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PERSPECTIVES IN PHARMACOLOGY
Department of Pharmacology and Toxicology, University of Kansas, Lawrence, Kansas
Received November 2, 2004; accepted December 14, 2004.
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Abstract |
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 Top Abstract Biochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
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1–1.7 million) or type 2 diabetes. Of serious consequence, the sensory deficits and microvascular disease of DPN foreshadow an increased likelihood of foot ulcerations and gangrenous infections that are accompanied by a 15% risk of amputation due to irreparable tissue damage. This is the second leading cause of limb amputation in the United States following accidental trauma and carries a considerable cost to both quality of life and health care economics (Feldman et al., 2003
).
The most prevalent form of DPN develops as a distal symmetric sensorimotor neuropathy that arises due to the degeneration of small sensory fibers that mediate pain/temperature sensation and large fibers that are involved primarily in proprioception/tactile sensation. Diabetic autonomic neuropathy may also accompany distal symmetric neuropathy and can disrupt many sympathetic or parasympathetic functions, leading to gastric paresis, changes in cardiac responsiveness, and genitourinary dysfunctions (Feldman et al., 2003). Diabetics often develop subclinical neuropathy that is asymptomatic but wherein nerve dysfunction is indicated by decreased peripheral nerve conduction velocity (Dyck and Dyck, 1999). The gradual progression to a clinical neuropathy may give rise to negative (painless) symptoms that include thermal hypoalgesia, loss of vibration, or pain sensation and numbness. In contrast, 10 to 20% of patients have positive (painful) symptoms, such as burning and/or lancinating pains, pins and needles, or increased touch sensation (hyperesthesia). Unfortunately, the mechanistic origin of neuropathic pain is complex and poorly understood, rendering much of the clinical management palliative.
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Biochemical Events Contributing to DPN |
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TopAbstractBiochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
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).
Both hyperglycemia and insulin deficiency initiate a rather dynamic and inter-related series of biochemical changes that contribute to the characteristic dying-back axonopathy of long myelinated fibers (Fig. 1). However, no compelling evidence has identified that this degeneration results from a single primary lesion specifically attributable to neuronal, glial, or vascular damage by hyperglycemia. Similarly, no data exists that unequivocally establish that DPN is initiated by a single biochemical event. However, attempts to order the molecular events that lead to the major metabolic alterations associated with DPN have identified oxidative stress as an initiating biochemical lesion in hyperglycemically stressed cultured endothelial cells (Nishikawa et al., 2000). Whether this same relationship exists in neurons and glia is unclear, but a growing body of evidence does support a central role for oxidative stress in the apoptosis of peripheral neurons and glia in diabetes. A critical role of oxidative stress in the physiological progression of DPN is also underscored by the efficacy of antioxidant therapies such as 
-lipoic acid (Vincent et al., 2004). Nevertheless, other metabolic abnormalities arising from the production of advanced glycation end products, protein kinase C activation, and increased flux of glucose through the polyol and hexosamine pathways clearly contribute to DPN. Finally, changes in neurotrophic support of neurons and glia also contribute to the axonopathy associated with DPN. The vital role of altered neurotrophism in influencing the balance between neuronal degeneration/regeneration in DPN has been recently emphasized in a comprehensive literature assessment (Leinninger et al., 2004). Therefore, to minimize reiteration and frame the issue of altered growth factor signaling as it relates to Schwann cell function in DPN, we provide a only brief synopsis of some of the salient literature related to altered neurotrophism in neurons.
