Therapeutic targets for altering mitochondrial dysfunction associated with diabetic retinopathy

Introduction: Retinopathy remains as one of the most feared blinding complications of diabetes, and with the prevalence of this life-long disease escalating at an alarming rate, the incidence of retinopathy is also climbing. Although the cutting edge research has identified many molecular mechanisms associated with its development, the exact mechanism how diabetes damages the retina remains obscure, limiting therapeutic options for this devastating disease.

Areas covered: This review focuses on the central role of mitochondrial dysfunction/damage in the pathogenesis of diabetic retinopathy, and how damaged mitochondria initiates a self-perpetuating vicious cycles of free radicals. We have also reviewed how mitochondria could serve as a therapeutic target, and the challenges associated with the complex double mitochondrial membranes and a well-defined blood-retinal barrier for optimal pharmacologic/molecular approach to improve mitochondrial function.

Expert opinion: Mitochondrial dysfunction provides many therapeutic targets for ameliorating the development of diabetic retinopathy including their biogenesis, DNA damage and epigenetic modifications. New technology to enhance pharmaceuticals uptake inside the mitochondria, nanotechnology to deliver drugs to the retina, and maintenance of mitochondrial homeostasis via lifestyle changes and novel therapeutics to prevent epigenetic modifications, could serve as some of the welcoming avenues for a diabetic patient to target this sight-threatening disease.     

Reversible sodium pump defect and swelling in the diabetic rat erythrocyte: effects on filterability and implications for microangiopathy.

We have found a defect in the ouabain-sensitive Na+, K+-ATPase (Na+ pump, EC 3.6.1.37) of erythrocytes from streptozocin diabetic rats. This defect was accompanied by an increase in cell volume and osmotic fragility and a decrease in the cytosolic K+/Na+ ratio. There was also a doubling in the time needed for diabetic erythrocytes to pass through 4.7-micron channels in a polycarbonate filter. Our data are consistent with a primary defect in the erythrocyte Na+ pump and secondary changes in cell volume, osmotic fragility, K+/Na+ ratio, and cell filterability. All were reversed or prevented in vivo by insulin or the aldose reductase inhibitor Sorbinil. Protein kinase C agonists (phorbol ester and diacylglycerol) and agonist precursor (myoinositol) reversed the Na+ pump lesion, suggesting that protein kinase C-dependent phosphorylation of the 100-kDa subunit regulates Na+ pump activity and that insulin can influence erythrocyte protein kinase C activity. Ouabain inhibition of the erythrocyte Na+ pump also produced increases in cell size and reductions in rates of filtration. Theoretical treatment of the volume changes also predicts reduction in filterability as a consequence of cell swelling. We suggest that enlarged erythrocytes could play a role in the evolution of the microvascular changes of diabetes mellitus.     

Myokymia,neuromyotonia, dermatomyositis,and voltage-gated K+ channel antibodies

A young woman presented with facial myokymia in association with dermatomyositis. There was no evidence of peripheral neuropathy. Needle electromyography showed prominent myokymic discharges and brief neuromyotonic discharges in addition to many small-amplitude, short-duration motor unit potentials. Myokymia and dermatomyositis both responded to immunosuppressive treatment. The presence of antibodies to voltage-gated potassium channels and the association with dermatomyositis indicated an autoimmune cause for myokymia, which may have been due to reversible peripheral nerve hyperexcitability.     

Two new diterpenoids, sarcophytins B and C, from the Indian Ocean soft coral Sarcophyton species

Two new diterpenoids, sarcophytins B and C (1, 2), and the previously known sarcophytin (4) have been isolated from the Indian Ocean soft coral Sarcophyton sp. Structures of 1 and 2 were established by spectral data and supported by X-ray analysis of 1.     

Fluoxetine attenuates thermal hyperalgesia through 5-HT1/2 receptors in streptozotocin-induced diabetic mice

