Bhoomika R. Goyal

Getting into the brain: approaches to enhance brain drug delivery.

Being the most delicate organ of the body, the brain is protected against potentially toxic substances by the blood-brain barrier (BBB), which restricts the entry of most pharmaceuticals into the brain. The developmental process for new drugs for the treatment of CNS disorders has not kept pace with progress in molecular neurosciences because most of the new drugs discovered are unable to cross the BBB. The clinical failure of CNS drug delivery may be attributed largely to a lack of appropriate drug delivery systems. Localized and controlled delivery of drugs at their desired site of action is preferred because it reduces toxicity and increases treatment efficiency. The present review provides an insight into some of the recent advances made in the field of brain drug delivery.The various strategies that have been explored to increase drug delivery into the brain include (i) chemical delivery systems, such as lipid-mediated transport, the prodrug approach and the lock-in system; (ii) biological delivery systems, in which pharmaceuticals are re-engineered to cross the BBB via specific endogenous transporters localized within the brain capillary endothelium; (iii) disruption of the BBB, for example by modification of tight junctions, which causes a controlled and transient increase in the permeability of brain capillaries; (iv) the use of molecular Trojan horses, such as peptidomimetic monoclonal antibodies totransport large molecules (e.g. antibodies, recombinant proteins, nonviral gene medicines or RNA interference drugs) across the BBB; and (v) particulate drug carrier systems. Receptor-mediated transport systems exist for certain endogenous peptides, such as insulin and transferrin, enabling these molecules to cross the BBB in vivo.The use of polymers for local drug delivery has greatly expanded the spectrum of drugs available for the treatment of brain diseases, such as malignant tumours and Alzheimer’s disease. In addition, various drug delivery systems (e.g. liposomes, microspheres, nanoparticles, nanogels and bionanocapsules) have been used to enhance drug delivery to the brain. Recently, microchips and biodegradable polymers have become important in brain tumour therapy.The intense search for alternative routes of drug delivery (e.g. intranasal drug delivery, convection-enhanced diffusion and intrathecal/intraventricular drug delivery systems) has been driven by the need to overcome the physiological barriers of the brain and to achieve high drug concentrations within the brain. For more than 30 years, considerable efforts have been made to enhance the delivery of therapeutic molecules across the vascular barriers of the CNS. The current challenge is to develop drug delivery strategies that will allow the passage of drug molecules through the BBB in a safe and effective manner.

Angiogenic targets for potential disorders

This review shall familiarize the readers with various fundamental aspects of angiogenesis. Angiogenesis is a feature of a limited number of physiological processes like wound healing, ovulation, development of the corpus luteum, embryogenesis, lactating breast, during immune response, and during Inflammation. It is driven by a cocktail of growth factors and pro‐angiogenic cytokines and is tempered by an equally diverse group of inhibitors of neovascularization. The properties and biological functions of angiogenic growth factors such as VEGF, FGF‐2, nitric oxide, MMP, angiopoietin, TGF‐β as well as various inhibitors such as angiostatin, endostatin, thrombospondin, canstatin, DII4, PEDF are discussed in this review with respect to their impact on angiogenic process. In recent years, it has become increasingly evident that excessive, insufficient, or abnormal angiogenesis contributes to the pathogenesis of many more disorders. A long list of disorders is characterized or caused by excessive or insufficient angiogenesis whereas several congenital or inherited diseases are also caused by abnormal vascular remodeling. It may be possible in the future to develop specific anti‐angiogenic agents that offer a potential therapy for cancer and angiogenic diseases.