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Altered Neurotrophism in DPN |
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TopAbstractBiochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
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). The decreased availability of neurotrophins and altered production of other growth factors such as insulin-like growth factor 1 (IGF-1), glial-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor have led to the hypothesis that treating animals with these proteins may alleviate some of the clinical symptoms of DPN. This strategy is also supported by electrophysiological studies that demonstrated the simultaneous presence of degenerating and regenerating nerve fibers in DPN, indicating that DPN is a highly dynamic and progressive dying-back neuropathy that does not occur in a temporally simultaneous fashion (Apfel, 1999). Concurrent with good glycemic control, growth factor therapy may be highly efficacious in minimizing initial damage or subsequent reinjury in regenerating cells early in disease progression when the state of degeneration/regeneration is more dynamic (Fig. 1). To this end, administration of NGF, IGF-1, or GDNF have all proven effective in alleviating both behavioral and biochemical measures of sensory neuropathy in diabetic rats and/or mice (Leinninger et al., 2004). These outcomes provided a compelling rationale for pursuing the clinical assessment of neurotrophic factor treatment in human DPN. GDNF is currently in clinical trials for managing some neurodegenerative diseases, and NGF therapy has traversed both phase II and phase III trials in treating DPN. Paradoxically, although phase II trials of recombinant human NGF in treating DPN revealed some relief of the sensory deficits of distal sensorimotor neuropathy, no significant differences emerged in a large phase III clinical trial that quantified multiple measures of sensory deficits between patients receiving placebo versus recombinant human NGF. Although multiple factors may have contributed to the failure of the phase III trial (Apfel, 2002), some of the limited success in the clinical trials of NGF therapy for DPN is attributed to our poor understanding of how diabetes-induced changes in the neuronal or glial proteome may alter the predicted response to growth factor administration. For example, recent evidence indicates that doses of insulin or IGF-1 that are insufficient to improve hyperglycemia can reverse some of the biochemical (Huang et al., 2003) and morphological (Brussee et al., 2004) changes in DPN through direct action on neurons. Since insulin resistance is a common feature in type 2 diabetics, these data suggest that increased insulin resistance in neurons (altered neurotrophism) may also directly contribute to the development of DPN in conjunction with the overlying episodes of hyperglycemia in these patients (Brussee et al., 2004). Therefore, to aid in predicting cellular responses to growth factors and enhancing their potential clinical effectiveness in DPN, it is important to determine whether diabetes alters normal signal transduction events in neurons and glia.
As is evident from the brief discussion above, considerable attention has been given to examining sensory nerve function in diabetes in response to growth factors. However, neurons are often interdependent on Schwann cells (SCs), which also undergo substantial degenerative changes in DPN and respond to many of the aforementioned growth factors. For example, IGF-1 rescues SCs from hyperglycemia-induced apoptosis (Delaney et al., 1999) and regulates SC motility (Cheng et al., 2000), a critical feature in re-establishing axonglial interactions. Neuregulins (NRGs) are a family of gliotrophic factors that transduce signals through Erb B receptor tyrosine kinases and are necessary for SC growth, survival, and differentiation (Adlkofer and Lai, 2000). Intriguingly, recent evidence also supports that altered neuregulin signaling may also induce the dedifferentiation of mature myelinated SCs and contribute to the development of peripheral neuropathies.
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Neuregulins and Erb B in Peripheral Neuropathies |
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TopAbstractBiochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
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). NRGs are membrane-bound and soluble EGF-like ligands comprised of four subfamilies (NRG1–4) whose diversity is enhanced by alternative splicing and differential promoter usage (Adlkofer and Lai, 2000). Neuregulins bind with high affinity to either Erb B3 or Erb B4, which form a kinase-active heterodimer with Erb B2. However, Erb B3 does not possess an intrinsic tyrosine kinase activity but undergoes trans-phosphorylation by Erb B2 upon heterodimerization.
Recent evidence indicates that Erb B family members are differentially expressed on the soma of small, medium, and large neurons of the dorsal root ganglion (Pearson and Carroll, 2004), but the functional role of this expression remains to be determined. In contrast, the cell biology of neuregulins in SC function is better characterized and directly relates to the regulation of cell proliferation, survival, and differentiation. Erb B2 is highly expressed in SCs of neonatal nerve but decreases during myelination, leading to a comparatively lower level of expression in the adult; however, levels of the high-affinity Erb B3 receptor remain relatively unchanged during SC development (Grinspan et al., 1996). Importantly, Erb B2 and Erb B3 levels can change in response to injury and influence SC responsiveness to autocrine or axon-derived neuregulins (Carroll et al., 1997).
Neuregulin Signaling in the Control of Myelination and Demyelination
Precursor SCs depend upon NRG-1 and Erb B2/B3 for maturation, proliferation, and survival since genetic deletion of nrg1, erbB2, or erbB3 resulted in a severe depletion of SC precursors (Garratt et al., 2000). Neuregulins also promote the survival of committed, axon-associated SCs (Syroid et al., 1996) and the early events of myelination (Garratt et al., 2000). Indeed, recent genetic studies provide strong evidence that axonally derived NRG1-type III is critical in regulating myelin sheath thickness (Michailov et al., 2004). Increased myelination was specific for the NRG1-type III isoform since transgenic overexpression of NRG1-type 1 did not change myelin thickness (Michailov et al., 2004). Since DPN is partly associated with demyelination of sensory and motor neurons, it will be important to determine whether the decreased expression of NRG1-type III in sensory axons may be associated with myelin degeneration and/or a decreased rate of remyelination in diabetes.
