/sec ankle rotational velocity with the ankle rotated from 0 to 80° (Fig 2A and 2B)

Summary

Introduction

The progressive development of muscle spasticity represents a serious complication associated with chronic traumatic spinal cord injury. In addition to a progressive appearance of muscle spasticity several other qualitatively distinct neurophysiological or functionally-defined deficits including exaggerated tendon reflex or muscle clonus are frequently seen in patients with chronic spinal trauma. The presence of muscle spasticity often represents a major limiting factor in achieving a clinically relevant motor recovery in patients with incomplete spinal cord injuries even if continuing and aggressive post-injury physical rehabilitation regimen is maintained [4, 5]. As such the development of new anti-spastic therapies, in conjunction with physical rehabilitation, are critical in leading to a more effective functional recovery in incomplete spinal trauma patients

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