The onset of diabetic neuropathy, a complication of diabetes mellitus, has been linked to poor glycemic control. We tested the hypothesis that the mitogen-activated protein kinases (MAPK) form transducers for the damaging effects of high glucose. In cultures of adult rat sensory neurons, high glucose activated JNK and p38 MAPK but did not result in cell damage. However, oxidative stress activated ERK and p38 MAPKs and resulted in cellular damage. In the dorsal root ganglia of streptozotocin-induced diabetic rats (a model of type I diabetes), ERK and p38 were activated at 8 wk duration, followed by activation of JNK at 12 wk duration. We report activation of JNK and increases in total levels of p38 and JNK in sural nerve of type I and II diabetic patients. These data implicate MAPKs in the etiology of diabetic neuropathy both via direct effects of glucose and via glucose-induced oxidative stress.

No abstract

This study examined the role of p38 mitogen-activated protein (MAP) kinase in transducing high glucose into deficits in nerve conduction velocity (NCV) that are characteristic of diabetic neuropathy. p38 activation and NCV were measured in streptozocin-induced diabetic rats treated with a p38 inhibitor, an aldose reductase inhibitor, and insulin. Dorsal root ganglia (DRG) from diabetic animals showed marked activation of p38 at 12 weeks of diabetes. Insulin treatment for the last 4 of 12 weeks of diabetes normalized p38 activation. Furthermore, activation was completely prevented by 12 weeks' treatment with the aldose reductase inhibitor, fidarestat. Immunocytochemistry localized activation of p38 to the nuclei of virtually all sensory neuronal phenotypes in the DRG, and activation was clear in diabetes, as was inhibition by fidarestat and by the p38 inhibitor SB 239063. In the ventral horn of the spinal cord, p38 was present in motoneuron cell bodies; and again, activation in diabetes and fidarestat inhibition was clear. Treatment of diabetic animals with a specific inhibitor of p38 (SB 239063), fidarestat, or insulin also prevented reductions in both motor and sensory NCV. These findings suggest that increased polyol pathway flux in diabetic animals leads to the activation of p38. This activation can mediate changes in gene transcription and cellular phenotype that are likely to underlie the NCV deficits. Insulin and aldose reductase inhibitors can prevent excess polyol pathway flux, and hence these agents may prevent NCV deficits by preventing p38 MAP kinase activation. Diabetes 53:1851-1856, 2004 R educed nerve conduction velocity (NCV) is an established hallmark of diabetic neuropathy, occurring in diabetes in both patients (1) and diabetic laboratory animals (2). Since the earliest demonstration (3) that aldose reductase inhibitors prevented slowing of motor NCV (MNCV) in rats with experimental diabetes, it has become a well-defined end point for the evaluation of this class of drugs. Conduction changes have also been the most responsive component of neuropathic diabetic defects in the clinic (4,5). Despite this, we have no proven link between exaggerated flux through the sorbitol pathway and the molecular basis of the conduction velocity deficit.The Diabetes Control and Complications Trial (6) has focused our attention on elevated glucose as a primary cause of diabetes complications, thus we assume that excessive glucose causes biochemical derangements that ultimately develop into diabetes complications. We have recently implicated the mitogen-activated protein (MAP) kinase p38 as a de facto glucose transducer in promoting some of the changes in neuronal phenotype caused by raised glucose. We showed consistent activation of p38 in neurons cultured with raised glucose in nerve from diabetic rats and in sural nerve specimens from diabetic patients (7). The present study was designed to test the hypothesis that nerve conduction deficits form a functional component of the downstream effects of persistent p38 ...

Background: Activation of extracellular signal-regulated protein kinase (ERK), a member of mitogen-activated protein kinase (MAPK) family, has been proposed to mediate neurite outgrowthpromoting 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.

Lateral femoral cutaneous nerve (LFCN) generally emerges from the pelvis behind the inguinal ligament (IL) to the thigh. Because of its proximity to the anterior superior iliac spine (ASIS) and hip joint, the LFCN is prone to injuries during various procedures. Anatomy of this nerve is highly variable among studies. Moreover, measurement data regarding its branches including the differences between genders and sides are still lacking. This study was, therefore, done to clarify these issues. Eighty-five thighs from 43 cadavers of both genders were dissected at the inguinal region. Distances from each branch of the LFCN to palpable landmarks: the ASIS, pubic tubercle (PT) and femoral artery (FA) were measured along the IL. Up to four branches of the LFCN were found; however, the single trunk was the most common form (>65%). The common site of this pattern on the IL was within 2 cm medial to the ASIS but could be present at over 6 cm. The distances in case of bifurcation were mostly comparable to those of the single trunk. In contrast, the values varied considerably in the cases with three or more branches (three cases). Regarding side and gender, asymmetry in the branching pattern was found in one fourth of specimens. However, only some minor differences between genders or sides in the measurement data were seen. These findings suggest that asymmetry and multiple branches of the LFCN should be concerned. The measurement data are also useful for localizing the LFCN with higher accuracy.