Distinct from the promyelinating effect of NRG1-type III, several lines of evidence indicate that the neuregulin/Erb B2 ligand-receptor pair can also induce SC dedifferentiation. Transgenic overexpression of NRG1-type II
3 (also called glial growth factor) specifically in SCs led to a demyelinating hypertrophic neuropathy that resulted in hindlimb paralysis (Huijbregts et al., 2003). Similarly, glial growth factor, but not fibroblast growth factor-2, induced substantial demyelination of fully myelinated SC/sensory neuron cocultures (Zanazzi et al., 2001). Demyelination was not dependent upon re-entry into the cell cycle, but dedifferentiated SCs gradually began to reproliferate. Finally, the targeted expression of a dominant-negative Erb B4 in nonmyelinating SCs induced a progressive small-fiber neuropathy. Altered neuregulin signaling induced by transgenic expression of the dominant-negative Erb B4 did not change sensitivity to mechanical stimuli but induced a thermal hypoalgesia (Chen et al., 2003). Thermal sensitivity is mediated in large part by C-fibers, and the thermal hypoalgesia correlated with a decrease in GDNF levels, which supports neuron survival in a specific subpopulation of C-fibers. Interestingly, Erb B signaling may provide a prosurvival signal in adult nonmyelinating SCs since the rate of apoptosis was also increased by the expression of the dominant-negative Erb B4 (Chen et al., 2003). Whether altered neuregulin signaling may contribute to minimizing the extent of SC apoptosis observed in DPN warrants examination. Collectively, these data provide compelling genetic and pharmacological support that altering the expression/activity of elements of the neuregulin/Erb B ligand-receptor pair is sufficient to alter the balance between regeneration and degeneration of both myelinating and non-myelinating adult SCs and induce the onset of peripheral neuropathies outside the context of diabetes.
Erb B-Dependent Signaling Cascades and the Regulation of SC Differentiation
Neuregulin-induced formation of Erb B heterodimers links these receptors to downstream signaling cascades that can have both a negative and positive impact upon SC differentiation. Tyrosine phosphorylation of Erb B heterodimers couples these receptors to activation of p42/p44 mitogen-activated protein kinase (MAPK) and phosphatidylinositol-3-kinase (PtdIns 3K). Although p42/p44 MAPK and PtdIns 3K are central to promoting SC survival, their effect on cell proliferation and differentiation vary depending upon the developmental stage of the SCs or the presence of axons (Maurel and Salzer, 2000). In this regard, activation of PtdIns 3K is critical to the progression from an immature SC phenotype to the promyelinating stage and the expression of myelin protein markers (Maurel and Salzer, 2000; Ogata et al., 2004). Conversely, activation of the p42/p44 MAPK pathway may have an inhibitory effect on myelination since the expression of a constitutively active MAPK kinase 1 in SCs increased the phosphorylation of p42/p44 MAPK and was sufficient to inhibit the forskolin-induced up-regulation of myelin-associated glycoprotein, a myelin marker protein (Ogata et al., 2004). Consistent with these results, tamoxifen-induced activation of raf-1 (MAPK kinase kinase) in myelinated SC/sensory neuron cocultures also increased SC dedifferentiation and the loss of myelin proteins (Harrisingh et al., 2004). SC dedifferentiation did not seem to involve activation of PtdIns 3K since pharmacologic or molecular inhibition of this lipid kinase did not prevent NRG1-induced demyelination of myelinated SC/sensory neuron cocultures (Harrisingh et al., 2004). Zanazzi et al. (2001) have also observed that treating myelinated SC/sensory neuron cocultures with glial growth factor induced extensive demyelination, but these authors observed a greater increase in PtdIns 3K activity than MAPK activity. Although the above discussion paints a rather complicated picture of the effect of neuregulins and downstream signaling events in regulating myelination, these data support the notion that the balance between p42/p44 MAPK and PtdIns 3K activity may have a significant effect on SC function in diabetes. Since p42/p44 MAPK is substantially activated in diabetic nerve (Purves et al., 2001), neuregulin-induced activation of the p42/p44 MAPK pathway may inhibit myelination and induce SC dedifferentiation in vivo.
