Spasticity therapy reacts to astrocyte GluA1 receptor upregulation following spinal cord injury (original) (raw)
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Journal of Neuroscience, 2007
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 [ED 50 of 0.44 g (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.
2021
Spinal cord injury (SCI) leads to severe motor and sensory functional impairments that affect personal and social behaviors. With no effective treatment, deficits in motor function are the most visible consequence of SCI. However, other complications produce a significant impact on SCI patient’s welfare. Spasticity is a neurological impairment that affects the control of muscle tone as a consequence of an insult in the central nervous system (e.g., SCI). Baclofen, a GABA agonist, is the most effective drug for spasticity treatment. This drug activates GABAB receptors decreasing the neurotransmitters release and neuronal hyperpolarization, which results in spasticity relief. Interestingly, emerging data reveals that Baclofen can also play a role on neuroprotection and regeneration after SCI. Our goal is to highlight the role of Baclofen as a potential treatment to promote recovery from SCI. We used a compression SCI mouse model with the administration of Baclofen at different time-po...
Management of Spasticity After Spinal Cord Injury: Current Techniques and Future Directions
Neurorehabilitation and Neural Repair, 2010
Spasticity, resulting in involuntary and sustained contractions of muscles, may evolve in patients with stroke, cerebral palsy, multiple sclerosis, brain injury, and spinal cord injury (SCI). The authors critically review the neural mechanisms that may contribute to spasticity after SCI and assess their likely degree of involvement and relative significance to its pathophysiology. Experimental data from patients and animal models of spasticity as well as computer simulations are evaluated. The current clinical methods used for the management of spasticity and the pharmacological actions of drugs are discussed in relation to their effects on spinal mechanisms. Critical assessment of experimental findings indicates that increased excitability of both motoneurons and interneurons plays a crucial role in pathophysiology of spasticity. New interventions, including forms of spinal electrical stimulation to suppress increased neuronal excitability, may reduce the severity of spasticity and its complications.
eNeuro
Clinical spinal cord injury (SCI) is accompanied by comorbid peripheral injury in 47% of patients. Human and animal modeling data have shown that painful peripheral injuries undermine long-term recovery of locomotion through unknown mechanisms. Peripheral nociceptive stimuli induce maladaptive synaptic plasticity in dorsal horn sensory systems through AMPA receptor (AMPAR) phosphorylation and trafficking to synapses. Here we test whether ventral horn motor neurons in rats demonstrate similar experience-dependent maladaptive plasticity below a complete SCI in vivo. Quantitative biochemistry demonstrated that intermittent nociceptive stimulation (INS) rapidly and selectively increases AMPAR subunit GluA1 serine 831 phosphorylation and localization to synapses in the injured spinal cord, while reducing synaptic GluA2. These changes predict motor dysfunction in the absence of cell death signaling, suggesting an opportunity for therapeutic reversal. Automated confocal time-course analysi...
Neurobiological perspective of spasticity as occurs after a spinal cord injury
Experimental Neurology, 2012
In this review we use the term spasticity to mean the generation of abnormal patterns of forces that are generated involuntarily. It is clear that spasticity can have both detrimental and beneficial effects on the neuromuscular system of the affected individuals. Muscle spasticity routinely occurs after a spinal cord injury and other neurological disorders. Although often studied as if there was a single mechanism associated with this phenomenon, it is clear that there are multiple mechanisms having both neural and muscular components, particularly when such terms also are applied to other neuromotor disorders. The aims of this review are to describe the neural and muscular adaptations that are associated with spasticity, highlight the major possible mechanisms producing spasticity, and discuss the role of selected pharmacological interventions in controlling spasticity. Spasticity appears to be related to altered membrane channel and receptor properties that are primarily associated with an increase in the excitability of spinal neurons, resulting in abnormal (in the intensity and combination of muscles activated) contractions that are generated involuntarily. While most of the efforts to understand the etiology of spasticity have focused on motoneurons, it is likely that spinal interneurons play a central role as well as the mechanical properties of muscle fibers and associated connective tissues. A number of pharmacological interventions have been used in attempts to suppress spasticity with varying results, but concomitant with suppressed muscle activation, there can be significant side effects including a reduction in the control of movement.
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, 2011
Two of the most prevalent secondary complications following spinal cord injury (SCI), besides loss of function and/or sensation below the level of injury, are uncontrolled muscle spasticity and hypertensive autonomic dysreflexia. Despite the desires of the SCI community, there have been few advances in the treatment and/or management of these fundamental impediments to the quality of life associated with chronic SCI. Therefore, the purpose of this review is to focus on current drug treatment strategies that alleviate symptoms of spasticity and autonomic dysfunction. Subsequently, looking ahead, we discuss whether individuals suffering from autonomic dysreflexia and/or muscle spasms can take certain compounds that specifically and rapidly block the neurotransmission of pain into the injured spinal cord to get rapid relief for both aberrant reflexes for which painful stimuli below the level of SCI are common precipitants.
Journal of Neurotrauma
Spasticity after spinal cord injury has considerable quality of life implications, impacts on rehabilitation efforts and requires long-term multidisciplinary pharmacological and nonpharmacological management. The potassium chloride co-transporter (KCC2) plays a central role in intracellular chloride homeostasis and the inhibitory function of mature neurons. Animal studies have consistently demonstrated a down-regulation of KCC2 activity following spinal cord transection, causing a shift from the inhibitory action of gamma-aminobutyric acid and glycine to an excitatory effect. Furosemide, a recognised KCC2 antagonist in animals, blocks the formation of inhibitory postsynaptic potentials in spinal motoneurons without affecting excitatory postsynaptic potentials. Based on observations in animals studies, we hypothesized that furosemide may be used to unmask KCC2 down-regulation following spinal cord injury in humans which contributes to reflex hyperexcitability. We have previously shown that furosemide reduces both presynaptic and postsynaptic inhibition in healthy subjects without altering monosynaptic excitatory transmission. These findings provide evidence that furosemide may be used in humans to evaluate inhibitory synapses in the spinal cord. In this present study, we show that furosemide fails to modulate both pre-and postsynaptic inhibitions relayed to soleus spinal motor neurons in people with spinal cord injury. The lack of furosemide effect following spinal cord injury, suggests KCC2 dysfunction in humans, resulting in reduced inhibitory synaptic transmission in spinal neurons. Our findings suggest that KCC2 dysfunction may be an important aetiological factor in hyperreflexia following spinal cord injury. These observations may pave the way to novel therapeutic strategies against spasticity centred on chloride homeostasis.