Effects of Clobetasol in an Aging Mouse Model of Spinal Cord Hemisection

TL;DR

Clobetasol, a steroid, worsened recovery in old mice with spinal cord injuries, reducing nerve connections and suppressing helpful immune responses.

Contribution

This study is the first to investigate clobetasol's effects on spinal cord injury recovery in aged mice.

Findings

Clobetasol-treated mice showed worse motor performance than untreated mice.

Clobetasol reduced synaptic density and suppressed microglia/macrophage responses.

The drug exacerbated synaptic loss and functional deficits in aged animals.

Abstract

Spinal cord injury causes permanent damage to the nerves that control sensory and motor functions, leaving people with severe disability. Recovery after such an injury is very limited, and this problem becomes even worse with aging, when the brain and spinal cord lose much of their ability to repair themselves. Scientists have been testing drugs that might boost the natural capacity of nerve cells to grow and make new connections. One such drug is clobetasol, a strong anti-inflammatory steroid that has also been suggested to activate a pathway important for nerve repair. In this study, clobetasol has been tested in old mice with a spinal cord injury. The results show that animals treated with clobetasol did not recover better than untreated animals. In fact, they performed worse in movement tests. Examination of the spinal cord tissue showed fewer nerve connections in the treated animals, while the usual immune response to injury was strongly reduced. These results suggest that, in older individuals, clobetasol may suppress helpful processes that support recovery, leading to worse outcomes. These findings underline the importance of including the effects of aging in the research for potential treatments of spinal cord injury.

Spinal cord injury leads to permanent neurological deficits, and aging further diminishes the plasticity and regenerative responses required for recovery. Activation of the Sonic hedgehog (Shh) pathway through the receptor Smoothened (Smo) has been proposed as a potential strategy to promote repair, and clobetasol, a potent glucocorticoid, has been identified as a pharmacological Smo agonist. However, the possible restorative effect of Smo agonists has never been studied during aging. Here, the effects of clobetasol treatment have been investigated in aging mice following spinal cord hemisection. Animals received weekly systemic injections of clobetasol or vehicle and were monitored for 11 weeks using the Basso Mouse Scale and open field test, followed by post-mortem histological analysis. Vehicle-treated mice exhibited a modest spontaneous recovery of locomotor function, whereas clobetasol-treated mice failed to improve and displayed significantly worse motor performance. Histological evaluation revealed reduced synaptic density in clobetasol-treated mice. Moreover, microglia/macrophage reaction was increased in vehicle-treated injured mice but suppressed by clobetasol, consistent with glucocorticoid-mediated inhibition of inflammatory responses. Together, these findings indicate that in aged animals clobetasol administration does not enhance plasticity or promote recovery but instead exacerbates synaptic loss and functional deficits. These results underscore the importance of age as a determinant of therapeutic efficacy after spinal cord injury.

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