Given the critical role of neuregulins in SC function, it is surprising that little effort has been directed toward examining the effect of hyperglycemia on the response of SCs to neuregulins or ascertained whether diabetes alters the level of neuregulins and Erb B family members in peripheral nerve or dorsal root ganglia. Recent data from our lab using immunofluorescent analysis for phospho-Erb B2 in SCs showed a very low level of activity in control nerve, consistent with previous results (Grinspan et al., 1996). In contrast, the intensity of phospho-Erb B2 immunostaining was significantly enhanced (>2-fold) in mice rendered diabetic for 8 weeks and strongly attenuated toward control levels following 2 weeks of insulin therapy (S. Rouen and R. T. Dobrowsky, unpublished observations). Although the mechanism by which Erb B2 activity may be affected in diabetes is unknown, it is clear that changes in the expression of proteins that differentially affect the activation of Erb B2 or its coupling to either MAPK or PtdIns 3K would be expected to have a marked impact on the contribution of neuregulin signaling in promoting myelination and/or demyelination. One such protein that is highly expressed in SCs and whose interaction with Erb B2 may affect its activity and coupling to downstream mediators is caveolin-1 (Cav-1).
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Caveolin-1 in Schwann Cell Function and DPN |
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TopAbstractBiochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
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). Thus, Cav-1 and -2 are coexpressed in many cells, whereas the expression of caveolin-3 is restricted primarily to muscle.
Despite extensive study, the exact function of Cav-1 and related family members in cell biology remains uncertain. This is especially the case for SCs since no direct function of Cav-1 has been identified. It is clear that Cav-1 serves a required structural role in the morphologic formation of caveolae since mice deficient in Cav-1 expression lack caveolae (Razani et al., 2001). The high level of Cav-1 expression in SCs (Mikol et al., 1999) would be consistent with recent morphological evidence that supports the presence of caveolae in myelinated SCs (Meier et al., 2004).
The formation of caveolae by Cav-1 is associated with the propensity of the protein to form oligomers and strongly bind cholesterol. Indeed, Cav-1 gene expression is responsive to changes in cellular cholesterol levels via two sterol regulatory elements in its promoter. Although Cav-1 serves as an integral membrane protein in the formation of caveolae, it can have a strong cytosolic localization in cells actively involved in sterol metabolism. This atypical localization is due to its role in transporting newly synthesized cholesterol in a vesicle-independent manner complexed with chaperones such as cyclophilins, heat shock protein 56 (Uittenbogaard et al., 1998), and annexin II (Uittenbogaard et al., 2002). Cholesterol comprises about 25% of myelin lipid, and SCs derive all their cholesterol for myelination from de novo synthesis (Jurevics and Morell, 1995). Facilitating cholesterol transport would be consistent with the presence of a cytosolic pool of Cav-1 in SCs (Mikol et al., 1999) and increased Cav-1 expression during periods of active myelination in vivo (Mikol et al., 2002). Furthermore, Cav-1 also strongly colocalizes with staining for myelin basic protein, a marker of myelinating SCs, suggesting a tight association of Cav-1 with myelination (Fig. 2A). However, it is important to note that Cav-1 is not necessarily essential for cholesterol shuttling but can facilitate both cholesterol influx and efflux (Fielding and Fielding, 2000). Whether Cav-1 has a functional role in regulating myelination via cholesterol shuttling or otherwise awaits further analysis of the Cav-1 knockout mice.
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Altered Cav-1 Expression in Diabetic Nerve
STZ is a glucose analog that induces diabetes in rats and mice by decreasing pancreatic -cell mass. The resulting loss of insulin secretion induced by STZ provides a well characterized animal model for type 1 diabetes. Importantly, insulin replacement can help normalize blood glucose levels and reverse many of the pathophysiological changes that arise from prolonged hyperglycemia induced by STZ.
Since myelinated SCs can undergo substantial degeneration in diabetes, we hypothesized that Cav-1 expression may be altered by hyperglycemia. In the control nerve (Fig. 2B), Cav-1 immunoreactivity (green) is evident surrounding many axons identified by their positive staining for neurofilament (red). Following 9 weeks of STZ-induced diabetes, Cav-1 expression in SCs of rat sciatic nerve decreased dramatically but maintained an intense abaxonal staining in limited regions of the nerve. This may represent residual Cav-1 that remains colocalized with myelinated axons. On the other hand, the phenotypic change in Cav-1 localization mimics the profile reported for increased glial fibrillary acidic protein expression, a marker for nonmyelinating SCs, following nerve transection (Cheng and Zochodne, 2002). Whether these areas of Cav-1 immunoreactivity represent dedifferentiated glial fibrillary acidic protein-positive SCs in the process of re-entering myelination awaits a more definitive assessment. Importantly, the decline in Cav-1 expression was not a consequence of apoptosis since staining for the SC marker S100 revealed no substantial loss of SCs (Tan et al., 2003).
