Can Drug Screening Lead to Candidate Therapies for Testing in Diabetic Neuropathy?

A key mechanism of dorsal root ganglia (DRG) neuron injury in high glucose is mitochondrial overload leading to oxidative stress. We screened selected compounds for the ability to prevent hyperglycemia-induced mitochondrial superoxide in primary sensory DRG neurons. Twenty five out of 1,040 compounds decreased both mitochondrial superoxide and subsequent neuronal injury. These data both validate our screening strategy and indicate further mechanistic evaluation of drug hits and related compounds. Such studies may lead to the design of rational therapeutic approaches for this severe complication of diabetes.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/63408/1/ars.2007.1815.pd

Cooperative Channel Capacity Learning

In this paper, the problem of determining the capacity of a communication channel is formulated as a cooperative game, between a generator and a discriminator, that is solved via deep learning techniques. The task of the generator is to produce channel input samples for which the discriminator ideally distinguishes conditional from unconditional channel output samples. The learning approach, referred to as cooperative channel capacity learning (CORTICAL), provides both the optimal input signal distribution and the channel capacity estimate. Numerical results demonstrate that the proposed framework learns the capacity-achieving input distribution under challenging non-Shannon settings.Comment: 5 pages, 6 figures, submitted to IEE

Rationale use of drugs in pregnancy induced hypertension at a tertiary care hospital

Background: Pregnancy induced hypertension known as preeclampsia is considered to be the second cause of death next to anaemia. There are significant sources of maternal and foetal mortality and morbidity. Antihypertensive medication reduces the progression of the course of hypertensive disorders. However, its effect on the outcomes of pregnancy may include development of preeclampsia, preterm delivery, foetal /neonatal demise, IUGR, low birth weight. Whether such associations are casual or confounded is unknown. Hence, we intended to study the rationale use of drugs in pregnancy induced hypertensive patients. Methods: Patients diagnosed with hypertensive disorders in pregnancy were recruited. Pregnant women in the age group of 18-45 years who consented to participate were included. Non pregnant women and women with PCOD, depression and on any medications were excluded. Details on drug treatment, type of drugs, combination, dose, dosage and duration were noted. Results: 105 patients were enrolled. 51% belonged to 18-25 years. 98% mothers received monotherapy and 2% received dual therapy. Labetalol was the most commonly prescribed drug. 50% of the patients received a combination of Nifedipine and Methyldopa while another 50% received Nifedipine with Labetalol. The outcome of new born babies born in mothers receiving antihypertensive drugs had complications of low birth weight and malformations. The dose of the medications prescribed was well within the range. Conclusions: Proper counselling to the patients regarding life style management, regular follow ups and monitoring of blood pressure is important to understand, resolve the burden and complication

Hyperlipidemia: a new therapeutic target for diabetic neuropathy

Abstract Emerging data establish dyslipidemia as a significant contributor to the development of diabetic neuropathy. In this review, we discuss how separate metabolic imbalances, including hyperglycemia and hyperlipidemia, converge on mechanisms leading to oxidative stress in dorsal root ganglia (DRG) sensory neurons. We conclude with suggestions for novel therapeutic strategies to prevent or reverse diabetes-induced nerve degeneration.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78728/1/j.1529-8027.2009.00237.x.pd

Short‐term hyperglycemia produces oxidative damage and apoptosis in neurons

Dorsal root ganglia neurons in culture die through programmed cell death when exposed to elevated glucose, providing an in vitro model system for the investigation of the mechanisms leading to diabetic neuropathy. This study examines the time course of programmed cell death induction, regulation of cellular antioxidant capacity, and the protective effects of antioxidants in neurons exposed to hyperglycemia. We demonstrate that the first 2 h of hyperglycemia are sufficient to induce oxidative stress and programmed cell death. Using fluorimetric analysis of reactive oxygen species (ROS) production, in vitro assays of antioxidant enzymes, and immunocytochemical assays of cell death, we demonstrate superoxide formation, inhibition of aconitase, and lipid peroxidation within 1 h of hyperglycemia. These are followed by caspase‐3 activation and DNA fragmentation. Antioxidant potential increases by 3–6 h but is insufficient to protect these neurons. Application of the antioxidant α‐lipoic acid potently prevents glucose‐induced oxidative stress and cell death. This study identifies cellular therapeutic targets to prevent diabetic neuropathy. Since oxidative stress is a common feature of the micro‐ and macrovascular complications of diabetes, the present findings have broad application to the treatment of diabetic patients.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154304/1/fsb2fj042513fje.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154304/2/fsb2fj042513fje-sup-0001.pd