Lalit Kishore

Diabetic peripheral neuropathy: Current perspective and future directions

Diabetic neuropathy is a heterogeneous group of disorders with extremely complex pathophysiology and affects both somatic and autonomic components of the nervous system. Neuropathy is the most common chronic complication of diabetes mellitus. Metabolic disruptions in the peripheral nervous system, including altered protein kinase C activity, and increased polyol pathway activity in neurons and Schwann cells resulting from hyperglycemia plays a key role in the development of diabetic neuropathy. These pathways are related to the metabolic and/or redox state of the cell and are the major source of damage. Activation of these metabolic pathways leads to oxidative stress, which is a mediator of hyperglycemia induced cell injury and a unifying theme for all mechanisms of diabetic neuropathy. The therapeutic intervention of these metabolic pathways is capable of ameliorating diabetic neuropathy but therapeutics which target one particular mechanism may have a limited success. Available therapeutic approaches are based upon the agents that modulate pathogenetic mechanisms (glycemic control) and relieve the symptoms of diabetic neuropathy. This review emphasizes the pathogenesis, presently available therapeutic approaches and future directions for the management of diabetic neuropathy.

Management of diabetic complications: A chemical constituents based approach ☆

ETHNOPHARMACOLOGICAL RELEVANCE Long term hyperglycemia leads to development of complications associated with diabetes. Diabetic complications are now a global health problem without effective therapeutic approach. Hyperglycemia and oxidative stress are important components for the development of diabetic complications. Over the past few decades, herbal medicines have attracted much attention as potential therapeutic agents in the prevention and treatment of diabetic complications due to their multiple targets and less toxic side effects. This review aims to assess the current available knowledge of medicinal herbs for attenuation and management of diabetic complications and their underlying mechanisms. MATERIAL AND METHODS Bibliographic investigation was carried out by scrutinizing classical text books and peer reviewed papers, consulting worldwide accepted scientific databases (SCOPUS, PUBMED, SCIELO, NISCAIR, Google Scholar) to retrieve available published literature. The inclusion criteria for the selection of plants were based upon all medicinal herbs and their active compounds with attributed potentials in relieving diabetic complications. Moreover, plants which have potential effect in ameliorating oxidative stress in diabetic animals have been included. RESULTS Overall, 238 articles were reviewed for plant literature and out of the reviewed literature, 127 articles were selected for the study. Various medicinal plants/plant extracts containing flavonoids, alkaloids, phenolic compounds, terpenoids, saponins and phytosterol type chemical constituents were found to be effective in the management of diabetic complications. This effect might be attributed to amelioration of persistent hyperglycemia, oxidative stress and modulation of various metabolic pathways involved in the pathogenesis of diabetic complications. CONCLUSION Screening chemical candidate from herbal medicine might be a promising approach for new drug discovery to treat the diabetic complications. There is still a dire need to explore the mechanism of action of various plant extracts and their toxicity profile and to determine their role in therapy of diabetic complications. Moreover, a perfect rodent model which completely mimics human diabetic complications should be developed.

Renoprotective effect of Bacopa monnieri via inhibition of advanced glycation end products and oxidative stress in STZ-nicotinamide-induced diabetic nephropathy

Abstract Hyperglycemia and oxidative stress are involved in the development of diabetic nephropathy (DN). This study was designed to evaluate the effect of alcohol and hydroalcohol extract of Bacopa monnieri and stigmasterol isolated from B. monnieri in the treatment of DN. Diabetes was induced in male wistar rats by streptozotocin (65 mg/kg i.p.) 15 min after nicotinamide (230 mg/kg, i.p.) administration. After 30 days, the rats were treated with different doses of extracts (100, 200, and 400 mg/kg) and stigmasterol (5 and 10 mg/kg) for 45 days to analyze their nephroprotective effect and produced significant attenuation in the serum glucose level, uric acid, creatinine, and lipid levels. Moreover, there is improvement in the level of superoxide dismutase (SOD), glutathione (GSH), and decrease in lipid peroxidation in terms of TBARS. The formation of AGEs in kidneys was also significantly reduced. These findings suggest that B. monnieri and its isolate (stigmasterol) might inhibit the progression of DN.