The association of prolonged hyperglycemia with decreased Cav-1 expression raises the issue of whether this is a direct or indirect effect of hyperglycemia. However, 2 weeks of insulin therapy strongly attenuated Cav-1 down-regulation implicating hyperglycemia, as opposed to nonspecific effects of STZ toxicity, as a primary event in decreasing Cav-1 expression (Tan et al., 2003). Alternatively, since STZ-treated animals are insulin-deficient, decreased Cav-1 expression may be a consequence of insulin deficiency. Arguing against this possibility, incubation of primary SCs in 20 to 40 mM glucose inhibited transcription from the Cav-1 promoter and decreased Cav-1 mRNA synthesis and protein expression. The ability to recapitulate the effect of hyperglycemia on Cav-1 expression in cultured primary SCs suggests that hyperglycemia, and not insulin deficiency per se, may be a sufficient primary effector in regulating Cav-1 expression in vivo.
Cav-1 is expressed in numerous cell types in peripheral nerve, but it is important to note that diabetes did not decrease Cav-1 expression in endoneurial blood vessels or the perineurial membrane of sciatic nerve (Tan et al., 2003). Similarly, axotomy also strongly down-regulated the expression of Cav-1 in SCs but had little effect on Cav-1 expression in blood vessels or the perineurium (Mikol et al., 2002). These observations suggest that the effect of diabetes on Cav-1 expression may have a very cell-specific basis. Indeed, 12 weeks of STZ-induced diabetes increased Cav-1 expression 1.9-fold in caveolae purified from lung endothelium using cationic colloidal silica (Bucci et al., 2004). The increased expression of Cav-1 in lung endothelium correlated with an increase in morphologically definable caveolae and enhanced trans-endothelial transport (Pascariu et al., 2004). Cav-1 expression was also increased in aortic endothelium of nonobese diabetic mice, a genetic model for type 1 diabetes (Bucci et al., 2004). The authors speculated that increased Cav-1 may inhibit endogenous endothelial nitric-oxide synthase (eNOS) activity and contribute to the decreased release of nitric oxide in type 1 diabetics (Bucci et al., 2004). This relationship is of potential physiological relevance since analysis of the Cav-1 knockout mice clearly supports the contention that this protein serves as a physiological regulator of eNOS; a marked phenotype of these animals relates to vascular abnormalities and increased microvascular permeability due to hyperactivation of eNOS (Razani et al., 2001).
Putative Roles of Altered Cav-1 Expression in Regulating Erb B2 Signaling in Diabetes
The well characterized inhibitory interaction of Cav-1 with eNOS provides an example of how Cav-1 may serve as a scaffolding protein that regulates signal transduction complexes within caveolae. Along this line, changes in the expression of Cav-1 may influence neuregulin signaling through its ability to bind directly to Erb B2 and inhibit the intrinsic tyrosine kinase activity of this receptor (Engelman et al., 1998). Given the critical role of Erb B2 signaling in SC biology, we have begun to examine the effect of hyperglycemia and Cav-1 down-regulation on neuregulin signaling. Either hyperglycemia or forced down-regulation of Cav-1 was sufficient to increase neuregulin-induced thymidine uptake in primary SCs. Since Cav-1 down-regulation was associated with prolonged Erb B2 tyrosine phosphorylation (Tan et al., 2003), we hypothesized that changes in Cav-1 expression may alter downstream components of neuregulin signaling through Erb B2. Indeed, expression of a Cav-1 antisense adenovirus in SCs increased the magnitude and prolonged the activation Erb B2 and the PtdIns 3K/Akt pathway but not the p42/p44 MAPK pathway (C. Yu and R. T. Dobrowsky, unpublished observations). Recent evidence in endothelia cells also supports this hypothesis since stimulation of primary endothelial cells with vascular endothelial growth factor following Cav-1 down-regulation by siRNA resulted in enhanced activation of the PtdIns 3K/Akt pathway with little effect on the MAPK pathway (Gonzalez et al., 2004). These studies provide proof-of-concept that altering Cav-1 expression can differentially affect the coupling of growth factors to downstream signaling pathways.
