Characterization of a planar cyclic form of water hexamer in an organic supramolecular complex: an unusual self-assembly of bimesityl-3,3'-dicarboxylic acid.
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Journal Article↗
Biomedical subjects
R Natarajan
Publications and source records attributed to R Natarajan.
Helical self-assembly of substituted benzoic acids: influence of weaker X...X and C-H...X interactions.
The X-ray crystal packing analyses of the sterically encumbered halogen-substituted benzene carboxylic acids 1-4 reveal a novel and unprecedented crystal packing in that the association of the carboxyl groups through O-H...O bonds results in the generation of a helix along the 41-screw axis. Such an organization of the acids is shown convincingly to be a result of the close packing, which exploits the weaker X...X and C-H...X interactions in conjunction with the stronger O-H...O hydrogen bonds. In contrast, the chloro- and bromo-substituted durene carboxylic acids 6 and 7 exhibit a pattern that is akin to tape/ribbon involving the centrosymmetric-dimer motif and X...X short intermolecular interactions. The structural investigations demonstrate the ability of the weaker interactions in modifying the supposedly "robust" centrosymmetric-dimer motif of the carboxyl groups in a decisive manner.
Journal Article↗
Role of 12-lipoxygenase and oxidant stress in hyperglycaemia-induced acceleration of atherosclerosis in a diabetic pig model.
AIMS/HYPOTHESIS: We previously showed that vascular smooth muscle cells and endothelial cells cultured under high glucose conditions produced more 12(S)-hydroxyeicosatetraenoic acid (12-HETE), the 12-lipoxygenase (12-LO) product of arachidonate metabolism, relative to normal glucose. Because the lipoxygenase (LO) pathway has been associated with oxidant stress and the pathogenesis of atherosclerosis, we now examined 12-LO activation in vivo in a pig model of diabetes-induced accelerated atherosclerosis which displays human characteristics. METHODS: The animal model was developed in pigs who were fed a normal or high fat diet and given streptozotocin injections to produce normolipemic-normoglycaemic (NLNG), normolipemic-hyperglycaemic (NLHG), hyperlipemic-normoglycaemic (HLNG) and hyperlipemic-hyperglycaemic (HLHG) pigs. Tissue samples were obtained from key arterial beds to examine 12-LO expression at 20 weeks after the pigs began their diet. RESULTS: All HG pigs maintained threefold higher serum glucose concentrations. The HL groups developed atherosclerosis but diabetic HLHG pigs showed markedly accelerated atherosclerosis (twofold) relative to non-diabetic HLNG pigs. Immunostaining showed progressive increases in 12-LO in arteries in the order NLNG, NLHG, HLNG and HLHG. Leukocyte-type 12-LO protein (immuno-blotting) as well as mRNA expression (by competitive PCR) in abdominal and coronary arteries were significantly greater in HLHG pigs than in all the other three groups. Furthermore, increased oxidant stress was observed in monocytes from NLHG and HLNG pigs, and greatly potentiated in HLHG pigs. CONCLUSIONS/INTERPRETATION: These results are consistent with the hypothesis that 12-LO activation plays a key role in accelerated atherosclerosis due to diabetes and hyperlipemia.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Efficient photocyclization of o-alkylbenzaldehydes in the solid state: direct observation of E-xylylenols en route to benzocyclobutenols.
The photocyclization to benzocyclobutenols of o-alkyl aromatic aldehydes that are predestined for gamma-hydrogen abstraction is found to occur efficiently in the solid state; in contrast, solution-phase photolysis is known to afford a mixture of several products. It is shown that mesitaldehyde, which is a liquid, also undergoes efficient cyclization when subjected to photolysis as a solid inclusion complex. The marginal energy differences in the relative energies of the E-enols and the corresponding cyclobutenols in the case of cyano-substituted mesitaldehydes has permitted direct observation, for the first time, of the E-enols en route to benzocyclobutenols. The AM1 calculations suggest that the cyano-substitution causes intrinsic stabilization of the E-enols relative to the corresponding cyclobutenols, while the bromo groups do the opposite. The lack of observation of the red color in bromo- and formyl-substituted aldehydes is attributed to rapid cyclization of the E-enols to the their respective cyclobutenols even at low temperatures.