Attenuating Diabetes: What Really Works?

Diabetes mellitus is characterized by loss of glucose homeostasis; altered metabolism of glucose, proteins and lipids. Although a number of effective allopathic medicines are currently available for treatment and management of diabetes, but prevalence of side effects and higher cost poses a big challenge to the goal of pharmacotherapy. Herbs are mine of medicinal agents that are found to be efficacious, cost effective and safe in preventing diabetes and a number of plants have been used in management or treatment of diabetes. Modern pharmacopoeia has a healthy number of plant derived medicines and a large number of medicines from allopathic system are derived from the plant sources. This review aims to assess currently available preclinical and clinical knowledge of medicinal herbs intended for the management of diabetes and their mode of action.

Diabetic Autonomic Neuropathy: Pathogenesis to Pharmacological Management

Diabetic autonomic neuropathy is a debilitating complication of diabetes which can cause heart disease, gastrointestinal symptoms, genitourinary disorders and metabolic diseases. Hyperglycemia induces glucose flux through the polyol pathway; excess/inappropriate activation of Protein Kinase C (PKC) isoforms; accumulation of Advanced Glycation End products (AGE’s) and these pathways are associated with metabolic and/or redox state of the cell. Activation of these metabolic pathways leads to oxidative stress which is a mediator of hyperglycemia induced cell injury and is a unifying theme for all mechanisms of diabetic autonomic neuropathy. Glycemic control can slow the onset of diabetic autonomic neuropathy and may reverse it. Pharmacologic and non-pharmacologic therapies are available to treat various symptoms of diabetic autonomic neuropathy. This review focuses on the pathology, animal models and therapeutic approaches available for the management of diabetic autonomic neuropathy.

Role of Gymnema sylvestre as Alternative Medicine

Context: Gymnema sylvestre R.Br, belonging to the family Asclepiadaceae, has been employed to control diabetes, obesity, atherosclerosis etc., by traditional medicinal practitioners of India for nearly two millennia. The active principals from the leaf extracts is assumed to be gymnemic acid and its derivatives which are of triterpenoids in chemical nature have the ability to renew the islet cell mass for the possible cure of diabetes. Objective: The present review deals with botanical description, chemical constituents, and pharmacological effect of the plant using herbal and homeopathic medicine from the past to recent developments. Methods: Scientific databases including SCOPUS, PUBMED, SCIELO, NISCAIR, and Google Scholar were used to retrieve articles and only relevant studies published in English were considered. Results: This paper gives an overview of G. sylvestre from antiquity to till date. There is sufficient evidence of pharmacological and phytochemical studies to draw a definite conclusion about the efficacy of the gymnemic acid for the treatment of diabetes and obesity but, there is still inadequate literature related to other activities. The reported studies on the effect of G. sylvestre as homeopathic medicine are not sufficient. Therefore further studies are needed to explore the role of G. sylvestre in homeopathy. Conclusion: There is still a dire need to explore the mechanism of action of G. sylvestre, toxicity profile and to determine its role as alternative medicine.

Distinct Biomarkers for Early Diagnosis of Diabetic Nephropathy.

BACKGROUND Diabetic nephropathy (DN) is one of the foremost causes of mortality in diabetic patients as a result of increased urinary albumin excretion (UAE) rate and compromised renal function. INTRODUCTION Determination of increased excretion of albumin in urine chiefly attribute to the onset and progression of DN. However, due to certain limitations of albuminuria, the search for more sensitive, specific and reliable renal biomarkers is required for early prediction of DN. METHODS Bibliographic investigation was made to scrutinize the data reporting relevant biomarkers associated with DN and may be used to predict the onset and progression of nephropathy. RESULT AND CONCLUSION Optimization of biomarkers for a clinical situation requires a prospective validation in large numbers of patients with diabetic nephropathy and needs to be performed in different critically ill populations.

