神經毒素(resiniferatoxin)造成之週邊神經退化與4-methylcatechol促進表皮神經再生之研究

Abstract

To generate an experimental neuropathy specifically affecting small-diameter sensory nerves, we treated mice with a capsaicin analogue, resiniferatoxin (RTX), through a single intraperitoneal injection (50 μg/kg). On day 7 (D7) after RTX treatment compared to the vehicle-treated group, unmyelinated nerves of the medial plantar nerves in the RTX group showed significant degeneration with skin denervation in the corresponding territory as evidenced by a 53% reduction in unmyelinated nerve density of medial plantar nerve (p = 0.0067) and a 66% reduction in epidermal nerve density of hindpaw skin (p = 0.0004). These changes were associated with functional deficits of prolonged withdrawal latencies to heat stimuli (p = 0.0007) on a hot plate test and reduced mechanical threshold (p = 0.0001). Immunoreactive for calcitonin gene-relative peptide (CGRP) and substance P (SP) epidermal nerves were different degree depleted and those confirmed by the mild depletion of dorsal root ganglion neurons immunoreactive for CGRP (p = 0.005) and markedly depleted for SP (p = 0.0001). Large-diameter motor and sensory nerves were not affected as assayed by nerve conduction studies and sural morphometric study showed no affected on the large and small-diameter myelinated sensory nerves. We then investigated the potential therapeutic effect of 4-methylcatechol (4MC) through a daily intraperitoneal injection of 4MC (10 μg/kg) from D7 to D35 after RTX-induced neuropathy. On D35, 4MC significantly promoted regeneration of unmyelinated nerves as demonstrated by an increase in unmyelinated nerve density (p = 0.014) with an increase in the epidermal nerve density (p = 0.0013) and a reduction in the thermal withdrawal latency (p = 0.0091) compared to the RTX group. Long-term of 4MC-treated only accelerated the reinnervation of PGP 9.5 and CGRP-immunreactive epidermal fibers, with SP-immunoreactive fibers remaining dereased. These findings indicate that 4MC promoted regeneration of unmyelinated nerves and accelerated the skin reinnervtion after RTX-induced neuropathy. Moreover, 4MC also reduced the duration of loss thermal responses and the reducing the mechanical thresholds.