Journal Article↗
Catalytic consumption of nitric oxide by 12/15- lipoxygenase: inhibition of monocyte soluble guanylate cyclase activation.
12/15-Lipoxygenase (LOX) activity is elevated in vascular diseases associated with impaired nitric oxide (( small middle dot)NO) bioactivity, such as hypertension and atherosclerosis. In this study, primary porcine monocytes expressing 12/15-LOX, rat A10 smooth muscle cells transfected with murine 12/15-LOX, and purified porcine 12/15-LOX all consumed *NO in the presence of lipid substrate. Suppression of LOX diene conjugation by *NO was also found, although the lipid product profile was unchanged. *NO consumption by porcine monocytes was inhibited by the LOX inhibitor, eicosatetraynoic acid. Rates of arachidonate (AA)- or linoleate (LA)-dependent *NO depletion by porcine monocytes (2.68 +/- 0.03 nmol x min(-1) x 10(6) cells(-1) and 1.5 +/- 0.25 nmol x min(-1) x 10(6) cells(-1), respectively) were several-fold greater than rates of *NO generation by cytokine-activated macrophages (0.1-0.2 nmol x min(-1) x 10(6) cells(-1)) and LA-dependent *NO consumption by primary porcine monocytes inhibited *NO activation of soluble guanylate cyclase. These data indicate that catalytic *NO consumption by 12/15-LOX modulates monocyte *NO signaling and suggest that LOXs may contribute to vascular dysfunction not only by the bioactivity of their lipid products, but also by serving as catalytic sinks for *NO in the vasculature.
Animals↗
Cloning of the human cholesteryl ester hydrolase promoter: identification of functional peroxisomal proliferator-activated receptor responsive elements.
Cholesteryl ester hydrolase (CEH) is responsible for hydrolysis of stored cholesterol esters in macrophage foam cells and release of free cholesterol for high-density lipoprotein-mediated efflux. PCR-based screening of human genomic libraries with human macrophage CEH specific primers resulted in amplification and cloning of 1.7 kb promoter sequence. Analysis of the sequence revealed a lack of consensus TATA-box but presence of a GC-rich proximal sequence, a CAAT box and several binding sites for the transcription factor Sp1. Three putative response elements for peroxisome proliferator-activated receptor (PPRE) were identified at position -176, -779, and -1316. Down-regulation of promoter activity was observed in the presence of either PPARalpha- or PPARgamma-specific ligands and introduction of a 4-point transverse mutation in the PPRE at -176 completely abolished the effect of PPAR ligands on the promoter activity. Analogous to other genes involved in macrophage cholesterol homeostasis, human CEH may also be regulated by PPAR.
Amino Acid Sequence↗
Nitric oxide suppresses IL-8 transcription by inhibiting c-Jun N-terminal kinase-induced AP-1 activation.
The role of activator protein-1 (AP-1) in tumor necrosis factor-alpha (TNF-alpha)-induced interleukin-8 (IL-8) gene expression was evaluated. We showed that TNF-alpha activates AP-1 in the transformed endothelial cell line ECV304 by transient transfections of IL-8 promoter construct pGL-3BF(2). Mutation of either the AP-1 site or the NF-IL-6 site on the IL-8 promoter suppressed the TNF-alpha-induced activation, suggesting cooperation between these transcription factors and transcription factor NF-kappaB. Overexpression of dominant negative mutants of c-Jun suppressed AP-1-driven transcription of the IL-8 promoter following stimulation by TNF-alpha, suggesting that cooperative interaction between AP-1 and NF-kappaB is essential for IL-8 transcription in the presence of TNF-alpha. We also showed that nitric oxide (NO), in the form of an exogenous NO donor, suppressed the level of activation of the AP-1 subunit, c-Jun, by down-regulation of c-Jun NH2 terminal kinase. This down-regulation could be the putative mechanism of action for NO-mediated inhibition of IL-8 secretion in activated endothelium. These observations suggest for the first time that NO has broad suppressive activities on various proinflammatory effectors in activated endothelium.