Beneficial role of telmisartan on cardiovascular complications associated with STZ-induced type 2 diabetes in rats

We studied the effect of an eight-week treatment with telmisartan (5 mg kg(-1)day(-1)) on cardiovascular complications that are associated with type 2 diabetes in a neonatal rat model. Type 2 diabetes was induced by the administration of 90 mg/kg streptozotocin (STZ), ip, in two-day-old rats. The development of diabetes was checked 12 weeks after STZ administration, and the animals were divided into different groups. Telmisartan treatment was given for eight weeks. At the end of the eight-week treatment, various biochemical and cardiac parameters were measured. Diabetic rats exhibited hyperglycemia, hyperinsulinemia, hyperlipidemia, increased blood pressure and heart rate, increased creatinine, cardiac enzyme and C-reactive protein (CRP) levels, a reduction in the rate of pressure development and decay, cardiac hypertrophy and oxidative stress. Chronic treatment with telmisartan significantly prevented STZ-induced hypertension and tachycardia and elevated fasting glucose and insulin levels. It significantly prevented the dyslipidemia and significantly reduced the elevated creatinine and CRP levels and the levels of other cardiac enzyme markers, like lactate dehydrogenase and creatinine kinase, in diabetic rats. There was an increase in rate of blood pressure development and decay with telmisartan treatment. Telmisartan also produced beneficial effects by preventing cardiac hypertrophy, which was evident from left ventricular collagen levels, the cardiac hypertrophy index and the left ventricular hypertrophy index in diabetic rats. Telmisartan successfully prevented oxidative stress, which was evidenced by a decrease in malondialdehyde and an increase in glutathione, catalase, superoxide dismutase levels. In conclusion, our data suggest that telmisartan prevented STZ-induced metabolic abnormalities and cardiovascular complications in type 2 diabetes.

Investigation into the cardiac effects of spironolactone in the experimental model of type 1 diabetes.

We have studied the effect of 8-week treatment with spironolactone (20 mg·kg−1·day−1) on cardiovascular complications associated with streptozotocin (STZ)-diabetic rats. Wistar rats were made diabetic with STZ (45 mg/kg, intravenously). Various biochemical and cardiac parameters were measured at the end of 8 weeks. STZ produced hyperglycemia; hypoinsulinemia; hyperlipidemia; increased blood pressure; increased creatinine, cardiac enzyme, and C-reactive protein levels; reduction in heart rate; and cardiac hypertrophy. Chronic treatment with spironolactone significantly prevented STZ-induced bradycardia, hypertension, and elevated fasting glucose level with simultaneous increase in serum insulin levels. It significantly reduced the elevated cholesterol, very-low-density lipoprotein, and triglyceride levels and increased the lower high-density lipoprotein-cholesterol levels in diabetic rats. Furthermore, spironolactone also produced a significant reduction in the elevated creatinine levels, C-reactive protein, and levels of lactate dehydrogenase and creatinine kinase. It also produced beneficial effect in diabetic rats by preventing cardiac hypertrophy as evident from decrease in left ventricular collagen levels, cardiac hypertrophy index, and left ventricular hypertrophy index. Our data suggest that spironolactone prevents not only the STZ-induced metabolic abnormalities but also cardiovascular complications.

Therapeutic opportunities of small interfering RNA

Formation of small interfering RNA (siRNA) occurs in two steps involving binding of the RNA nucleases to a large double‐stranded RNA (dsRNA) and its cleavage into fragments called siRNA. In the second step, these siRNAs join a multinuclease complex, which degrades the homologous single‐stranded mRNAs. The delivery of siRNA involves viral‐ and non‐viral‐mediated delivery systems; the approaches for chemical modifications have also been developed. It has various therapeutic applications for disorders like cardiovascular diseases, central nervous system (CNS) disorders, cancer, human immunodeficiency virus (HIV), hepatic disorders, etc. The present review gives an overview of the applications of siRNA and their potential for treating many hitherto untreatable diseases.

Investigation Into the Mechanism of Anti-Asthmatic Action of Moringa oleifera

ABSTRACT. We have studied the possible mechanism of the antiasthmatic action of Moringa oleifera seed kernel ethanolic extract (EXMO, 400 mg/kg). EXMO produced an increase in the Preconvulsion Dyspnea time induced by histamine and acetylcholine aerosol, a significant reduction in the elevated eosinophil and monocyte counts in the Broncho-Alveolar Lavage fluid of sensitized guinea pigs, reduction in the paw edema volume as compared to the control rats, and decrease in the elevated histamine release from the sensitized guinea pig lungs. The pD2 values of histamine in tracheal chain and taenia coli were significantly greater and that in lung strip was lower in the sensitized animals and treatment with EXMO significantly decreased pD2 values in all three preparations. Our data suggest inhibition of the immediate hypersensitive reaction, histamine release, and the infiltration of various inflammatory cells as possible antiasthmatic mechanisms of action.