Diabetic neuropathic pain, an important microvascular complication in diabetes mellitus, is recognised as one of the most difficult types of pain to treat. A lack of understanding of its aetiology, inadequate relief, development of tolerance and potential toxicity of classical antinociceptives warrant the investigation of newer agents to relieve this pain. The aim of the present study was to explore the antinociceptive effect and possible mechanism of action of a serotonin reuptake inhibitor, fluoxetine, in streptozotocin-induced diabetic mice. Four weeks after a single intraperitoneal injection of streptozotocin (200 mg/kg), mice were tested in the tail-immersion and hot-plate assays. Diabetic mice exhibited significant hyperalgesia compared with control mice. Fluoxetine (10 and 20, but not 5 mg/kg, i.p.) injected into diabetic mice produced an antinociceptive effect in both the tail-immersion and hot-plate assays. The percentage maximum possible effect (% MPE) produced by fluoxetine (20 mg/kg, i.p.) was significantly lower in diabetic mice than in control mice. The antinociceptive effect of fluoxetine (20 mg/kg) in diabetic mice was dose-dependently potentiated by pindolol (5 and 10 mg/kg, i.p., a selective 5-HT(1A/1B) receptor antagonist), attenuated by ritanserin (1 and 2 mg/kg, i.p., a selective 5-HT(2A/2C) receptor antagonist) and remained unaffected by ondansetron (1 and 2 mg/kg, i.p., a selective 5-HT(3) receptor antagonist) in both test systems. These results suggest that fluoxetine-induced antinociception primarily involves serotonin pathway modulation through 5-HT(1) and 5-HT(2) receptors, but not through 5-HT(3) receptors, in the chronic pain associated with streptozotocin-induced diabetic neuropathy. Further, the potentiation of the antinociceptive effect of fluoxetine by pindolol indicates the usefulness of a combination of an antidepressant and a 5-HT(1A/1B) receptor antagonist in the treatment of diabetic neuropathic pain in humans.     

Attenuation of cyclosporine-induced renal dysfunction by catechin: possible antioxidant mechanism

One of great use of immunosuppressant, Cyclosporine-A (CsA) is in the solid organ transplantation; however the extensive use of this is cautionable due to its toxic effect in renal tissue, characterized by the tubular atrophy, interstitial fibrosis, and progressive renal impairment. However, there are many mediators are associated with pathogenesis of nephrotoxicity of CsA, the exact mechanism is still in debate. Recent studies indicate that Reactive Oxygen Species (ROS) induced oxidative stress and lipid peroxidations are the important mechanisms implicated in the pathophysiology of nephrotoxicity with CsA. In the present study we examined effect of dietary flavonoid catechin on oxidative damage in cyclosporine-A induced nephrotoxicity. Chronic administration of CsA (20 mg/kg/day) subcutaneously for 21 days significantly decreased the body weight as compared with vehicle treated rats. CsA (20 mg/kg/day) administration for 21 days significantly decreased the renal function by increase in the serum creatinine, blood urea nitrogen, and decrease in the creatinine and urea clearance as compared with vehicle treated rats. Catechin (100 mg/kg/day) for 21 days along with CsA significantly reversed the changed renal parameters, however lower dose of catechin (50 mg/kg/day) restored only increased serum creatinine levels as compared with CsA alone treated group. Biochemical analysis revealed that chronic administration of CsA (20 mg/kg/day) for 21 days significantly induced lipid peroxidation and decreased the glutathione levels in the kidney homogenate of rats. It is also observed that chronic CsA administered rats showed decrease in antioxidant defense enzyme superoxide dismutase and increase in the catalase activity as compared with vehicle treated rats. Co-administration of catechin (100 mg/kg/day) orally along with CsA for 21 days significantly reduced the lipid peroxidation and restored the decreased glutathione levels as compared with CsA alone group, but lower dose of catechin (50 mg/kg/day) restored only decreased glutathione levels induced by CsA. Co-administration of only higher dose of catechin (100 mg/kg/day) along with CsA significantly increased the superoxide dismutase (SOD) levels as compared with CsA alone treated group. It is also observed that catechin (100 mg/kg/day) along with CsA further increased the catalase levels as compared with CsA alone treated group, but not with lower dose of catechin. Animals administered with catechin (100 mg/kg/day) alone for 21 days showed significant increase in the catalase levels as compared with vehicle treated group. The major findings of the present study suggest that oxidative stress might play a significant role in CsA-induced nephrotoxicity. In conclusion, dietary administration of flavonoid catechin could be a useful component for the prevention/treatment of CsA-induced nephrotoxicity.     

X-ray powder diffraction patterns for certain fluoroquinolone antibiotic drugs

X-ray powder diffraction (XRD) data for six pure fluoroquinolone antibiotic drugs, ciprofloxacin, norfloxacin, enrofloxacin, ofloxacin, pefloxacin and sparfloxacin have been obtained using a powder diffractometer. The drugs were scanned from a Bragg angle (2theta) of 10 degrees to 70 degrees. The obtained data were tabulated in terms of the lattice spacing (A) and relative line intensities (I/I(I)). This new information may be useful for the identification of these drugs.