As discussed in the previous sections, strong genetic evidence clearly supports a potential physiological role of altered neuregulin signaling in contributing to peripheral neuropathies independent of diabetes. Although results from the diabetic animal models support the idea that prolonged hyperglycemia leads to a decrease in Cav-1 expression that correlates with an increase in Erb B2 phosphorylation in vivo, the relationship between these events in contributing to SC degeneration and DPN remains unclear. However, the available data have led us to develop a working model for the putative relationship between Cav-1 and Erb B2 in contributing to an altered neuregulinism in the progression of DPN (Fig. 3). Clearly, the progressive down-regulation of Cav-1 in SCs is a consequence of both metabolic (Tan et al., 2003) and physical (Mikol et al., 2002) insults to peripheral nerve. In vitro data indicate that the gradual loss of Cav-1 expression may remove an inhibitory regulation of endogenous Erb B2 and contribute to an increase in its tyrosine kinase activity. Prolonged activation of Erb B2 in myelinated SCs from axon-supplied neuregulin may lead to activation of the PtdIns 3K and/or MAPK pathways. The differential ability of these pathways to decrease or increase expression of myelin proteins at specific developmental stages of the SCs may contribute to the highly dynamic degeneration/regeneration of myelinated axons in DPN.
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Summary and Conclusions |
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TopAbstractBiochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
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Although the role of both neuregulins and Cav-1 in DPN is unknown, intensive analysis of the Cav-1 knockout animals has not identified Cav-1 as the monogenic cause of any specific disease. On the other hand, the data strongly indicate that decreases in Cav-1 may have cell-specific effects on insulin receptor expression and cell signaling events relevant to both cardiovascular disease and diabetes (Cohen et al., 2003). Comparing the effect of diabetes between wild-type and Cav-1-null animals on rates of myelination/demyelination, Erb B2 activation, and the onset of sensory deficits in diabetes will provide genetic insight into the potential role of this protein in affecting sensory dysfunction in DPN. Similarly, use of primary SCs from the Cav-1-null animals will prove valuable in assessing the sufficiency and necessity of this protein in regulating neuregulin signaling and affecting the expression of myelin proteins. Although caves are gloomy upon entry, spelunking into SC caveolae may shed light on enhancing the effectiveness of existing and novel growth factor therapies in the difficult therapeutic management of DPN.
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: DPN, diabetic peripheral neuropathy; NGF, nerve growth factor; STZ, streptozotocin; IGF, insulin-like growth factor; GDNF, glial cell-derived neurotrophic factor; SC, Schwann cell; NRG, neuregulin; EGF, epidermal growth factor; MAPK, mitogen-activated protein kinase; PtdIns 3K, phosphatidylinositol 3 kinase; Cav, caveolin; eNOS, endothelial nitric-oxide synthase.
Address correspondence to. Dr. Rick T. Dobrowsky, Department of Pharmacology and Toxicology, University of Kansas, 5064 Malott Hall, 1251 Wescoe Hall Dr., Lawrence, KS 66045. E-mail: dobrowsky{at}ku.edu
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References |
|---|
|
TopAbstractBiochemical Events Contributing...Altered Neurotrophism in DPNNeuregulins and Erb B...Caveolin-1 in Schwann Cell...Summary and ConclusionsReferences |
|---|
Adlkofer K and Lai C (2000) Role of neuregulins in glial cell development. Glia 29: 104–111.[CrossRef][Medline]
Apfel SC (1999) Nerve regeneration in diabetic neuropathy. Diabetes Obes Metab 1: 3–11.[CrossRef][Medline]
Apfel SC (2002) Nerve growth factor for the treatment of diabetic neuropathy: what went wrong, what went right, and what does the future hold? Int Rev Neurobiol 50: 393–412.[Medline]
Brussee V, Cunningham FA, and Zochodne DW (2004) Direct insulin signaling of neurons reverses diabetic neuropathy. Diabetes 53: 1824–1830.
Bucci M, Roviezzo F, Brancaleone V, Lin MI, Di Lorenzo A, Cicala C, Pinto A, Sessa WC, Farneti S, Fiorucci S, et al. (2004) Diabetic mouse angiopathy is linked to progressive sympathetic receptor deletion coupled to an enhanced caveolin-1 expression. Arterioscler Thromb Vasc Biol 24: 721–726.
Carroll SL, Miller ML, Frohnert PW, Kim SS, and Corbett JA (1997) Expression of neuregulins and their receptors, Erb B2 and Erb B3, is induced during Wallerian degeneration. J Neurosci 17: 1642–1659.