Effect of long term treatment of aqueous extract of Enicostemma littorale in Type 2 diabetic patients

SUMMARY We have evaluated the effect of long term treatment of Enicostemma littorale (E. littorale) in type 2diabetic patients taking pills of aqueous extract of E. littorale regularly as a complimentary medicinefor at least 9 months. The effects of E. littorale on glycemic control, lipid profile, cardiac functionand DNA damage in these patients were compared with those who had not been regular intaking E. littorale but regular in taking other conventional anti-diabetics. Our data suggest that, E.littorale can maintain normal blood glucose, serum insulin, serum triglycerides levels of type 2diabetic patients if taken regularly. E. littorale also improves insulin sensitivity, and normalizedisturbed lipogram and elevated creatinine levels, thereby produces beneficial effect inpreventing cardiovascular complications and may preserve the kidney function. The finding thatE. littorale also prevents DNA damage suggest a long term effect in diabetic patients. E. littoralethus can be considered as safe supplementary therapy for a long term and effective managementof type 2 diabetic patients.Key words: E. littorale; anti-diabetic; lipid tolerance test; comet assay; DNA damage

Beneficial Effect of Achyranthes apsera Linn. In Toluene-Di-Isocyanate Induced Occupational Asthma in Rats~!2008-08-07~!2008-10-15~!2008-12-05~!

To study the bronchoprotective effect of ethanolic extract of Achyranthes aspera Linn. in toluene diisocyanate (TDI) induced occupational asthma in wistar rats. Wistar rats were divided into four different groups of eight animals each. All animals except control group were sensitized by the intranasal application of 10% TDI to induce airway hypersensitivity. At the end of the study, after provocation with 5%TDI the symptoms were observed in all animals. The total and differential leucocytes were counted in blood and bronchoalveolar (BAL) fluid. Liver homogenate was utilized for assessment of oxidative stress and lung histological examination was performed to investigate the inflammatory status in the airway. Our results suggest that, TDI sensitized rats exhibited asthmatic symptoms while A. aspera and dexamethasone treated rats did not show any airway abnormality. The neutrophils and eosinophils in blood were decreased significantly; the total cells and each different cell in particular eosinophils in BAL fluid were markedly decreased in treatment groups as compared to TDI sensitized rats. The antioxidant activity and histopathological observations also shows protective effect. From all above findings and observations, it can be concluded that A. aspera has beneficial role in occupational asthma in wistar rats.

Investigation into the mechanism of anti-asthmatic action of Lepidium sativum

We have studied the possible mechanism of anti-asthmatic action of ethanolic extracts of dried seeds of Lepidium sativum (EXLS, 400 mg/kg) using various experimental models. EXLS produced an increase in the Pre-Convulsion Dyspnoea time induced by histamine and acetylcholine aerosol, a significant reduction in the elevated leucocyte counts in the Broncho-Alveolar Lavage fluid of sensitized guinea-pigs and reduction in the paw edema volume as compared to the control rats. Treatment with EXLS also produced decrease in the elevated histamine release from the sensitized guinea-pig lungs. The anti-asthmatic anti-inflammatory responses of EXLS was supported by improvement in microscopic changes like infiltration of inflammatory cells, submucosal edema, epithelial desquamation and reduced lumen size of the bronchi. The values of histamine in tracheal chain and taenia-coli were significantly greater and that in lung strip was lower in the sensitized animals as compared to control. Treatment of sensitized guinea pigs with EXLS significantly decreased values of histamine in all three preparations. Our data suggest the prevention of hyper-responsiveness in bronchial smooth muscles and inhibition of the immediate hypersensitive reaction, histamine release in the lungs and the infiltration of various inflammatory cells as the possible mechanisms of anti-asthmatic activity of EXLS.