Fig. 2. (A) Localization of carboxymethyl lysine, receptor for advanced glycation end products, activated nuclear factor-KBp65, and interleukin-6 antigens in epineurial vessels (top), perineurium (middle), and endoneurial vessels (bottom) of sural nerve biopsies from a representative patient with diabetes mellitus and Charcot-Marie-Tooth disease (Scale bars: 100 |im). (B) Quantification of staining intensities of epineurial vessels, perineurium, and endoneurial vessels in nondiabetic (n = 8) and diabetic (n = 10) patients (mean ± SD, *p < 0.05, **p < 0.005). (C) Comparison of the staining intensity for carboxymethyl lysine and the receptor for advanced glycation end products ligand S100A8/A9 on epineurial vessels x400 ref. 36.
primary ligands (activated NF-kB, and interleukin-6) have been colocalized in the sural nerve microvasculature of patients with diabetic neuropathy (36) (Fig. 2). The formation of AGE's can be limited by inhibitors such as pyridoxamine, tenilsetam, 2, 3-diaminophenazone and aminoguanidine, or recombinant RAGE may hinder the AGE-RAGE interaction (37). However, no agents are currently in clinical trials for human diabetic neuropathy.
Oxidative stress has been implicated strongly in the pathogenesis of diabetic neuropathy in animal models (38), but to a lesser extent for somatic and autonomic diabetic neuropathy in patients (39). Benefits have been observed with a-lipoic acid (LA), a powerful antioxidant that scavenges hydroxyl radicals, superoxide and peroxyl radicals and regenerates glutathione (40). The Alpha Lipoic Acid in Diabetic Neuropathy (ALADIN) study demonstrated that 3 weeks of intravenous LA improved neuropathic symptoms (41) and in the oral pilot (ORPIL) study, oral LA improved the total symptom score and surprisingly the neuropathy disability score (42). In ALADIN-II, 5 days of intravenous LA followed by 2 years of oral treatment led to a significant improvement in sural sensory nerve conduction velocity (SNCV), sensory nerve action potential (SNAP), and tibial motor nerve conduction velocity (MNCV) but not neuropathy disability score (NDS) (43). Finally, the SYDNEY study has demonstrated a significant improvement in the neuropathy symptom score, neuropathy impairment score, and one attribute of nerve conduction after 14 (5 days/week) intravenous treatments with racemic LA (44).
A substantial body of data implicates vascular disease in the pathogenesis of diabetic neuropathy (45). Large vessel revascularization improved NCV in one study (46), prevented worsening in another study (47), but failed to show any benefit in another study (48). It was also shown to improve, but not totally correct microvascular perfusion (49). In 55 type 2 patients with diabetes, independent of traditional risk factors, systolic blood pressure and pulse pressure were related strongly to the severity of diabetic neuropathy (50). Whereas in 1172 type 1 patients with diabetes in the European Diabetes (EURODIAB) prospective complications study, apart from glycemic control, the incidence of neuropathy was associated with potentially modifiable cardiovascular risk factors, including a raised triglyceride level, body-mass index, smoking, and hypertension (51). The recent nerve biopsy studies demonstrate the early occurrence of a significant diabetic microangiopathy in patients with IGT (52) and minimal neuropathy (53) (Fig. 3). In diabetic patients it has been previously shown that resistance vessel endothelial function is worse in those with hypertension (54), but can improve markedly even with short-term treatment with an angiotensin II receptor blocker (55). Thus, in a 12-week open label dose escalation study with lisinopril, a significant improvement was observed in electrophysiology and quantitative sensory testing (56). A larger double-blind placebo-controlled clinical trial with Trandalopril showed an improvement in peroneal motor NCV, M-wave amplitude F-wave latency, and sural nerve amplitude (57). However, in the appropriate blood pressure control in diabetes trial although a significant reduction in blood pressure was achieved, neuropathy did not improve with Enalapril (58).
1,2-diacylglycerol induced activation of protein kinase C (PKC)-P, has been proposed to play a major role in diabetic neuropathy (59). Although a fall in 1,2-diacylglycerol levels and a consistent pattern of change in PKC activity has not been observed in diabetic animal models, inhibition of PKC-P in diabetic rats appears to correct reduced nerve blood flow and NCV (60). In a multinational, randomized, phase II, double-blind, placebo-controlled parallel-group trial comparing 32 mg/d or 64 mg/d of the PKC-P inhibitor ruboxistaurin with placebo for 1 year, 205 diabetic patients were enrolled. The primary analysis failed to show an improvement in VDT and NTSS-6 scores, although an improvement was seen in a posthoc analysis of patients with less severe symptomatic DPN (61). Indeed two phase II trials with ruboxistaurin have recently failed to show an improvement in symptoms, although a larger randomized double-blind placebo-controlled trial assessing an effect on neurological deficits is currently underway and is due for report in 2007.
As noted previously, abnormal lipids also appear to be important in the pathogenesis and progression of human diabetic neuropathy (51). Thus, the statins and fibrates may
well be expected to benefit the patients by reducing low-density lipoproteins and triglycerides, respectively and improving endothelial function (62). In addition statins can completely prevent AGE-induced NF-kP induced protein-1 activation and upregulation of vascular endothelial growth factor (VEGF) mRNA, in microvascular endothelial cells (63). Thus simvastatin has shown a trend toward slower progression of neuropathy assessed using vibration perception threshold, but no change in clinical neuropathy (64).
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