CCAAT-Enhancer-Binding Protein-beta↗
Solid-state photochromism and photoreactivity of o- and p-anisaldehydes. Remarkable stabilization of o-xylylenols.
[reaction: see text] All of the crystalline o-anisaldehyde derivatives 1 and 3 change to brick-red color upon brief exposure to UV-vis radiation. The red color, attributed to (E)-xylylenol, is remarkably persistent for hours (ca. 10 h) in the case of 1c; such a long lifetime for the reactive o-xylylenols is unprecedented. In contrast, the p-anisaldehydes 2 undergo cyclization. Solid-state photolysis of 2b affords the benzocyclobutenol 7b regioselectively, which is not accessible from solution-phase photolysis.
Journal Article↗
Effect of endplate conditions and bone mineral density on the compressive strength of the graft-endplate interface in anterior cervical spine fusion.
STUDY DESIGN: Destructive compression tests and finite element analyses were conducted to investigate the biomechanical strength at the graft-endplate interface in anterior cervical fusion. OBJECTIVES: To investigate the effect of endplate thickness, endplate holes, and bone mineral density of the vertebral body on the biomechanical strength of the endplate-graft interface in an anterior interbody fusion of the cervical spine. SUMMARY OF BACKGROUND: Subsidence of the graft into the vertebral body is a well-known complication in anterior cervical fusion. However, there is no information in the literature regarding the compressive strength of the graft-endplate interface in relation to the endplate thickness, holes in the endplate, and bone mineral density of the vertebral body. METHODS: Biomechanical destructive compression tests and finite element analyses were performed in this study. Cervical vertebral bodies (C3-C7) isolated from seven cadaveric cervical spines (age at death 69-86 years, mean 79 years) were used for compression tests. Bone mineral density of each vertebral body was measured using a dual energy radiograph absorptiometry unit. Endplate thickness was measured using three coronal computed tomography images of the middle portion of the vertebral body obtained using a computer-assisted imaging analysis. Then each vertebral body was cut into halves through the horizontal plane. A total of 54 specimens, consisting of one endplate and half of the vertebral body, were obtained after excluding eight vertebrae with gross pathology on plain radiograph. Specimens were assigned to one of three groups with different endplate conditions (Group I, intact; Group II, partial removal; and Group III, complete removal) so that group mean bone mineral density became similar. Each endplate was slowly compressed until failure using an 8-mm-diameter metal indenter, and the load to failure was determined as a maximum force on a recorded force-displacement curve. The effect on the strength of the graft-endplate interface of various hole patterns in the endplate was studied using a finite element technique. The simulatedhole patterns included the following: one large central hole, two lateral holes, two holes in the anterior and posterior portion of the endplate, and four holes evenly distributed from the center of the endplate. Stress distribution in the endplate was predicted in response to an axial compressive force of 110 N, and the elements with von Mises stress greater than 4.0 MPa were determined as failed. RESULTS: The endplate thickness and bone mineral density were similar at all cervical levels, and the superior and inferior endplates had similar thickness at all cervical levels. There was no significant association between bone mineral density and endplate thickness. Load to failure was found to have a significant association with bone mineral density but not with endplate thickness. However, load to failure tends to decrease with incremental removal of the endplate, and load to failure of the specimens with an intact endplate was significantly greater than that of the specimens with no endplate. Finite element model predictions showed significant influence of the hole pattern on the fraction of the upper endplate exposed to fracture stress. A large hole was predicted to be more effective than the other patterns at distributing a compressive load across the remaining area and thus minimizing the potential fracture area. CONCLUSION: Results of this study suggest that it is important to preserve the endplate as much as possible to prevent graft subsidence into the vertebral body, particularly in patients with poor bone quality. It is preferable to make one central hole rather than multiple smaller holes in the endplate for vascularity of the bone graft because it reduces the surface area exposed to fracture stresses.
