Over past several years, the importance of vascular vs nonvascular mechanisms in the pathogenesis of PDN remained a subject of debate. The key role of reduced NBF and resulting endoneurial hypoxia in diabetes-associated nerve conduction deficit appears to be supported by the findings with a variety of vasodilators; for example, the ^-adrenoceptor antagonist prazosin (20), the K(ATP) channel openers, celikalim and WAY135201 (21), the AT-converting enzyme (ACE) inhibitor enalapril, and the AT II receptor antagonist L158809 (7). In author's study (20), prazosin prevented diabetes-induced neurovascular dysfunction and MNCV deficit, without counteracting accumulation of sorbitol pathway intermediates, depletion of myo-inositol and taurine, downregulation of Na, K-ATPase activity, and enhanced lipid peroxidation in the peripheral nerve. Therefore, none of these neurochemical changes appears to be of critical importance for the development of nerve conduction slowing in, at least, short-term diabetes. However, it is unclear whether the aforementioned and other vasodilators can affect peripheral nerve metabolism and conduction independent from their vasodilator properties (see the information on lisinopril and salbutamol provided on page 70).
The vascular concept of PDN is seemingly supported by the recent findings with the high molecular weight metal chelator, hydroxy ethyl starch-deferoxamine (HESD), known to be confined to vascular space when administered intravenously and therefore, not to penetrate into neural elements of the peripheral nerve. Alleviation of both NBF and nerve conduction deficits (22,23), combined with reduced superoxide and peroxyni-trite formation in vasa nervorum (23), in HESD-treated streptozotocin (STZ)-diabetic rats in comparison with the corresponding untreated group could be interpreted as a proof for the key role of vascular mechanism in MNCV and SNCV deficit in early diabetes. However, it is not excluded that in vascular space, HESD is metabolized with formation of deferoxamine, with its subsequent delivery to a neural compartment of the peripheral nerve. In addition, such reactive oxygen species (ROS) as hydrogen peroxide, lipid peroxide (free form), and peroxynitrite can move from vascular to nonvascular space, and alleviation of oxidative stress in one nerve compartment will automatically diminish ROS abundance in others. The role of NBF in early PDN is also seemingly supported by the studies with the endothelial nitric oxide synthase inhibitor NG-nitro-L-arginine (L-NNA). Cotreatment with L-NNA abolished the effects of pharmacological agents, i.e., vasodilators, antioxidants, AR inhibitors (ARIs), and so on, on both NBF and nerve conduction velocity (5). However, the spectrum of pharmacological effects of L-NNA is not studied to the extent that would allow to exclude adverse effects on MNCV and SNCV through some unidentified mechanism.
The neurochemical consequences of nerve ischemia in the peripheral nerve have not been studied in detail. Retinal response to ischemia involves a compensatory upregula-tion of several neurotrophic factors partially protecting retinal neurons from the lack of oxygen and nutrients (24). Correspondingly, administration of neurotrophic factors to rats with experimental PDN prevents nerve conduction slowing, without counteracting a decrease in NBF. This phenomenon has been observed with neurotrophin-3, brain-derived neurotrophic factor as well as prosaposin (16). Furthermore, the most recent study by Calcutt et al. (25) demonstrated that treatment of diabetic rats with a sonic hedgehog-IgG fusion protein (1) ameliorated retrograde transport of nerve growth factor (NGF) increased sciatic nerve concentrations of calcitonin-gene related product and neuropeptide Y, (2) restored normal MNCV and SNCV, and (3) maintained the axonal caliber of large myelinated fibers.
These beneficial effects have been observed in the absence of any improvement in NBF. The importance of neurochemical mechanisms in diabetes-associated nerve conduction deficits, energy failure, and abnormal sensation and pain is also supported by several other reports (26-29). In the study (26), the PARP inhibitor PJ34 caused only a modest 17% increase of NBF, but essentially normalized nerve energy state and completely reversed diabetes-induced MNCV and SNCV deficits. Therefore, a complete normalization of NBF is not required for correction of MNCV or SNCV in diabetic rats. Furthermore, in the recent low-dose PARP inhibitor-containing combination therapy study (27), two combination therapies, i.e., the PARP inhibitor 1,5-isoquinolinediol (ISO) plus the ACE inhibitor lisinopril and ISO plus the P2-adrenoceptor agonist salbutamol equally efficiently counteracted diabetes-associated neurovascular dysfunction, but only ISO plus salbutamol corrected MNCV deficit, whereas the effect of ISO plus lisinopril was statistically nonsignificant. Thus, correction of NBF is insufficient for correction of MNCV deficit. Note that both lisinopril and salbutamol have signal transduction and metabolic effects that could be completely independent of vasodilator properties of these agents. Lisinopril acts as a weak antioxidant (30) and nitric oxide scavenger (31). The spectrum of pharmacological effects of salbutamol is even more impressive: the agent inhibits expression of intercellular adhesion molecule-1, CD-40, and CD-14 (32) as well as eicosanoid biosynthesis (33), increases intracellular cyclic adenosine monophosphate concentration, cyclic adenosine monophosphate-dependent PKA, adenylyl cyclase, phosphatase PP2A and L-type Ca2+ channel activities, modulates G protein signaling (34), and stimulates pentose phosphate pathway (35). At least, several of these effects might account for better MNCV response to ISO plus salbutamol in comparison with ISO plus lisinopril treatment.
The most impressive evidence for dissociation of NBF and nerve conduction changes has recently been generated in two studies in animal models of type 2 diabetes (28,29). In type 2 BBZDR/Wor rats, neurovascular defects were not accompanied by sensory nerve conduction slowing or hyperalgesia (28). Furthermore, in type 2 Zucker diabetic fatty rats development of motor nerve conduction deficit at 12-14 weeks of age markedly preceded decrease in sciatic endoneurial nutritive blood flow (at 24-28 weeks of age ). In contrast, in Zucker rats with impaired glucose tolerance, but absent fasting hyperglycemia (a model of the initial stage of type 2 diabetes) neurovascular dysfunction developed earlier than motor nerve conduction deficit (at 24-28 weeks of age and 32 weeks of age, respectively ).
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