Dillenia indica L. attenuates diabetic nephropathy via inhibition of advanced glycation end products accumulation in STZ-nicotinamide induced diabetic rats

The present study was aimed to evaluate advanced glycation end products (AGEs) inhibitory activity of alcohol and hydro-alcohol extract (DAE and DHE) of Dillenia indica L. (Family: Dilleniaceae) and its potential in treatment of diabetic nephropathy by targeting markers of oxidative stress. D. indica was evaluated for its in vitro inhibitory activity against formation of AGEs by using bovine serum albumin. Diabetes was induced in male Wistar rats by streptozotocin (65 mg/kg i.p.) 15 min after nicotinamide (230 mg/kg, i.p.) administration. Diabetic rats were treated with different doses of extracts (100, 200 and 400 mg/kg) to analyze their nephroprotective effect. Tissue antioxidant enzymes level was measured along with the formation of AGEs in kidney to assess the effect of D. indica in ameliorating oxidative stress. D. indica showed significant inhibition of AGEs formation in vitro. D. indica produced significant attenuation in the glycemic status, renal parameter, lipid profile and level of antioxidant enzymes proving efficacy in diabetic nephropathy. Moreover, D. indica produced significant reduction in the formation of AGEs in kidneys. The present study concludes that D. indica as a possible therapeutic agent against diabetic nephropathy.

Chromane isolated from leaves of Dillenia indica improves the neuronal dysfunction in STZ-induced diabetic neuropathy

ETHNOPHARMACOLOGICAL RELEVANCE According to the Indian traditional medicine, Dillenia indica L. has shown therapeutic efficacy in various diseases. Fruits and leaves of the plant possess anti-oxidant and anti-inflammatory properties. Reactive oxygen species, formation of advanced glycation end products (AGEs) and apoptosis are implicated in the pathogenesis of diabetic neuropathy. AIM OF THE STUDY The aim of the present study was to explore the effect of D. indica and its isolate, chromane (CR), on thermal and mechanical hyperalgesia, allodynia, MNCV and oxidative-nitrosative stress in streptozotocin-induced experimental diabetes. MATERIAL AND METHODS Diabetes was induced by intraperitoneal administration of Streptozotocin (STZ; 65mg/kg) for the development of diabetic neuropathy. Chronic treatment with DAE (100, 200 and 400mg/kg, p.o.) and CR (5 and 10mg/kg, p.o.) for 30 days was started from the 60th day of STZ administration. Development of neuropathy was evident from a marked hyperalgesia and allodynia; reduced MNCV associated with increased formation of AGEs and reactive oxygen species. RESULTS significantly attenuated behavioral and biochemical changes associated with diabetic neuropathy. Present study suggested that DAE and CR ameliorated hyperglycemia and diabetic neuropathic pain via modulation of oxidative-nitrosative stress and reduction in AGEs formation in the diabetic rats. CONCLUSION Thus D. indica might be beneficial in chronic diabetics, ameliorate the progression of diabetic neuropathy and may also find application in diabetic neuropathic pain.

Method development and validation: Skills and tricks

Because of the introduction of a lot of drugs in the market every year, it becomes necessary to develop newer analytical methods for such drugs. Method development can take a number of forms. At one extreme, it involves adapting an existing method or making minor changes so as to make it suitable for the new application, as for developing a method for the estimation of drugs using a complex analytical technique like HPLC. After the development, there is a need of method validation. Method validation is defined as the process of proving that an analytical technique is acceptable for the intended use and this is an important requirement for analytical purpose. Validation is done according to the guidelines of ICH and FDA. Here, in this review, we have discussed method development and the various parameters used for method validation, namely accuracy, precision, limit of detection, limit of quantification, specificity, robustness, ruggedness, and range.