Chen S, Rio C, Ji RR, Dikkes P, Coggeshall RE, Woolf CJ, and Corfas G (2003) Disruption of ErbB receptor signaling in adult non-myelinating Schwann cells causes progressive sensory loss. Nat Neurosci 6: 1186–1193.[CrossRef][Medline]
Cheng C and Zochodne DW (2002) In vivo proliferation, migration and phenotypic changes of Schwann cells in the presence of myelinated fibers. Neuroscience 115: 321–329.[CrossRef][Medline]
Cheng HL, Steinway ML, Russell JW, and Feldman EL (2000) GTPases and phosphatidylinositol 3-kinase are critical for insulin-like growth factor-I-mediated Schwann cell motility. J Biol Chem 275: 27197–27204.
Cohen AW, Razani B, Wang XB, Combs TP, Williams TM, Scherer PE, and Lisanti MP (2003) Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. 285: C222–C235.
Delaney CL, Cheng HL, and Feldman EL (1999) Insulin-like growth factor-I prevents caspase-mediated apoptosis in Schwann cells. J Neurobiol 41: 540–548.[CrossRef][Medline]
Dyck PJB and Dyck PJ (1999) Diabetic polyneuropathy, in Diabetic Neuropathy (Dyck PJ and Thomas A eds) pp 255–278, W. B. Saunders, Philadelphia.
Engelman JA, Lee RJ, Karnezis A, Bearss DJ, Webster M, Siegel P, Muller WJ, Windle JJ, Pestell RG, and Lisanti MP (1998) Reciprocal regulation of neu tyrosine kinase activity and caveolin-1 protein expression in vitro and in vivo. Implications for human breast cancer. J Biol Chem 273: 20448–20455.
Feldman EL, Stevens MJ, Russell JW, and Greene DA (2003) Somatosensory neuropathy, in Diabetes Mellitus (Porte DS, Sherwin RS, and Baron A eds) pp 771–788, McGraw-Hill, New York.
Fielding CJ and Fielding PE (2000) Cholesterol and caveolae: structural and functional relationships. Biochim Biophys Acta 1529: 210–222.[Medline]
Garratt AN, Voiculescu O, Topilko P, Charnay P, and Birchmeier C (2000) A dual role of erbB2 in myelination and in expansion of the Schwann cell precursor pool. J Cell Biol 148: 1035–1046.
Gonzalez E, Nagiel A, Lin AJ, Golan DE, and Michel T (2004) siRNA-mediated down-regulation of caveolin-1 differentially modulates signaling pathways in endothelial cells. J Biol Chem 279: 40659–40669.
Grinspan JB, Marchionni MA, Reeves M, Coulaloglou M, and Scherer SS (1996) Axonal interactions regulate Schwann cell apoptosis in developing peripheral nerve: neuregulin receptors and the role of neuregulins. J Neurosci 16: 6107–6118.
Harrisingh MC, Perez-Nadales E, Parkinson DB, Malcolm DS, Mudge AW, and Lloyd AC (2004) The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO (Eur Mol Biol Org) J 23: 3061–3071.
Hellweg R, Raivich G, Hartung HD, Hock C, and Kreutzberg GW (1994) Axonal transport of endogenous nerve growth factor (NGF) and NGF receptor in experimental diabetic neuropathy. Exp Neurol 130: 24–30.[CrossRef][Medline]
Huang TJ, Price SA, Chilton L, Calcutt NA, Tomlinson DR, Verkhratsky A, and Fernyhough P (2003) Insulin prevents depolarization of the mitochondrial inner membrane in sensory neurons of type 1 diabetic rats in the presence of sustained hyperglycemia. Diabetes 52: 2129–2136.
Huijbregts RPH, Roth KA, Schmidt RE, and Carroll SL (2003) Hypertrophic neuropathies and malignant peripheral nerve sheath tumors in transgenic mice overexpressing glial growth factor 3 in myelinating Schwann cells. J Neurosci 23: 7269–7280.
Jurevics H and Morell P (1995) Cholesterol for synthesis of myelin is made locally, not imported into brain. J Neurochem 64: 895–901.[Medline]
Leinninger GM, Vincent AM, and Feldman EL (2004) The role of growth factors in diabetic peripheral neuropathy. J Peripher Nerv Syst 9: 26–53.[CrossRef][Medline]
Maurel P and Salzer JL (2000) Axonal regulation of Schwann cell proliferation and survival and the initial events of myelination requires PI 3-kinase activity. J Neurosci 20: 4635–4645.
