Abstract:

Spinal ventral root injury leads to significant loss of motor function due to the inefficient

axon regeneration and severe atrophy of target muscle. Pharmacological methods present

a valuable and clinically feasible strategy for promoting regeneration following injury. Here,

we propose two small peptides, ISP and PAP4, which promote regeneration by inhibiting

chondroitin sulfate proteoglycans (CSPG) and phosphatase and tensin homolog (PTEN),

respectively. CSPGs, the dominant suppressors of axonal regeneration in scar tissue,

exert an inhibitory effect via neuronal receptors such as protein tyrosine phosphatase-σ

(PTPσ). It has previously been verified that ISP can modulate PTPσ to reduce the inhibitory

effect of CSPGs. It is well established that PI3K/AKT signaling pathway exerts a positive

role in axon regeneration. Conversely, PTEN acts as a negative regulator of this pathway,

inhibiting the regeneration of axons. PTEN antagonist peptides (in particular PAP4) can

promote descending serotonergic fibers growth and corticospinal fiber sprouting in the

rostral spinal cord following SCI. In this study, we demonstrate that ISP and PAP treatment

can remarkably improve motor function recovery following a spinal ventral root crush

surgery. Peptide-treated animals showed increased motoneuron survival, a greater number

of regenerated axons, healthier neuromuscular junctions and enhanced potentiated

electrical responses in motor units. Our study suggests that ISP and PAP4 present a novel

pharmacological method for accelerating motor functional recovery after peripheral nerve

injury.