Aged↗
Adenoviral delivery of a leukocyte-type 12 lipoxygenase ribozyme inhibits effects of glucose and platelet-derived growth factor in vascular endothelial and smooth muscle cells.
The lipoxygenase (LO) pathway has been implicated as an important mediator of chronic glucose and platelet-derived growth factor (PDGF)-induced effects in the vascular system. Endothelial cells treated with 12LO products or cultured in high glucose showed enhanced monocyte adhesion, an important step in atherogenesis. We have previously reported that PDGF increased HETE levels in porcine aortic smooth muscle cells. Although several pharmacological inhibitors to the LO pathway are available, most lack specificity and may harbor undesirable side effects. Therefore, we developed a recombinant adenovirus expressing a hammerhead ribozyme (AdRZ) targeted against the porcine leukocyte-type 12LO mRNA to investigate the involvement of LO in glucose- and PDGF-mediated effects in vascular cells. Infection of porcine aortic endothelial cells with AdRZ reduced the level of glucose-enhanced 12LO mRNA expression as determined by quantitative, real-time reverse transcriptase-polymerase chain reaction. Reverse-phase HPLC and RIA analysis also revealed a corresponding decrease in glucose-stimulated 12HETE production in both the cellular and supernatant fractions. In the ribozyme-treated porcine aortic endothelial cells, there was marked inhibition of high glucose-stimulated monocyte adhesion. Infection with AdRZ also reduced PDGF-induced porcine aortic smooth muscle cell migration by approximately 50%. These studies demonstrate the efficacy of recombinant adenovirus expressing 12LO ribozyme in studying the effects of 12LO in vascular wall cells. They document an important role for the 12LO pathway in regulating inflammatory changes in endothelial cells and smooth muscle cells.
12-Hydroxy-5,8,10,14-eicosatetraenoic Acid↗
Ribozyme-mediated inhibition of rat leukocyte-type 12-lipoxygenase prevents intimal hyperplasia in balloon-injured rat carotid arteries.
BACKGROUND: 12-Lipoxygenase (12-LO) products of arachidonate metabolism have growth and chemotactic effects in vascular smooth muscle cells. We have also recently demonstrated increased 12-LO mRNA and protein expression in the neointima of balloon-injured rat carotid arteries. In this study, we evaluated whether 12-LO activation plays a role in neointimal thickening in this rat model by using a specific ribozyme (Rz) directed to rat 12-LO. METHODS AND RESULTS: We designed a chimeric DNA-RNA hammerhead Rz to cleave rat leukocyte-type 12-LO mRNA. This Rz dose-dependently cleaved a 166-nucleotide target 12-LO mRNA substrate in vitro and reduced 12-LO mRNA and protein expression in rat vascular smooth muscle cells. A control mutant Rz (MRz) with a point mutation in the catalytic site was inactive. To test the in vivo efficacy of the 12-LO Rz, the left common carotid arteries of rats were injured with a balloon catheter. The distal half of the injured arteries was treated with Rz or MRz mixed with lipofectin. The proximal half received only lipofectin. Twelve days after injury, intima-to-media ratios were significantly lower in the Rz-treated sections than in untreated sections from the same rat (0.742+/-0.16 versus 1.749+/-0.12, P:<0.001). In contrast, the MRz had no significant effect. CONCLUSIONS: These results indicate the important role of the leukocyte-type 12-LO pathway in restenosis in response to injury.
Analysis of Variance↗
Evidence that increased 12-lipoxygenase activity induces apoptosis in fibroblasts.
