In Vivo Local Administration of Para-Amino-Bebblistatin to the Injured Spinal Cord Fails to Improve the NaChBac-Expressing DRGs Transplantation

TL;DR

A drug called para-amino-blebbistatin did not improve recovery in spinal cord injury when used with transplanted neurons, despite showing promise in lab tests.

Contribution

The study shows that in vivo administration of para-amino-blebbistatin failed to enhance functional recovery despite in vitro success.

Findings

Blebbistatin and epothilone B individually increased axonal elongation in sensory neurons.

Combining NaChBac-expressing DRG transplantation with blebbistatin reduced functional recovery in vivo.

Local drug administration alone was insufficient for effective spinal cord injury treatment.

Abstract

Spinal cord injury (SCI) is a devastating, debilitating, and life-altering condition that lacks a cure or effective treatment as of today. An altered excitation/inhibition ratio after an injury, with an increase in inhibitory input, limits motor and sensory function. Together with the limited endogenous regeneration capacity of the affected neuronal circuits, this results in further loss of function. Hingorani and collaborators recently reported that transplantation of dissociated sensory neurons from neonatal dorsal root ganglia (DRGs) expressing the bacterial sodium channel NaChBac significantly improved locomotion in a severe SCI by increasing the excitatory neuronal input at the injury site. Here, we additionally target the potential axonal regeneration of endogenous and transplanted cells, using cytoskeleton-modulating drugs to enhance axonal length. We employ, alone or in combination, blebbistatin and epothilone B, tested in vitro. We found that individually, each compound significantly induced the sensory neurons’ axonal elongation; however, their combination completely abolished it. Interestingly, a combinatory treatment including the modification of DRGs to express the NaChBac sodium channel and the treatment with blebbistatin increased the axonal elongation in vitro. Nevertheless, when applied in vivo in a model of SCI, local and single para-amino-blebbistatin (a stable analogue of blebbistatin) administration and the transplanted NaChBac expressing sensory neurons limit the functional recovery enabled by neuronal transplantation alone. Thus, despite the beneficial outputs of isolated neuronal cultures that allow selection of in vivo combinatory strategies, the multifaced characteristics of CNS injuries limit the potential success of single and local treatment administration, demanding extended and sustained treatments.

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