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p38 member of mitogen-activated protein kinase (MAPK) family has been shown to participate in neuropathic pain and axonal regeneration after nerve injury. However, its role in axotomy-induced neuronal apoptosis remains unclear. This study was aimed to examine p38 phosphorylation in the dorsal root ganglia (DRG) and its role in DRG neuronal loss after axotomy.Left sciatic nerve transection was performed in all rats. For the temporal study of p38 phosphorylation, the rats were sacrificed at 1 day, 2 weeks, and 2 months after injury. In the second experiment, the rats were divided into control and inhibitor groups receiving vehicle and p38 inhibitor (SB203580, 200 μg/kg/day intraperitoneally once daily), respectively, for 2 weeks.The p38 phosphorylation was increased in L4/5 DRG at 2 weeks after transection. Immunoreactivity of phospho-p38 was mainly observed in the cytoplasm of small neurons with additional nuclear localization in the axotomized neurons at 2 weeks. SB203580 could reduce the phosphorylation of p38 and its substrate, ATF2, including the upregulation of total caspase-3 expression in the DRG. Moreover, count of L4/5 DRG neurons revealed significantly decreased cell loss in the inhibitor than control groups (17·4% versus 32·5%).These data suggest the role of p38 in sensory neuronal loss after nerve transection. Future studies should be done to confirm the apoptotic role of p38 in this condition.

Activation of extracellular signal-regulated protein kinase (ERK), a member of the mitogen-activated protein kinase family, has been shown to mediate neurite outgrowth-promoting effects of various neurotrophic factors in vitro. Moreover, in vivo, ERK is activated in the primary sensory neurons and associated glial cells after nerve injury. However, the precise role of ERK in nerve regeneration remains unclear.This work was aimed to investigate the effects of ERK inhibition on axonal regeneration and neuronal loss after axotomy.Unilateral sciatic nerve crush was performed, and inhibition of ERK was achieved by intraperitoneal injection of 300 microg kg(-1) day(-1) of u0126 for 2 weeks in the inhibitor group. For the control group, only the vehicle was given with the same schedule.ERK was activated in the crushed sciatic nerve, and this was significantly reduced by the inhibitor. In contrast, there was no activation of ERK in the L4/L5 spinal ganglia. Morphological analysis revealed the similar extent of neuronal loss in the two groups. In addition, the mean regeneration distance in the inhibitor group was lower than that of the control group.These results suggest the crucial role of ERK in nerve regeneration but not sensory neuronal loss after trauma.

Cisplatin is used as an anti-neoplastic agent against several cancers. Neuropathy is one of its major side effects that contributes to patients' intolerance to the standard regimen. Sex-related differences have been reported in nerve injury and neuropathies. However, there has been no study on cisplatin regarding this issue.Compare various abnormalities in cisplatin neuropathy between sexes.Two mg/kg of cisplatin was administered intraperitoneally twice a week for five consecutive weeks. Body weight, heat latency of hind paw and sciatic motor nerve conduction velocity (MNCV), pathological alterations in the sciatic nerve and dorsal root ganglion (DRG) including the level of NGF in the sciatic nerve were examined. Untreated rats of both sexes were used as controls.Weight loss, prolonged heat latency, and slow MNCV in the treated rats of both sexes with higher severity in males were showed. Furthermore, reduction in myelinated fiber diameter, myelin thickness, and myelinated fiber density was more severe in females, whereas, atrophy of neuronal cell body, nucleus, and nucleolus was more striking in males. The decreased level of NGF was similar between sexes.These data suggest the differences in various aspects of cisplatin neurotoxicity between sexes. However, future studies are needed to verify this issue in a clinical condition and clarify the underlying mechanisms.

Paclitaxel, an anti-neoplastic agent effective against several solid tumors, has several side effects including peripheral neuropathy. So far, there are no effective treatments for this complication. Monosialic acid ganglioside (GM1) has been shown to protect neurons against injuries and degeneration. However, its efficacy in the treatment of paclitaxel-induced neuropathy has not been verified.To evaluate the effect of porcine GM1 on neurophysiological abnormalities in rats receiving paclitaxel.Fifty-four Wistar rats were divided into control, vehicle for paclitaxel (Cremophor EL), paclitaxel, and paclitaxel + GM1 groups. Paclitaxel 16 mg/kg/week for five consecutive weeks was given intraperitoneally. Treatment with 30 mg/kg 5 days per week of GM1 was started 3 days prior to the first dose and continued until 3 days after the last dose of paclitaxel. Tail and hind paw thermal thresholds including tail motor nerve conduction velocity (MNCV) were measured prior to and after the start of treatments. Histopathology of the sciatic nerve was also examined.Paclitaxel alone induced thermal hypoalgesia and reduced tail MNCV Less severe abnormalities were also found with the vehicle. GM1 appeared to prevent the development of hypoalgesia and ameliorated the decreased MNCV without any evidence of Guillain-Barre Syndrome. Mild endoneurial edema and axonal degeneration in the sciatic nerve sections were seen in paclitaxel treated rats. Microtubule accumulation and activated Schwann cell were also presented in the paclitaxel treated groups.These data suggest that porcine GM1 may be useful in the prevention and treatment of paclitaxel-induced neuropathy. However the adverse effect of Cremophor EL should be of concern.

Background Activation of extracellular signal-regulated protein kinase (ERK), a member of mitogen-activated protein kinase (MAPK) family, has been proposed to mediate neurite outgrowth-promoting effects of several neurotrophic factors in vitro. However, the precise activity of ERK during axonal regeneration in vivo remains unclear. Peripheral axotomy has been shown to activate ERK in the cell bodies of primary afferent neurons and associated satellite cells. Nevertheless, whether ERK is also activated in the axons and surrounded Schwann cells which also play a key role in the regeneration process has not been clarified. Results Phosphorylation of ERK in the sciatic nerve in several time-points after crush injury has been examined. Higher phosphorylation of ERK was observed in the proximal and distal nerve stumps compared to the contralateral intact nerve from one day to one month after crush. The activation of ERK was mainly localized in the axons of the proximal segments. In the distal segments, however, active ERK was predominantly found in Schwann cells forming Bungner's bands. Conclusion The findings indicate that ERK is activated in both the proximal and distal nerve stumps following nerve injury. The role of activated ERK in Wallerian degeneration and subsequent regeneration in vivo remains to be elucidated.