The 12-lipoxygenase (LO) enzyme has been implicated in playing a role in pancreatic beta cell inflammatory damage and atherosclerosis. 12-LO reacts with fatty acids to form hydroperoxides which may alter cellular growth. In this study we investigated the direct effect of mouse leukocyte type 12-LO cDNA overexpression on apoptosis in Chinese hamster ovary fibroblast cells that also stably overexpress the angiotensin II type 1a receptor. CHO-AT1a cells expressing background levels of 12-LO exhibited clear increases in growth in response to angiotensin II. In contrast, the new 12-LO transfected cells (CHO-AT1a/ML12-LO cells) displayed reduced basal and angiotensin Il-induced growth compared to CHO-AT1a cells. Furthermore, serum-deprivation resulted in a significantly greater number of non-viable cells in clones having the greatest magnitude of 12-LO overexpression. These results suggested that reduction of the proliferation rate of CHO-AT1a/ML12-LO cells was due to an increasing rate of cell death. To determine whether the increase in cell death was due to apoptosis, we evaluated nuclear DNA fragmentation, cell morphologic changes, and activation of caspase-3. Cells overexpressing 12-LO cDNA displayed all these changes characteristic of apoptosis. In addition the 12-LO product, 12-hydroperoxyeicosatetraenoic acid (12-HPETE), directly induced apoptosis in CHO-AT1a cells. These results demonstrate for the first time that 12-LO activation can lead to apoptosis in fibroblasts, suggesting a role of 12-LO in leading to inflammatory mediated cellular damage.
Angiotensin II↗
Fluorescent Plasmodium berghei sporozoites and pre-erythrocytic stages: a new tool to study mosquito and mammalian host interactions with malaria parasites.
To track malaria parasites for biological studies within the mosquito and mammalian hosts, we constructed a stably transformed clonal line of Plasmodium berghei, PbFluspo, in which sporogonic and pre-erythrocytic liver-stage parasites are autonomously fluorescent. A cassette containing the structural gene for the FACS-adapted green fluorescent protein mutant 2 (GFPmut2), expressed from the 5' and 3' flanking sequences of the circumsporozoite (CS) protein gene, was integrated and expressed at the endogenous CS locus. Recombinant parasites, which bear a wild-type copy of CS, generated highly fluorescent oocysts and sporozoites that invaded mosquito salivary glands and were transmitted normally to rodent hosts. The parasites infected cultured hepatocytes in vitro, where they developed into fluorescent pre-erythrocytic forms. Mammalian cells infected by these parasites can be separated from non-infected cells by fluorescence activated cell sorter (FACS) analysis. These fluorescent insect and mammalian stages of P. berghei should be useful for phenotypic studies in their respective hosts, as well as for identification of new genes expressed in these parasite stages.
Animals↗
12-lipoxygenase is increased in glucose-stimulated mesangial cells and in experimental diabetic nephropathy.
BACKGROUND: Arachidonic acid-derived 12-lipoxygenase (12-LO) products have potent growth and chemotactic properties. The present studies examined whether 12-LO and fibronectin are induced in cultured rat mesangial cells (MCs) exposed to high glucose and whether they are expressed in experimental diabetic nephropathy. METHODS: To determine the effect of high glucose on MC 12-LO mRNA and protein expression, rat MCs were incubated with RPMI medium containing 100 (NG) or 450 mg/dL glucose (HG). For animal studies, rats were injected with diluent (control) or streptozotocin. The latter were left untreated (DM) or treated with insulin (DM + I). At sacrifice after four months, GAPDH, 12-LO, and fibronectin mRNA were measured by competitive reverse transcription-polymerase chain reaction (RT-PCR) in microdissected glomeruli (G). Renal sections were semiquantitatively scored (0 to 4+) for diabetic changes and for 12-LO and fibronectin by immunohistochemistry. RESULTS: 12-LO mRNA expression in MC exposed to HG (12.71 +/- 1.17 attm/microL) and DM G (1.78 +/- 0.65 x 10-3 attm/glomerulus) was significantly higher than those of MCs in NG media (6.71 +/- 0.78 attm/microL) and control G (0.34 +/- 0.12 x 10-3 attm/glomerulus, P < 0.005), respectively. Western blot revealed a 1.7- and a 2.8-fold increase in MC and G 12-LO protein expression, respectively (P < 0.05). The immunohistochemistry score for G 12-LO and diabetic nephropathy score was significantly greater in DM and DM + I than controls. MC and G GAPDH mRNA remained unchanged. CONCLUSIONS: In MCs exposed to HG and in diabetic rat glomeruli, increments in 12-LO mRNA and protein are associated with changes modeling diabetic nephropathy. These findings suggest a role for the 12-LO pathway in the pathogenesis of diabetic nephropathy.
