Abstract
In the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia. Among various pathological conditions underlying spasticity, upregulated expression of 5-HT receptors (5-HTR) on the spinal motor neurons due to 5-HT denervation is considered one of crucial factors for hyperexcitability of the spinal circuit. As a 5-HT signal modulator, selective serotonin re-uptake inhibitors (SSRIs) are ordinarily prescribed for diseases associated with 5-HT in the CNS, and are known for their ability to increase 5-HT levels as well as to desensitize 5-HTR. Here, we hypothesized that early SSRI administration as a preemptive treatment strategy would effectively prevent the onset of spasticity. We used a rat model of contusive SCI and administered escitalopram during the first 4 weeks after injury, which is the period required for spasticity development in rodent models. We performed a swimming test to quantify spastic behaviors and conducted the Hoffman reflex test as well as histological analyses for 5-HT2AR and KCC2 expressions. Four weeks of escitalopram administration suppressed spastic behaviors during the swimming test and reduced the population of spasticity-strong rats. Moreover, the treatment resulted in decreased immunoreactivity of 5-HT2AR in the spinal motor neurons. Result of the H-reflex test and membrane expression of KCC2 were not significantly altered. In summary, early escitalopram administration could prevent the onset of spastic behaviors via regulation of 5-HT system after SCI, but could not modulate exaggerated spinal reflex. Our results suggest a novel application of SSRIs for preventative treatment of spasticity.
Highlights
In the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia
We found that four weeks of escitalopram administration in a rat model of contusive SCI could prevent the onset of spastic behaviors during the swimming test which examined from 3 weeks after the injury
We examined the effect of early administration of escitalopram for 4 weeks post-injury on spasticity using a contusive SCI rat model
Summary
In the majority of spinal cord injury (SCI) patients, spasticity develops in the subacute phase and chronically persists with muscle hypertonia. Because reduced 5-HT activity in the brain is known as one of the pathological mechanisms leading to depression[21], antidepressants are aimed at restoring 5-HT levels as well as at the proper activation of 5-HT receptors[22] Among these drugs, selective serotonin re-uptake inhibitors (SSRIs) are frequently prescribed; they are known to modify the 5-HT system by both elevating 5-HT concentration via blocking the 5-HT transporter (SERT) and decreasing the sensitivity of 5-HT r eceptors[23,24]. We hypothesized that the upregulation of 5-HT receptors and spastic symptoms may be suppressed by an increase in the 5-HT concentration at the injury site via SSRI administration in the early stages of SCI.
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