Proliferative effects of melatonin on Schwann cells: implication for nerve regeneration following peripheral nerve injury

Abstract

Activation of proliferation of Schwann cells is crucial for axonal guidance and successful nerve regeneration following peripheral nerve injury (PNI). Considering melatonin plays an important role in proliferative regulation of central glial cells, the present study determined whether melatonin can effectively promote Schwann cell proliferation and improve nerve regeneration after PNI. The spontaneous immortalized rat Schwann cell line (RSC 96 cells) was first analyzed by quantitative polymerase chain reaction (QPCR) to detect the potential existence of melatonin receptors. The melatonin receptor-mediated signaling responsible for proliferation was examined by measuring the phosphorylation of extracellular signal-regulated kinases (ERK1/2) pathway. The in vivo model of PNI was performed by the end-to-side neurorrhaphy. The quantity of Schwann cells as well as the number of re-innervated motor end plates (MEP) on target muscles was examined to represent the functional recovery of injured nerves. QPCR results indicated that MT1 is the dominant receptor in Schwann cells. Immunoblotting and proliferation assay revealed an enhanced phosphorylation of ERK1/2 and increased number of RSC 96 cells following melatonin administration. Nonselective melatonin receptor antagonist (luzindole) treatment significantly suppressed all the above findings, suggesting that the proliferative effects of melatonin were mediated by a receptor-dependent pathway. In vivo results corresponded well with in vitro findings in which melatonin effectively increased the amount of proliferated Schwann cells and re-innervated MEP on target muscles following PNI. As melatonin successfully improves nerve regeneration by promoting Schwann cell proliferation, therapeutic use of melatonin may thus serve as a promising strategy to counteract the PNI-induced neuronal disability.

Melatonin and its therapeutic actions on peripheral nerve regeneration

“…It has been suggested that correct re-innervation of the neuromuscular junctions, rather than collateral axonal branching at the lesion site, may be the critical limiting factor for recovery of function after peripheral nerve injury [17]. Chang et al [7] recently demonstrated that re-innervated motor end plates (as labelled by PGP 9.5 and a-bungarotoxin) following peripheral nerve injury was much higher in the animals receiving melatonin treatment when compared to that of saline-treated ones.…”

“…However, the clinical in vitro and in vivo conditions following peripheral nerve injury and improved nerve regeneration [7]. The increased expression of Schwann cells induced by melatonin was clearly expressed by cell counting and the proliferative assay in spontaneous immortalised rat Schwann cell line derived from long-term culture of rat primary Schwann cells (RSC 96 cells) as well as by quantitative bromodeoxyuridine (BrdU) immunostaining and S-100β immunoexpressions in the lesioned nerves [7].…”

“…The proliferative effect of melatonin on Schwann cells has further been demonstrated to be mediated by MT1 receptor-dependent phosphorylation of extracellular signal-regulated kinases (ERK1/2) pathway [7,28]. Increased ERK1/2 activation would transmit signals into perikarya of the nerve for transcriptional regulation of genes related to Schwann cell differentiation and proliferation [54,62].…”

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“…and exogenous MLT is effective as a direct and indirect antioxidant. [12][13][14][15][16] Wallerian degeneration, also known as anterograde or orthograde degeneration, occurs after axonal injury in both the PNS and the CNS. Axonal degeneration is followed by degradation of the myelin sheath (►Fig.…”

“…Their results indicated that therapeutic use of MLT could be a promising strategy for counteracting PNI-induced neuronal disability. 14 Furthermore, some studies have shown the effect of MLT via surgical removal of the pineal gland, called pinealectomy (Px).…”