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.