Animals↗
p38 MAPK and MAPK kinase 3/6 mRNA and activities are increased in early diabetic glomeruli.
BACKGROUND: The p38 mitogen-activated protein kinase (MAPK) pathway is activated by several stress factors, potentially leading to cellular apoptosis and growth. Little is known about the pattern of glomerular p38 MAPK pathway activation during the course of diabetic nephropathy (DN). We examined the activity and expression of the p38 MAPK pathway members, p38 MAPK, MKK3/6, cAMP-responsive element binding protein (CREB), and MAPK phosphatase-1 (MKP-1), in experimental DN in rats over the course of four months. METHODS: Control (C; N = 16) and diabetic (DM; N = 16) rats were studied. Four rats from each group were sacrificed monthly, and competitive reverse transcription-polymerase chain reaction and Western blot were performed with microdissected and sieved glomeruli, respectively. RESULTS: Glomerular p38 MAPK mRNA expression was significantly higher in DM than C (P < 0.01) throughout the four-month period. Western blot revealed an average 3.1-fold increase in p38 MAPK protein throughout the study period (P < 0.05). However, p38 MAPK activity was significantly increased only in one- and two-month diabetic glomeruli. Glomerular MKK3/6 and CREB mRNA as well as activity were significantly increased only in one- and two-month DM compared with C. MKP-1 mRNA showed a similar pattern. CONCLUSIONS: Glomerular p38 MAPK activity was increased in early DN. Parallel to this, we also showed, to our knowledge for the first time, that there were increased MKK3/6 and CREB activities and mRNA expression. This activated p38 MAPK pathway in diabetic glomeruli may, in part, play a role in the pathogenesis of early hypertrophy and extracellular matrix accumulation.
Animals↗
Redox imbalance in Crohn's disease intestinal smooth muscle cells causes NF-kappaB-mediated spontaneous interleukin-8 secretion.
Interleukin-8 (IL-8), a chemokine secreted by cells at injury sites, has recently been recognized as involved in the pathogenesis of Crohn's disease. However, the pathogenesis of enhanced spontaneous transcription of IL-8 by the bowel in patients with Crohn's disease is undefined. Although IL-8 is secreted primarily by neutrophils, macrophages, and endothelial and epithelial cells, we observed the involvement of mesenchymal cells in the inflammatory process. A smooth muscle cell line isolated from the ileum of a patient with Crohn's disease (CDISM) and maintained in culture exhibited spontaneous transcription and secretion of IL-8 when compared with intestinal smooth muscle cells obtained from a normal subject (NHISM). Furthermore, IL-8 transcription from CDISM cells was associated with remarkable spontaneous activation of the oxidant-sensitive transcription factor NF-kappaB, as assessed by transient transfection assays with an IL-8 promoter reporter construct, Western blot analysis, and electrophoretic mobility shift assays (EMSA). Finally, we report here that CDISM cells exhibit significantly altered redox balance. The antioxidant pyrrolidine dithiocarbamate (PDTC) restored the redox equilibrium by mechanisms that inhibit binding of NF-kappaB to its cognate site on the IL-8 promoter. These findings suggest that restoration of the redox balance could hold promise for therapeutic intervention in Crohn's disease.