Meier C, Dermietzel R, Davidson KGV, Yasumura T, and Rash JE (2004) Connexin 32-containing gap junctions in Schwann cells at the internodal zone of partial myelin compaction and in Schmidt-Lanterman incisures. J Neurosci 24: 3186–3198.
Michailov GV, Sereda MW, Brinkmann BG, Fischer TM, Haug B, Birchmeier C, Role L, Lai C, Schwab MH, and Nave KA (2004) Axonal neuregulin-1 regulates myelin sheath thickness. Science (Wash DC) 304: 700–703.
Mikol DD, Hong HL, Cheng HL, and Feldman EL (1999) Caveolin-1 expression in Schwann cells. Glia 27: 39–52.[CrossRef][Medline]
Mikol DD, Scherer SS, Duckett SJ, Hong HL, and Feldman EL (2002) Schwann cell caveolin-1 expression increases during myelination and decreases after axotomy. Glia 38: 191–199.[CrossRef][Medline]
Nishikawa T, Edelstein D, Du XL, Yamagishi S, Matsumura T, Kaneda Y, Yorek MA, Beebe D, Oates PJ, Hammes HP, et al. (2000) Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemic damage. Nature (Lond) 404: 787–790.[CrossRef][Medline]
Ogata T, Iijima S, Hoshikawa S, Miura T, Yamamoto S, Oda H, Nakamura K, and Tanaka S (2004) Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination. J Neurosci 24: 6724–6732.
Pascariu M, Bendayan M, and Ghitescu L (2004) Correlated endothelial caveolin overexpression and increased transcytosis in experimental diabetes. J Histochem Cytochem 52: 65–76.
Pearson RJ Jr and Carroll SL (2004) ErbB transmembrane tyrosine kinase receptors are expressed by sensory and motor neurons projecting into sciatic nerve. J Histochem Cytochem 52: 1299–1311.
Pinkas-Kramarski R, Shelly M, Guarino BC, Wang LM, Lyass L, Alroy I, Alimandi M, Kuo A, Moyer JD, Lavi S, et al. (1998) ErbB tyrosine kinases and the two neuregulin families constitute a ligand-receptor network. Mol Cell Biol 18: 6090–6101.
Purves TD, Middlemas A, Agthong S, Jude EB, Boulton AJM, Fernyhough P, and Tomlinson DR (2001) A role for mitogen-activated protein kinases in the etiology of diabetic neuropathy. FASEB J 15: 2508–2514.
Razani B, Engelman JA, Wang XB, Schubert W, Zhang XL, Marks CB, Macaluso F, Russell RG, Li M, Pestell RG, et al. (2001) Caveolin-1 null mice are viable but show evidence of hyperproliferative and vascular abnormalities. J Biol Chem 276: 38121–38138.
Syroid DE, Maycox PR, Burrola PG, Liu N, Wen D, Lee KF, Lemke G, and Kilpatrick TJ (1996) Cell death in the Schwann cell lineage and its regulation by neuregulin. Proc Natl Acad Sci 93: 9229–9234.
Tan W, Rouen S, Barkus KM, Dremina YS, Hui D, Christianson JA, Wright DE, Yoon SO, and Dobrowsky RT (2003) Nerve growth factor blocks the glucose-induced downregulation of caveolin-1 expression in Schwann cells via p75 neurotrophin receptor signaling. J Biol Chem 278: 23151–23162.
The Diabetes Control and Complications Trial Research Group (1995) The effect of intensive diabetes therapy on the development and progression of neuropathy. Ann Intern Med 122: 561–568.
Uittenbogaard A, Everson WV, Matveev SV, and Smart EJ (2002) Cholesteryl ester is transported from caveolae to internal membranes as part of a caveolin-annexin II lipid-protein complex. J Biol Chem 277: 4925–4931.
Uittenbogaard A, Ying Y, and Smart EJ (1998) Characterization of a cytosolic heat-shock protein-caveolin chaperone complex. J Biol Chem 273: 6525–6532.
Vincent AM, Russell JW, Low P, and Feldman EL (2004) Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev 25: 612–628.
Zanazzi G, Einheber S, Westreich R, Hannocks MJ, Bedell-Hogan D, Marchionni MA, and Salzer JL (2001) Glial growth factor/neuregulin inhibits Schwann cell myelination and induces demyelination. J Cell Biol 152: 1289–1299.
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