Spasticity therapy reacts to astrocyte GluA1 receptor upregulation following spinal cord injury

Abstract

For almost three decades intrathecal baclofen therapy has been the standard treatment for spinal cord injury spasticity when oral medication is ineffective or produces serious side effects. Although intrathecal baclofen therapy has a good clinical benefit-risk ratio for spinal spasticity, tolerance and the life-threatening withdrawal syndrome present serious problems for its management. Now, in an experimental model of spinal cord injury spasticity, AMPA receptor blockade with NGX424(Tezampanel) has been shown to reduce stretch reflex activity alone and during tolerance to intrathecal baclofen therapy.These results stem from the observation that GluA1 receptors are overexpressed on reactive astrocytes following experimental ischaemic spinal cord injury. Although further validation is required, the appropriate choice of AMPA receptor antagonists for treatment of stretch hyperreflexia based on our recent understanding of reactive astrocyte neurobiology following spinal cord injury may lead to the development of a better adjunct clinical therapy for spasticity without the side effects of intrathecal baclofen therapy.

Figure 1

Schematic representation of the key pathophysiological mechanisms of spinal cord injury spasticity and the role of local GABAergic dis-inhibition and astrocyte GluA1 receptor over-expression below the primary lesion site (black area) within the area of secondary lesion (gray area). Disruption of descending inhibitory pathways (1) following experimental spinal cord injury leads to stretch reflex hyperreflexia (Taylor et al., 1999). Spinal cord injury may also lead to excessive muscle hyperreflexia (6) in response to both proprioceptive and cutaneous afferent input (2) following disinhibition of local GABAergic control at the pre and post synaptic site (3). Astrocyte GluA1 overexpression (4) following experimental ischaemic spinal cord inury (Hefferan et al., 2007) has now been identified as an important therapeutic target for reduction of stretch reflex activity following administration of NGX424 (Tezampanel) as monotherapy or during baclofen tolerance (Oshiro et al., 2010). However, the action of NGX424 at other synaptic sites, such as within the dorsal horn (2) or directly upon the motoneurone (5), cannot be excluded. Development of an experimental therapy capable of promoting regeneration of descending inhibitory pathways (1) while reducing glutamate receptor overexpression and reactive gliosis (4) within the injured spinal cord should be particularly effective for the management of a wide range of spasticity symptoms in the future.