Antioxidants↗
Signaling mechanisms of nuclear factor-kappab-mediated activation of inflammatory genes by 13-hydroperoxyoctadecadienoic acid in cultured vascular smooth muscle cells.
Oxidatively modified low density lipoprotein (LDL) has been implicated in the pathogenesis of atherosclerosis. LDL oxidation may be mediated by several factors, including cellular lipoxygenases. The lipoxygenase product of linoleic acid, 13-hydroperoxyoctadecadienoic acid (13-HPODE), is a significant component of oxidized LDL and has been shown to be present in atherosclerotic lesions. However, the mechanism of action of these oxidized lipids in vascular smooth muscle cells (VSMCs) is not clear. In the present study, we show that 13-HPODE leads to the activation of Ras as well as the mitogen-activated protein kinases, extracellular signal-regulated kinase 1/2, p38, and c-Jun amino-terminal kinase, in porcine VSMCs. 13-HPODE also specifically activated the oxidant stress-responsive transcription factor, nuclear factor-kappaB, but not activator protein-1 or activator protein-2. 13-HPODE-induced nuclear factor-kappaB DNA binding activity was blocked by an antioxidant, N-acetylcysteine, as well as an inhibitor of protein kinase C. 13-HPODE, but not the hydroxy product, 13-(S)-hydroxyoctadecadienoic acid, also dose-dependently increased vascular cell adhesion molecule-1 promoter activation. This was inhibited by an antioxidant as well as by inhibitors of Ras p38 mitogen-activated protein kinase and protein kinase C. Our results suggest that oxidized lipid components of oxidized LDL, such as 13-HPODE, may play a key role in the atherogenic process by inducing the transcriptional regulation of inflammatory genes in VSMCs via the activation of key signaling kinases.
Active Transport, Cell Nucleus↗
A double-blind, placebo-controlled study of the use of amphetamine in the treatment of aphasia.
BACKGROUND AND PURPOSE: A number of studies suggest that drugs which increase the release of norepinephrine promote recovery when administered late (days to weeks) after brain injury in animals. A small number of clinical studies have investigated the effects of the noradrenergic agonist dextroamphetamine in patients recovering from motor deficits following stroke. To determine whether these findings extend to communication deficits subsequent to stroke, we administered dextroamphetamine, paired with speech/language therapy, to patients with aphasia. METHODS: In a prospective, double-blind study, 21 aphasic patients with an acute nonhemorrhagic infarction were randomly assigned to receive either 10 mg dextroamphetamine or a placebo. Patients were entered between days 16 and 45 after onset and were treated on a 3-day/4-day schedule for 10 sessions. Thirty minutes after drug/placebo administration, subjects received a 1-hour session of speech/language therapy. The Porch Index of Communicative Ability was used at baseline, at 1 week off the drug, and at 6 months after onset as the dependent language measure. RESULTS: Although there were no differences between the drug and placebo groups before treatment (P=0.807), by 1 week after the 10 drug treatments ended there was a significant difference in gain scores between the groups (P=0.0153), with the greater gain in the dextroamphetamine group. The difference was still significant when corrected for initial aphasia severity and age. At the 6-month follow-up, the difference in gain scores between the groups had increased; however, the difference was not significant (P=0.0482) after correction for multiple comparisons. CONCLUSIONS: Administration of dextroamphetamine paired with 10 1-hour sessions of speech/language therapy facilitated recovery from aphasia in a small group of patients in the subacute period after stroke. Neuromodulation with dextroamphetamine, and perhaps other drugs that increase central nervous system noradrenaline levels, may facilitate recovery when paired with focused behavioral treatment.
Adrenergic Uptake Inhibitors↗