In this multicentre, placebo-controlled, 16-week trial, the efficacy and safety of oxcarbazepine monotherapy in patients with neuropathic pain of diabetic origin was evaluated. Eligible patients had a 6-month to 5-year history of neuropathic pain symptoms of diabetic origin and a pain rating of > or =50 units on the visual analogue scale (VAS). Oxcarbazepine was initiated at a dose of 300 mg/day and titrated to a maximum dose of 1800 mg/day. In total, 146 patients (oxcarbazepine, n=69; placebo, n=77) were randomized. After 16 weeks, oxcarbazepine-treated patients experienced a significantly larger decrease in the average change in VAS score from baseline compared with placebo (-24.3 vs. -14.7 units, respectively; p=0.01). The reduction from baseline in mean VAS score for oxcarbazepine-treated patients was of a greater magnitude than placebo as early as week 2 (-8.0 vs. -4.7; p<0.05). A significantly greater proportion of oxcarbazepine-treated patients experienced a >50% reduction from baseline in VAS score at the end of treatment compared with placebo (35.2% vs. 18.4%, respectively; p=0.0156; number needed to treat=6.0). Global assessment of therapeutic effect rating was improved in more oxcarbazepine patients than placebo patients (48% vs. 22%, respectively; p=0.0025). Patients on oxcarbazepine were awakened less frequently due to pain than patients on placebo. Most adverse events were mild to moderate in severity, transient, and in line with the known tolerability profile of oxcarbazepine. These observations suggest that oxcarbazepine monotherapy, pending additional trials, may be efficacious and may provide clinically meaningful pain relief in patients with neuropathic pain of diabetic origin.

New functions have been identi®ed for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) including its role in neurodegenerative disease and in apoptosis. GAPDH binds speci®cally to proteins implicated in the pathogenesis of a variety of neurodegenerative disorders including the b-amyloid precursor protein and the huntingtin protein.However, the pathophysiological signi®cance of such interactions is unknown. In accordance with published data, our initial results indicated there was no measurable difference in GAPDH glycolytic activity in crude whole-cell sonicates of Alzheimer's and Huntington's disease ®broblasts. However, subcellular-speci®c GAPDH±protein interactions resulting in diminution of GAPDH glycolytic activity may be disrupted or masked in whole-cell preparations. For that reason, we examined GAPDH glycolytic activity as well as GAPDH± protein distribution as a function of its subcellular localization in 12 separate cell strains. We now report evidence of an impairment of GAPDH glycolytic function in Alzheimer's and Huntington's disease subcellular fractions despite unchanged gene expression. In the postnuclear fraction, GAPDH was 27% less glycolytically active in Alzheimer's cells as compared with age-matched controls. In the nuclear fraction, de®cits of 27% and 33% in GAPDH function were observed in Alzheimer's and Huntington's disease, respectively. This evidence supports a functional role for GAPDH in neurodegenerative diseases. The possibility is considered that GAPDH : neuronal protein interaction may affect its functional diversity including energy production and as well as its role in apoptosis.

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The regulation of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has been implicated both in age-related neurodegenerative disease and in apoptosis. Previous in vitro studies suggest an interaction between GAPDH and the beta-amyloid precursor protein (beta-APP), a protein directly involved in Alzheimer's disease (AD). New studies indicate that GAPDH is a multidimensional protein with diverse membrane, cytoplasmic, and nuclear functions; each is distinct from its role in glycolysis. The nuclear functions of GAPDH include a role in apoptosis that requires its translocation to the nucleus. Accordingly, beta-APP-GAPDH interactions, altering GAPDH structure in vivo, may affect energy generation, inducing hypometabolism, a characteristic AD phenotype. Because GAPDH is a multifunctional protein, pleiotropic effects may also occur in a variety of fundamental cellular pathways in AD cells. This may include unique GAPDH-RNA interactions. We report here the identification of a high-molecular-weight (HMW) GAPDH species present exclusively in the postnuclear fraction of AD cells. The latter is characterized by reduced GAPDH activity. The HMW GAPDH species was not detected in postnuclear age-matched control (AMC) fractions nor in AD whole-cell preparations. Each is characterized by normal GAPDH activity. By definition, the preparation of whole-cell extracts entails the destruction of subcellular structure. The latter findings indicate that the dissociation of the GAPDH protein from the HMW species restores its enzymatic activity. Thus, these results reveal a new, unique intracellular phenotype in AD cells. The functional consequences of subcellular alteration in GAPDH structure in AD cells are considered.

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