Early escitalopram administration as a preemptive treatment strategy against spasticity after contusive spinal cord injury in rats

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.

Delayed viral vector mediated delivery of neurotrophin-3 improves skilled hindlimb function and stability after thoracic contusion in rats

“…These data are consistent with previous studies following moderate thoracic contusion from a weight drop mechanism (Bose et al, 2012, Basso et al, 1995. The locomotor impairments we report were, unexpectedly, not as severe as studies which also utilised a 250 kdyn contusion at either T7 (Park et al, 2016) or T8 (Chang et al, 2019, Ryu et al, 2021 spinal level. In these studies, injured animals had limited hindlimb movement one week after injury and plateaued in recovery from week four showing the ability to perform dorsal stepping and plantar placement in stance but not weight supportive plantar stepping during movement (e.g., at BBB=9 in Chang et al 2019 versus BBB=10 in ours).…”

“…Only one animal showed noticeable spasm, clonus or otherwise abnormal activation of the hindlimbs or trunk during swimming (during one single instance) (Figure 3E) and only five animals showed presumptive spasm activity once following swimming (Figure 3F). This was unexpected as this is activity typically associated with this injury (Ryu et al, 2021).…”

The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model

“…11C, ****p , 0.0001 for first trial, *p = 0.0235 for second trial, Student's t test; Movies 5 and 6). During this time, the mutants extended hindlimbs with toes spread, which is similar to adult rats exhibiting spasticity phenotypes as a consequence of injury to upper motor neurons (Ryu et al, 2017(Ryu et al, , 2021 or neonatal V2b-ablated mice with pronounced extension of the hindlimbs and impairment of hindlimb flexion movement in the tail suspension test (Britz et al, 2015). Following this temporary spastic phenotype, prh mutants eventually started to move their hindlimbs but showed reduced frequency of alternating hindlimbs relative to WT (Fig.…”

Evidence of treating spasticity before it develops: a systematic review of spasticity outcomes in acute spinal cord injury interventional trials

“…Five of the studies investigated a single medication administered early after SCI to reduce spasticity: pentobarbital, 27 clonidine, 26 gabapentin, 25 nimodipine, and escitalopram. 22 One pharmacologic study investigated several medications: albumin (Alb), oleic acid (OA), Alb-OA, and Alb-elaidic acid. 24 Hou et al incorporated treadmill training in both of his studies, with the addition of early spinal cord magnetic stimulation in the 2020 publication.…”

“…Ryu et al 22 injected intraperitoneal escitalopram (selective serotonin reuptake inhibitor) versus saline for 28 days starting on Day 1 after SCI and measured outcomes at 3- and 4- weeks post-injury. They found a reduction of spastic behaviors during the swimming test, without significant electrophysiologic changes of the H-reflex or improved locomotor recovery.…”